American Chemical Society Division of Organic Chemistry 243rd ACS National Meeting, San Diego, CA, March 25-29, 2012

A. Abdel-Magid, Program Chair; R. Gawley, Program Chair

SUNDAY MORNING

Ralph F. Hirschmann Award in Peptide Chemistry: Symposium in Honor of Jeffery W. Kelly D. Huryn, Organizer; D. Huryn, Presiding Papers 1-4

Biologically-Related Molecules and Processes A. Abdel-Magid, Organizer; T. Altel, Presiding Papers 5-16

New Reactions and Methodology A. Abdel-Magid, Organizer; N. Bhat, Presiding Papers 17-28

Asymmetric Reactions and Syntheses A. Abdel-Magid, Organizer; D. Leahy, Presiding Papers 29-39

Material, Devices, and Switches A. Abdel-Magid, Organizer; S. Thomas, Presiding Papers 40-49

SUNDAY AFTERNOON

James Flack Norris Award in Physical Organic Chemistry: Symposium to Honor Hans J. Reich G. Weisman, Organizer; G. Weisman, Presiding Papers 50-53

Understanding Additions to Alkenes D. Nelson, Organizer; D. Nelson, Presiding Papers 54-61

Biologically-Related Molecules and Processes A. Abdel-Magid, Organizer; B. C. Das, Presiding Papers 62-73

New Reactions and Methodology A. Abdel-Magid, Organizer; T. Minehan, Presiding Papers 74-85

Asymmetric Reactions and Syntheses A. Abdel-Magid, Organizer; A. Mattson, Presiding Papers 86-97

Material, Devices, and Switches A. Abdel-Magid, Organizer; Y. Cui, Presiding Papers 98-107

SUNDAY EVENING

Material, Devices, and Switches, Molecular Recognition, Self-Assembly, Peptides, Proteins, Amino Acids, Physical Organic Chemistry, Total Synthesis of Complex Molecules R. Gawley, Organizer Papers 108-257

MONDAY MORNING

Herbert C. Brown Award for Creative Research in Synthetic Organic Chemistry: Symposium in Honor of Jonathan A. Ellman S. Sieburth, Organizer; S. Sieburth, Presiding Papers 258-261

Playing Ball: Molecular Recognition and Modern Physical Organic Chemistry C. Nuckolls, Organizer; D. Johnson, Organizer; F. Hof, Organizer; A. Sather, Presiding Papers 262-271

Chemistry of Life A. Abdel-Magid, Organizer; M. Smith, Presiding Papers 272-283

New Reactions and Methodology A. Abdel-Magid, Organizer; B. Banik, Presiding Papers 284-295

Asymmetric Reactions and Syntheses A. Abdel-Magid, Organizer; M. Watson, Presiding Papers 296-307

Material, Devices, and Switches A. Abdel-Magid, Organizer; J. F. Tannaci, Presiding Papers 308-317

MONDAY AFTERNOON

Elias J. Corey Award for Outstanding Original Contribution in Organic Synthesis by a Young Investigator: Symposium in Honor of Jeffrey S. Johnson M. Kozlowski, Organizer; M. Kozlowski, Presiding Papers 318-321

Recent Progress and Applications of Multicomponent Reactions A. Doemling, Organizer; A. Doemling, Presiding Papers 322-327

Chemistry of Life A. Abdel-Magid, Organizer; M. Distefano, Presiding Papers 328-339

New Reactions and Methodology A. Abdel-Magid, Organizer; N. A. Yakelis, Presiding Papers 340-351

Asymmetric Reactions and Syntheses A. Abdel-Magid, Organizer; C. Larsen, Presiding Papers 352-363

Material, Devices, and Switches A. Abdel-Magid, Organizer; M. C. Stefan, Presiding Papers 364-373

MONDAY EVENING

Sci-Mix R. Gawley, Organizer Papers 138, 143-144, 164, 169, 173, 177, 189, 195-197, 229, 230, 236, 246, 514, 522, 529, 537, 542, 550, 557, 560, 562, 573, 578, 588-589, 602, 619, 778, 785, 791-792, 797, 802, 806, 833, 850, 852, 863, 866, 868, 870, 892, 902, 913

TUESDAY MORNING

Ernest Guenther Award in the Chemistry of Natural Products: Symposium in Honor of Stephen Hanessian V. Snieckus, Organizer; V. Snieckus, Presiding Papers 375, 374, 376-377

Chemical Neuroscience C. Lindsley, Organizer; C. Hopkins, Organizer; S. Kuduk, Organizer; C. Lindsley, Presiding Papers 378-384

Peptides, Proteins, and Amino Acids A. Abdel-Magid, Organizer; L. Desai, Presiding Papers 385-395

New Reactions and Methodology A. Abdel-Magid, Organizer; B. Wakefield, Presiding Papers 396-407

Physical Organic Chemistry: Calculations, Mechanisms, Photochemistry, and High-Energy Species A. Abdel-Magid, Organizer; S. J. Schmidtke, Presiding Papers 408-418

Metal-Mediated Reactions and Syntheses A. Abdel-Magid, Organizer; M. Organ, Presiding Papers 419-429

Molecular Recognition and Self-Assembly A. Abdel-Magid, Organizer; B. Purse, Presiding Papers 430-440

TUESDAY AFTERNOON

ACS Award for Creative Work in Synthetic Organic Chemistry: Symposium in Honor of Gregory C. Fu C. Maryanoff, Organizer; C. Maryanoff, Presiding Papers 441-445

Nanostructured Electronic Materials G. Girolami, Organizer; L. McElwee-White, Organizer; L. McElwee-White, Presiding Papers 446-453

Heterocycles and Aromatics A. Abdel-Magid, Organizer; J. Fotie, Presiding Papers 454-464

New Reactions and Methodology A. Abdel-Magid, Organizer; B. Goess, Presiding Papers 465-476

Physical Organic Chemistry: Calculations, Mechanisms, Photochemistry, and High-Energy Species A. Abdel-Magid, Organizer; H. Banks, Presiding Papers 477-486

Metal-Mediated Reactions and Syntheses A. Abdel-Magid, Organizer; G. Melikyan, Presiding Papers 487-498

Molecular Recognition and Self-Assembly A. Abdel-Magid, Organizer; E. Masson, Presiding Papers 499-510

TUESDAY EVENING

Asymmetric Reactions and Syntheses, New Reactions and Methodology R. Gawley, Organizer Papers 511-657

WEDNESDAY MORNING

Ronald Breslow Award for Achievement in Biomimetic Chemistry: Symposium in Honor of Alanna Schepartz A. Phillips, Organizer; A. Phillips, Presiding Papers 658-661

Building Blocks for Chemical Biology K. Kumar, Organizer; K. Kumar, Presiding Papers 662-666

Heterocycles and Aromatics A. Abdel-Magid, Organizer; S. C. Rasmussen, Presiding Papers 667-677

Molecular Recognition and Self-Assembly A. Abdel-Magid, Organizer; A. Sykes, Presiding Papers 678-688

Total Synthesis of Complex Molecules A. Abdel-Magid, Organizer; G. Wei, Presiding Papers 689-700

Metal-Mediated Reactions and Syntheses A. Abdel-Magid, Organizer; R. Stockland, Presiding Papers 701-711

WEDNESDAY AFTERNOON

New Reactions and Methodology A. Abdel-Magid, Organizer; R. Rios-Torres, Presiding Papers 712-723

Heterocycles and Aromatics A. Abdel-Magid, Organizer; J. Schomaker, Presiding Papers 724-734

Molecular Recognition and Self-Assembly A. Abdel-Magid, Organizer; A. Gorodetsky, Presiding Papers 735-745

Total Synthesis of Complex Molecules A. Abdel-Magid, Organizer; L. Rossano, Presiding Papers 746-757

Metal-Mediated Reactions and Syntheses A. Abdel-Magid, Organizer; D. Watson, Presiding Papers 758-768

WEDNESDAY EVENING

Chemistry of Life, Biologically-Related Molecules and Processes, Heterocycles and Aromatics, Metal-Mediated Reactions and Syntheses R. Gawley, Organizer Papers 769-914 ORGN 1

Electronic effects on protein structure

Ronald T. Raines, [email protected]. Departments of Biochemistry and Chemistry, University of Wisconsin - Madison, Madison, WI 53706-1544, United States

In 1951, Linus Pauling first reported on the hydrogen bonds between backbone amides that are common in α-helices and β-sheets. We have discovered another intimate interaction between backbone amides. This interaction arises from the delocalization of a lone pair of electrons (n) from an oxygen atom to the anti-bonding orbital (π*) of the subsequent carbonyl group. The signature of this n→π* interaction is most evident in the pyramidalization of the acceptor carbonyl group. Our ab initio calculations predict significant n→π* interactions in certain regions of the Ramachandran plot. We have validated these predictions by a statistical analysis of a large, non-redundant subset of protein structures determined to high resolution. We find n→π* interactions to be especially abundant in common secondary structures such as α-, 310-, and polyproline II helices, and twisted β-sheets. n)(π Pauli repulsion attenuates the n→π* interaction with olefins and compromises their utility as peptidomimetics. In addition to their evident effects on peptide and protein conformation, n→π* interactions could play important roles in protein folding and function, and merit inclusion in computational force fields. Finally, we have identified important n→π* interactions in small molecules (such as aspirin) and with the chromophore of GFP and other fluorescent proteins, and noted that an n→π* interaction could have directed the prebiotic genesis of ribonucleotides.

ORGN 2

Building selective diatomic gas sensors: Nature’s way

Michael A. Marletta, [email protected]. Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, United States

Nitric oxide (NO) is a signaling agent in the cardiovascular system and other tissues. The immune system also utilizes NO in the host response to infection. Signaling concentrations of NO are low (pM), thereby avoiding toxicity. Immune system-derived NO is formed at µM concentrations and these local high levels function in cell killing. NO is formed via nitric oxide synthase (NOS) through the conversion of arginine to citrulline and NO. A primary NO receptor is the soluble isoform of guanylate cyclase (sGC) that uses a heme cofactor to trap NO. The heme domain of sGC was found to be part of the H-NOX (H eme-N itric oxide OX ygen) family of proteins with homologues in aerobic and anaerobic prokaryotes. Structural and biochemical studies have provided molecular explanations for the observed selectivity in ligand binding in various H-NOXs. Study of H-NOX sensors has uncovered novel functions in biology for gaseous ligands.

ORGN 3 ATP-independent reversal of a membrane protein aggregate by a novel chaperone

Shu-ou Shan, [email protected]. Department of Chemistry and chemical engineering, California Institute of Technology, Pasadena, California 91125, United States

Protein homeostasis is essential to all cells. The misfolding and aggregation of proteins are often detrimental to cells and underlie numerous human diseases. The chaperone network plays essential roles in maintaining proper protein homeostasis. However, compared to our understanding of how chaperones prevent protein aggregation, our understanding of how chaperones overcome preexisting protein aggregates lags far behind. Here we describe a novel chaperone, cpSRP43, that uses ATP-independent binding interactions with its substrate proteins to recognize and resolubilize the protein aggregates. cpSRP43 provides one of the first proof-of-principle examples to demonstrate that efficient rescue of protein aggregation can be achieved by a small protein fold and without external energy input, as long as adequate binding interactions are established with its substrate protein. Lessons from this system will provide new insights into the diversity and capability of cellular chaperones, and into new strategies to intervene in protein aggregation problems.

ORGN 4

Award Address (Ralph F. Hirschmann Award in Peptide Chemistry sponsored by Merck Research Laboratories). Strategic incorporation of N-glycans and peptidomimetics into reverse turns to enhance protein energetics

Joshua L. Price1,3, Elizabeth K. Culyba1,3, Wentao Chen1,3, Sarah R. Hanson1,3, Apratim Dhar4, Chi-Huey Wong1,3, Martin Gruebele4, Amelia A. Fuller1,3, Evan T. Powers1,2,3, Jeffery W. Kelly1,2,3, [email protected]. (1) Departments of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, United States (2) Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, United States (3) The Skaggs Institute of Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, United States (4) 4Center for Biophysics and Computational Biology and Departments of Chemistry and Physics, University of Illinois, Urbana, Illinois 61801, United States

The majority of the human proteome that traverses the cellular secretory pathway is co- translationally N-glycosylated at Asn within the Asn-Xxx-Thr/Ser sequon within the endoplasmic reticulum. We have shown that placing an aromatic residue one, two or three positions prior to a N-glycosylated Asn in specific reverse turn types enables stabilizing hydrophobic interactions between the aromatic side chain, the first N- acetylglucosamine (GlcNAc) of the glycan and the Thr side chain. Glycosylation of a specific “enhanced aromatic sequon” in the complementary reverse turn type substantially stabilizes the native state of several different glycosylation-naïve proteins and slows unfolding. This approach for native state stabilization will be compared to and contrasted with the incorporation of Beta-turn mimics into four-residue reverse turns in place of the i+1 and i+2 residues. Beta-turn incorporation is envisioned to nucleate folding by preorganizing the flanking polypeptide chains through hydrophobic interactions and/or conformational biases, thereby lowering the activation barrier for beta-sheet formation. Kinetic evidence will be presented that the inclusion of beta-turn mimics alters beta-sheet folding rates, enabling us to classify beta-turn mimics into 3 categories. Strong nucleators accelerate folding relative to beta-sheet folds incorporating all alpha-amino acid sequences. This seminar is dedicated to the memory of Ralph F. Hirschmann, who was a pioneer in peptidomimetic concepts and applications.

ORGN 5

Small molecule control on biofilm inhibition and antibiotic resensitization activity: Assembly and screening of 4,5-disubstituted-2-aminoimidazole-triazole conjugates

Zhaoming Su, [email protected], Christian Melander. Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695, United States

We have synthesized a variety of 4,5-disubstituted-2-aminoimidazole-triazole conjugates and tested for their antibiofilm/antibiotic resensitization activity. This class of small molecules was varified to inhibit biofilm formation by methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii (A. baumannii) at low micromolar concentration. Biological activity was further augmented by modification of substituents at 4 position. Lead compounds were also determined to resensitize MRSA to oxacillin by 4 fold.

ORGN 6

Designed PDT agents: Synthesis and biological evaluation of steroid-porphyrin conjugates

Sara Sadler1, [email protected], Rahul Ray2, Graham B Jones1. (1) Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, United States (2) School of Medicine, Boston University, Boston, MA 02118, United States

Photodynamic therapy (PDT) offers the potential to target neoplastic cells by utilizing a photosensitizer that specifically accumulates in tumors. Light (620-750 nm) is used to activate the photosensitizer, which generates singlet oxygen that subsequently destroys the cells. Currently available photosensitizers however have shown limited specificity to cancer cells and we are developing a series of steroid hormone conjugates where the steroid acts as a delivery vector for the photosensitizer. Examples include C17-α- alkynylestradiol porphyrin derivatives that can be converted to pegylated nanoparticles to enhance uptake via their improved transport properties. Initial assays demonstrated selective entry into the nucleus of MCF-7 breast cancer cells. Synthesis and further biological evaluation of these agents will be presented along with scope and future potential.

ORGN 7

Synthesis of structurally diverse compounds from gibberellic acid enables the discovery of a novel anticancer compound

Karen C Morrison, [email protected], Paul J Hergenrother. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States

Current drug discovery programs, which often use combinatorially-derived libraries or commercial compound screening collections to discover potent hits, are limited by low structural diversity and minimal complexity. We present a new synthetic approach, termed Complexity to Diversity (CtD), to obtain small molecules possessing novel, complex architectures from readily available natural products in 2-5 steps. The plant hormone gibberellic acid was identified as an optimal natural product for this strategy, and a series of ring distortion reactions were employed to reorganize the original scaffold into five structurally-distinct and unique core skeletons that contain points for further derivatization. All compounds synthesized through the CtD paradigm were subjected to further biological screening to identify new active compounds. One such compound, GA4, has shown potent anticancer activity in cell lines and in vivo, and kills via an unusual mechanism.

ORGN 8

Mechanistic insights into the alkylation reactions of quinone methide precursors: Towards the realkylation of aged acetylcholinesterase after exposure to nerve agents

Carolyn S Reid, [email protected], Michael Woodruff, Sarah Ercegovic, Jeremy M Beck, Christopher S Callam, Christopher M Hadad. Department of Chemistry, The Ohio State University, Columbus, Ohio 43210, United States

Organophosphorus (OP) nerve agents are covalent inhibitors of acetylcholinesterase (AChE), an essential enzyme that degrades acetylcholine in the nervous system. Following inhibition by OPs, AChE can undergo a subsequent irreversible aging process in which the OP-AChE adduct is dealkylated, thereby resulting in the accumulation of excess acetylcholine at the neuromuscular junction. Current oximes used to treat the nerve agent-inhibited AChE are ineffective because the aged enzyme is recalcitrant to oxime therapy. Previous studies have shown that quinone methides (QM) could potentially reverse the aging process of AChE through a kinetically favored alkylation of the OP phosphonate. Guided by computational methods, we have designed and synthesized a series of QM precursors and investigated their ability to alkylate a panel of nucleophiles. Mechanistic studies were conducted using GC-MS, LC-MS and NMR spectrophotometric techniques. The most promising QM precursors will be tested for the alkylation of aged AChE

ORGN 9

Design and synthesis of boron containing potential Pan-RAR inverse agonists

Bhaskar C Das1, [email protected], Xiang-Ying Tang1, Todd Evans2. (1) Developmental Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10994, United States (2) Surgery, The Weill Cornell Medical College, New York, NY 10065, United States

The NR (Nuclear Receptor) families that possess bona fide ligand binding domains are attractive drug targets because (1) they are master regulators of a large variety of major (patho)physiological processes and (2) their cognate ligands are small molecules that are convenient for chemical synthesis. The retinoic acid receptors (RARs) belong to a family of NRs that can be activated by all-trans retinoic acid and 9-cis retinoic acid. The success of studying the RA biology and developing new therapeutic agents, reducing toxicity and side effect, depends on receptor subtype and isotype specific cognate ligand synthesis. Our ongoing chemical biology project studies the role of retinoic acid signaling pathways during zebrafish embryogenesis, with a goal of developing new therapeutic and diagnostic agents for diseases modulated by retinoic acid signaling pathways. Therefore, we synthesized novel retinoid libraries and screened for bioactivity. In the present study we designed and synthesized two new types (A & B) of Pan RAR inverse agonists based on the existing BMS 493 compound.

ORGN 10

Scalable amide bond formation and transfer hydrogenation for the synthesis of a hepatoselective glucokinase activator

Joshua R. Dunetz1, [email protected], Martin A. Berliner1, Yun Huang2, Douglas Farrand2, Yanqiao Xiang2, Timothy L. Houck1, Fabrice Salingue3. (1) Chemical Research and Development, Pfizer, Inc., Groton, CT 06340, United States (2) Analytical Research and Development, Pfizer, Inc., Groton, CT 06340, United States (3) Chemical Research and Development, Pfizer, Inc., Sandwich, Kent, United Kingdom

Low-epimerization amide coupling conditions have been developed using T3P (n- propanephosphonic acid anhydride) for the synthesis of a key intermediate to a hepatoselective glucokinase activator. These conditions were incorporated into a process involving very easy reaction setup and product isolation. Subsequent debenzylation via transfer hydrogenation at ambient pressure provides API with excellent purity and throughput.

ORGN 11

Development of a process for methotrexate conjugate synthesis

Jonathan Grote, [email protected], Gangamani Beligere, Susil Rege.D09YP, Abbott Laboratories, Abbott Park, IL 60064-6016, United States

In clinical use for over sixty years, methotrexate is a well known antineoplastic drug that targets increased intracellular levels of the enzyme dihydrofolate reductase, resulting in the arrest of cell proliferation for several acute human leukemias, chlorocarcinoma, osteogenic sarcoma, and a variety of head and neck carcinomas. Subsequently, methotrexate has demonstrated utility for treatment of a variety of other disorders, such as psoriasis, Wegner's granulomatosis, sarcoidosis, and rheumatoid arthritis. Because of the potential for overdose, therapeutic drug monitoring is required to identify patients with poor drug absorption, unusual metabolism or clearance, changes in bioavailability, or saturation, and to prevent drug-induced toxicity. We describe here an improved, reproducible process for the synthesis of a fluorescent methotrexate conjugate which resulted in a fifty-fold improvement in yield over the prior manufacturing process, and confirmation of the structure of the conjugate by comparison with materials prepared from protected methotrexate derivatives.

ORGN 12

Engineering pH-gated transitions for selective and efficient double strand DNA photocleavage in hypoxic tumors

Saumya Roy, [email protected], Wang-Yong Yang, Boondaniwon Phrathep, Zach Rengert, Rachael Kenworthy, Diego Zorio, Igor V Alabugin. Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306-4390, United States

The more acidic extracellular environment of solid tumors, relative to that of the normal cells, can be explored in the design of tumor-specific DNA cleaving agents. Because control of reactivity and selectivity becomes especially challenging when chemical processes have to work in the complexity of biological environments, we designed a group of “switchable” molecular systems for pH-gated ds DNA-cleavage which combine a potent DNA-photocleaver and a pH-regulated part derived from a dipeptide. The basic amino groups are protonated throughout all biologically relevant pH range; whereas the pH-gating amines undergo protonation at the pH threshold which separates cancer (pH <7) and normal cells (pH >7). Control over the reactivity and selectivity is achieved via transformation of the initial protonation state (a monocation or a dication) into a trication at the relatively acidic pH. This change leads to an extraordinary increase in the efficiency of ds DNA cleavage leading to the ds:ss ratios comparable with the most efficient non-enzymatic ds DNA cleavers.

ORGN 13

Discovery of 2-aminopyrimidines as gram-postivie bacterial biofilm inhibitors

Erick A. Lindsey, [email protected], Christian C Melander. Department of Chemisty, North Carolina State University, Raleigh, NC 27695, United States

The ability to control bacterial processes is of great importance. We have developed novel anti-fouling agents based on the 2-aminoimidazole core scaffold. Expanding upon this work, four classes of 5-substituted 2-aminopyrimidines were synthesized through the use of Pd-mediated chemistry. This led to the discovery of seven novel gram- positive bacterial biofilm modulators.

ORGN 14

Increasing NIR light sensitivity via chemical amplification

Nadezda Fomina2, [email protected], Cathryn McFearin2, Adah Almutairi1,2. (1) Department of NanoEngineering, University of California at San Diego, La Jolla, California 92093, United States (2) Skaggs School Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, California 92093, United States

Photoactivation using Near Infrared (NIR) light has been recognised as an attractive avenue for non-invasive delivery of bioactive molecules to target sites. Two-photon excitation provides excellent spato-temporal resolution. However, the development of new two-photon sensitive organic materials with sufficiently high two-photon uncaging cross-sections remains a challenge.

Here we demonstrate that the principal of chemical amplification through a cascade of efficient rearrangement reactions may be applied to create materials with improved sensitivity to NIR light. First and second generation quinone-methide based dendrimers incorporating the 4-bromo-7-hydroxycoumarin protecting group and L-glutamic acid effector molecules were synthesised. NIR light induced cleavage of the triggering group and subsequent degradation of the dendrimers was followed by HPLC-MS. The amount of caged L-glutamic acid released was quantified by Amplex Red enzymatic assay. Introduction of a self-immolative dendritic moiety between the known two-photon absorber and the caged molecule resulted in 170% higher release of the caged compound.

ORGN 15

New series of 3-trifluoromethyl-3-aryldiazirine photo probes exhibiting enhanced stability to ambient light conditions

Arun Babu Kumar, [email protected], Roman Manetsch. Department of Chemistry, University of South Florida, Tampa, Florida 33620, United States

3-Trifluoromethyl-3-phenyldiazirine combines very good protein labeling selectivity with respectable resistance against pseudo-labeling. Nevertheless, it suffers from spontaneous photodecomposition even under ambient light conditions. This property of the 3-trifluoromethyl-3-phenyldiazirine makes its use cumbersome, restricting to be kept constantly in darkness. Herein, we describe the development of a photolabel that has photolabeling profile similar to that of 3-trifluoromethyl-3-phenyldiazirine, but displays enhanced stability to ambient light condition. The development of this photolabel is significant since the use of photo probes is made practical under ambient light without compromising its labeling capability.

ORGN 16 siRNA complexation, delivery, and release by new biodegradable molecular transporters

Erika I Geihe1, [email protected], Christina B Cooley1, Jeff Simon1, Matthew K Kiesewetter1, Justin Edward1, Robyn P Hickerson2, Roger L Kaspar2, James L Hedrick3, Robert M Waymouth1, Paul A Wender1. (1) Department of Chemistry, Stanford University, Stanford, CA 94305, United States (2) Transderm Inc., Santa Cruz, CA 95060, United States (3) IBM Almaden Research Center, San Jose, CA 95120, United States We report a potentially general solution to the grand challenge of delivering siRNA in vitro and in vivo. RNA interference (RNAi) represents a transformative approach to biochemical pathway analysis, diagnostics, imaging, drug discovery and therapy. However, the poly-charged nature of oligonucleotides and their enzymatic degradation present challenges for the widespread use of siRNA as biological tools and therapy. To address this problem, we designed and synthesized guanidinium-rich amphipathic oligocarbonates which noncovalently complex, deliver, and release siRNA, resulting in up to 90% knockdown of target proteins. The organocatalytic oligomerization to access these co-oligomers is step-economical, remarkably versatile for the design and discovery of siRNA delivery vehicles, and affords an exceptionally quick strategy to explore chemical space and optimize siRNA delivery. The versatility of this approach, and the biodegrability of the designed agents make this an attractive strategy for therapy and biological tool development.

ORGN 17

Total synthesis of synechoxanthin via iterative cross-coupling

Seiko Fujii, [email protected], Stephanie Y. Chang, Martin D. Burke. Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States

The first total synthesis of the antioxidant carotenoid synechoxanthin was achieved through a novel iterative cross-coupling (ICC) strategy, termed Reversed-Polarity (RP) ICC. In this approach, the polarity of bifunctional building blocks is reversed to match the preferred polarity for C-C bond formation in the target structures. The convergent, stereocontrolled, and flexible nature of this synthesis stands to enable systematic studies of the biological activities of this natural product.

ORGN 18

General approach for polyene synthesis

Eric M Woerly, [email protected], Martin D Burke. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States

The polyene motif is prevalent in small molecules derived from a wide range of biosynthetic pathways, including polyketides, hybrid peptides/polyketides, polyterpenes, and fatty acids. These natural products are highly modular in their constitution, which suggests a potential general capacity for simple, efficient, and flexible construction via iterative cross-coupling of pre-assembled building blocks. Herein we describe how the iterative assembly of 25 halo MIDA boronate building blocks can allow for the construction of the core polyene motifs of >90% of all polyene natural products that have ever been isolated.

ORGN 19

Alkynyl ethers as efficient precursors of aldoketenes and ketoketenes: Synthesis of 2-indanones and cyclobutanones

Thomas Minehan, [email protected], Armen Tudjarian, Vincent Tran. Chemistry and Biochemistry, Cailfornia State University, Northridge, Northridge, California 91330, United States

The [3,3]-sigmatropic rearrangement of benzyl alkynyl ethers furnishes a ketoketene intermediate that undergoes 5-exo-dig cyclization to furnish substituted 2-indanones in good yields. The process takes place at low temperatures (-78°C-60°C) and in moderate to high diastereoselectivities. Similarly, aldoketenes dervived from tert-butyl alkynyl ethers via retro-ene reaction at 90°C react with pendant alkenes and enol ethers to provide fused cyclobutanones and donor-accpetor cyclobutanes in high yields and good to excellent diastereoselectivities. These examples illustrate the potentially broad utility of the alkynyl ether functional group for carbon-carbon bond formation in organic synthesis.

ORGN 20

Enhanced hydrogen bond donor catalysis

Anita E. Mattson, [email protected]. Department of Chemistry, The Ohio State University, Columbus, Ohio 43210, United States

Reactions catalyzed by small organic molecules through noncovalent interactions are emerging as powerful tools for the synthesis of valuable target molecules. Hydrogen bond donors (HBDs) are useful noncovalent catalysts able to interact with a variety of functional groups and operate in a number of transformations. Despite the undeniable potential of HBD catalysis there are challenges still facing the field, such as high catalyst loadings and limited reactivity patterns, which often prevent its widespread use in academia and industry. In an effort to overcome these barriers we have identified internal Lewis acid assisted ureas and silanediols as two new families of HBDs with improved activity. Specific aspects behind the development of these enhanced HBD catalysts, including the rationale behind their design, mechanistic studies and applications toward the synthesis of bioactive targets, will be presented.

ORGN 21

Rasta resin-triphenylphoshpine based reagents and catalysts

Patrick H. Toy, [email protected]. Department of Chemistry, University of Hong Kong, Pokfulam, NA, Hong Kong Special Administrative Region of China

We have developed a heterogeneous phosphine functionalized polystyrene based on the rasta resin architecture, rasta resin-triphenylphosphine, and used this as a reagent in a variety of one-pot Wittig reactions. Furthermore, it has been converted into the corresponding phosphine oxide and a phosphonium salt by reaction with hydrogen peroxide and benzyl chloride, respectively. The former was used as a reagent precursor in alcohol halogenation and aziridine ring-opening reactions, while the later was used as a catalyst in carbonyl group cyanosilylation reactions. Both of these materials were readily recyclable. Finally, bifunctional versions of rasta resin-triphenylphosphine that incorporate tertiary amine groups in addition to the phosphine groups have been prepared, and used in one-pot Wittig reactions and related cascade processes. Recent results regarding this research will be presented.

ORGN 22

Oxidative carbonylation of amines to formamides using NaIO4

Ciera J. Gerack, [email protected], Lilli E. Carpo, Lisa McElwee-White. Department of Chemistry, University of Florida, Gainesville, Florida 32611-7200, United States

NaIO4-mediated carbonylation of amines provides an alternative to current methods of synthesizing formamides, which can involve high temperatures, metal catalysts, or stoichiometric equivalents of formic acid. Although NaIO4-mediated carbonylation converts amines to ureas in non-polar solvents, the formamide can be formed from p- methoxybenzyl amine in yields as high as 91% when the reaction is performed in neat methanol. Optimization of formamide yields, functional group compatibility, scope of the reaction, and solvent participation will be discussed.

ORGN 23

Palladium(II) catalyzed allylic C-H alkylation of unactivated α-olefins

Andrew J Young, [email protected], M Christina White. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States

The mechanism of allylic C-H alkylation catalyzed by Pd(II)/bis-sulfoxide involves a delicate interplay of several kinetically labile ligands. A different ligand must bind to the metal to promote each step of the catalytic cycle, and subsequently dissociate. We report an investigation of the disruption of this balance by overly competitive ligands. The DMSO ligand required for functionalization was found to disrupt formation of the Pd/bis-sulfoxide catalyst required for C-H cleavage, and thus inhibit the catalytic cycle. Insights derived from this study were applied to identify a series of alternate bis- sulfoxide ligands that could better compete with DMSO for binding to Pd. This has led to the development of the first intermolecular allylic C-H alkylation of unactivated α-olefins. The reaction demonstrates broad substrate scope and orthogonality to traditional C-C bond forming methods.

ORGN 24

Aqueous O-allylation of phenols using a magnetically separable nano-catalytic system

Amit Saha, [email protected], John Leazer, Rajender S. Varma. Department of NRMRL, STD, U. S. Environmental Protection Agency, Cincinnati, Ohio 45268, United States

Pd has been immobilized on the surface of dopamine-functionalized ferrite nanoparticles, ([Fe3O4-Dopamine-Pd]); their use as magnetic retrievable and recyclable catalysts for O-allylation of phenols with allylic acetates in water is described for easy access to allyl ethers in open aerial atmosphere. Phenols undergo unprecedented allylic substitution reactions with various allylic acetates under refluxing conditions (3-10 hours); mild base, sodium bicarbonate, is adequate to produce the allyl ethers in good yields. The catalyst was recycled for 5 consecutive reactions without any significant loss of efficiency. Aqueous reaction medium, ease of recovery using an external magnet, efficient recycling and the high stability of the catalyst renders the protocol economic and sustainable.

ORGN 25

Further studies on the allylic diazene rearrangement (ADR)

Maha L Shrestha, [email protected], Matthias C McIntosh. Chemistry and Biochemistry Department, University of Arkansas, Fayetteville, Arkansas 72701, United StatesChemistry and Biochemistry Department, University of Arkansas, Fayetteville, Arkansas 72701, United States

We have reported diastereoselective reductive 1,3-transpositions of acyclic α,β- unsaturated tosyl hydrazones to afford substrates with a 1,4-syn or 1,4-anti relationship between alkoxy and methyl groups that proceed via an ADR (McIntosh et al Tetrahedron Lett. 2011 , in press doi:10.1016/j.tetlett. 2011.09.027; Org. Lett. 2008 , 10,357; Tetrahedron 2008 , 64, 7021). In these reports, silica gel was employed to accelerate the reduction. We recently found that CH3CO2H gives the same results with high diastereoselectivity in the reaction. We further optimized the reaction by lowering the amount of catecholborane to 3 eq. Effects of hydrazone E/Z geometry and implication for reaction mechanism will be described.

ORGN 26

Novel anodic coupling in the synthesis of benzoxazole derivetives with CV and mechanism studies

Yung-tzung Huang, [email protected]. Department of Applied Chemistry, National University of Kaohsiung, Kaohsiung, Taiwan, R.O.C. 81148, Taiwan Republic of China

A variety of methods for the synthesis of 5-membered N,O-heterocyclic benzoxazole rings were reported, in which various toxic chemical reagents were used in the reactions. To avoid and reduce the pollutions from the usage of toxic chemicals, we report a new synthetic method in a green pathway, which utilizing intramolecular anodic coupling to observe the benzoxazole ring.

Through screening various substituents and reaction conditions, efficient anodic cyclizations for the synthesis of benzoxazole derivatives were observed. Mechanism and CV studies will be discussed.

ORGN 27

Stereoselective synthesis of b-nucleoside, synthesis of 2'-deoxy-2',2'- difluorocytidine

C-K Jack Hwang, [email protected]. Chemistry Department, PharmaEssentia Corp., Taipei, Taiwan Republic of China

A stereoselective synthesis of 2'-deoxy-2',2'-difluorocytidine is described. The predominant product of b-nucleoside 3 obtained from the glycosylation was accomplished by reacting 1 with 2 in the presence of a transition metal salt, Ag2CO3. The glycosyaltion process is presumably via an SN1 mechanism.

ORGN 28

Creating time in synthetic organic labs: Optimization and substrate screening using microwave flow chemistry

Michael J. Karney1, [email protected], Keith A. Porter2, Grace S. Vanier1. (1) Synthesis Division, CEM Corporation, United States (2) Business Development, CEM Corporation, United States

Microwave chemistry has burgeoned in recent years, primarily within combinatorial chemistry and batch synthesis on the discovery level. There has been a desire to perform reactions in a continuous-flow setup, permitting safe and efficient processing of large quantities of reagents.

Our research team is currently advancing new technologies using flow chemistry to demonstrate the utility of a microwave based system. Reagent concentration, temperature, time and other conditions are optimized in a practically “hands free” fashion, allowing chemists to work more efficiently. Ideal reaction conditions can then be directly applied to nearly kilogram scale production in a day or synthesis of a library of compounds. This presentation will focus on monophasic and biphasic reaction optimization for metal catalyzed and non-catalyzed reactions using a microwave- assisted continuous-flow reactor. A small survey of reaction substrate scope will also be analyzed using this instrument as well as the impact of selective heating of metals in a flow chemistry setting.

ORGN 29

Development and mechanistic investigation of an enantioselective thiourea- catalyzed nucleophilic ring opening of episulfonium ions

Song Lin, [email protected], Eric N Jacobsen. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States

Multi-functional thioureas were shown to catalyze enantioselective ring opening of episulfonium ions with various indole derivatives. Experimental mechanistic investigation revealed definitive evidence for a transition-state stabilization effect enabled by the thiourea in the rate- and enantio-determining step – the nucleophilic ring opening. This stabilization is achieved through a network of weak, non-covalent interactions, including hydrogen-bonding to the sulfonate anion and indole, as well as a cation-pi interaction between the extended aromatic group on the catalyst and the cationic transition-state.

ORGN 30

Enantioselective synthesis of alkyne-substituted quaternary carbon stereogenic centers through NHC-Cu-catalyzed allylic substitution reactions with (i- Bu)2(alkynyl)aluminum reagents

Jennifer A Dabrowski, [email protected], Amir H. Hoveyda. Department of Chemistry, Boston College, Chestnut Hill, MA 02467, United States

Organocuprates have been used extensively in synthesis, particularly with alkynes as non-transferable ligands; however, alkynes are an important functional group in potent pharmaceutical drugs as well as their precursors. Therefore, an efficient enantioselective synthesis of alkyne-containing all-carbon stereogenic centers is needed. The bidentate Cu–NHC derived from the corresponding NHC–Ag complex efficiently and enantioselectively facilitates the addition of alkynylaluminum reagents to allylic phosphates to obtain quaternary stereogenic centers as a single enantiomer. Alkynyl additions proceed with >98% site selectivity for the desired SN2' product; no competitive isobutyl addition product is observed.

ORGN 31

Control of organocatalytic action modes for reaction development: Recent advance with N-heterocyclic carbene catalysis

Yonggui Robin Chi, [email protected] of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences,, Nanyang Technological University, Singapore, Singapore 637371, Singapore

Our recent efforts in reaction development through carefully controlled activation of simple substrates with amines, acids, and N-heterocyclic carbenes as the catalysts will be discussed. Application of catalytic reactions toward the modification of biomolecules and materials will be briefed.

ORGN 32

Organocatalytic enantioselective methodologies with MBH carbonates Ramon Rios, [email protected]. Department of Organic Chemistry, Universitat de Barcelona, Barcelona, Spain

Different highly enantioselective methodologies based in MBH carbonates will be presented. The addition of methylene sulfones, fluoromethylene sulfones, fluoromalonates or anthrones will be disclosed.

ORGN 33

WITHDRAWN

ORGN 34

Pinene-derived iminodiacetic acid (PIDA): A powerful ligand for stereoselective synthesis and iterative cross-coupling of C(sp)3 boronate building blocks

Junqi Li, [email protected], Martin D Burke. Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States

We herein report that a pinene-derived iminodiacetic acid (PIDA) ligand enables the highly diastereoselective synthesis of a wide range of oxiranyl Csp3 boronates from the corresponding olefins. These oxiranyl PIDA boronates, in turn, can be readily transformed into stable α-boryl aldehydes via a novel 1,2-migration of the boronate group with complete maintenance of stereochemical purity. Dual C(sp3)-hybridized B- protected haloboronic acids are readily accessible from the α-boryl aldehyde, enabling the synthesis of a pharmaceutical target via stereocontrolled iterative C(sp3)-C(sp2) cross-coupling.

ORGN 35

Nonenzymatic dynamic kinetic resolution of alcohols catalyzed by planar-chiral DMAP derivatives

Sarah Y Lee, [email protected], Jaclyn M Murphy, Gregory C Fu. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States With the aid of a planar-chiral 4-dimethylaminopyridine (DMAP) derivative and an alcohol racemization catalyst, nonenzymatic dynamic kinetic resolution of secondary alcohols can be achieved through enantioselective acylation. The reaction proceeds in high yield and high enantiomeric excess with a variety of alcohols. Studies into the development and the scope of this methodology will be discussed.

ORGN 36

Organocatalytic asymmetric domino Michael-lactonisation

Dorine Belmessieri, [email protected] of Chemistry, University of St Andrews, St Andrews, Fife KY169ST, United Kingdom

We have developed a highly diastereo and enantioselective intramolecular Michael addition-lactonisation of enone-acid substrates. This transformation involves the in situ organocatalytic generation of ammonium enolates directly from carboxylic acids. Judicious choice of catalyst allows the synthesis of syn or anti polycyclic lactones in high levels of enantioselectivity (up to 99% ee) and diastereoselectivity (up to 99 : 1 dr). Derivatisation of the lactone by ring opening gave access to a range of polysubstituted stereodefined scaffolds.

ORGN 37

Divergent outcomes reactions of methyl 3-TBSO-2-diazo-3-butenoate with nitrones from dirhodium- and copper-based catalysts separately or in combination Xinfang Xu, [email protected], Xiaochen Wang, James Michael Bonifant, Michael P. Doyle, [email protected]. Department of Chemistry and Biochemistry, University of Maryland at College Park, College Park, MD 20742, United States

That a reaction pathway can be redirected to a different product by changing a reactant or reaction conditions is well known and widely practiced. Such processes are referred to as “divergent”, and this term is broadly applied to methodology, synthesis, reactivity and selectivity, among others. We and others have reported exceptionally efficient catalyst-dependent processes that occur with the same diazo substrates to form structurally different compounds.

We wish to present novel reactions of methyl 3-TBSO-2-diazo-3-butenoate and nitrones (Figure 1). In the presence of a catalytic amount of dirhodium tetraacetate, formal [3 + 3] addition occurs to form methyl N,3-diphenyl-3,6-dihydro-1,2-oxazine 3 in >95% yield (Path A). Under the same conditions, however, only Mannich addition occurs between these substrates in the presence of catalytic copper(I) hexafluorophosphate (Path B), and by combination of these two catalysts, a one-pot three-step pyrrole synthesis was achieved in high yield (Path C).

ORGN 38

Enantioselective synthesis of spiroindolones

Joseph J. Badillo, [email protected], Abel Silva-Garcia, Benjamin H. Shupe, Gary E. Arevalo, Annaliese K. Franz. Department of Chemistry, University of California, Davis, California 95616, United States

Spirocyclic oxindoles are important scaffolds found in many natural products and pharmaceutical lead compounds, and their potency in biological systems is often dependent on the absolute configuration of the 3,3'-spirocyclic center. This presentation will discuss several recently developed catalytic methods for accessing spirooxindoles in excellent yields with high regio- and stereoselectivity. For example, we will discuss the enantioselective synthesis of spirocyclic tetrahydro-ß-carbolines (spiroindolones), which represent a core structure found in the anti-malarial lead compound NITD609. A comparison of chiral Lewis acids and chiral BINOL-derived phosphoric acids as catalysts for this reaction will be presented. In addition, we will discuss the regio- and stereoselective synthesis of spirooxindole oxazolines catalyzed by various Lewis acids. Mechanistic details and computational studies for the stereo- and regiocontrol of both reactions will also be discussed.

ORGN 39

Asymmeric formal [3+3]-cycloaddition reactions of nitrones with electrophilic vinylcarbene intermediates: Scope and limitations

Xiaochen Wang, [email protected], Xinfang Xu, Michael P Doyle. Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States

With metal carbene access to dipolar intermediates, the formal [3+3]-cycloaddition process between TBSO-activated vinyldiazoacetate and nitrones occurs in high yields and selectivities under the catalysis of chiral dirhodium(II) carboxylates. The formed 3,6- dihydro-1,2-oxazines are versatile intermediates for the synthesis of α-substituted β- amino acids and related compounds that are not easily accessible by other methods. The scope and the limitations of the reaction will be discussed. The potential suitability of a spectrum of 1,3-dipoles and β-substituted vinyldiazoacetates for this transformation suggest broad applicability.

ORGN 40

Synthesis of new semiconductors: Tuning the molecular and packing structure of rubrenes

Kathryn A. McGarry, [email protected], Christopher J. Douglas. Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, United States

From the considerable research seeking to advance electronics, organic semiconductors have emerged as promising new tools due to their synthetic versatility and low cost of production. These characteristics have prompted the formation of devices that utilize the unique nature of organic materials. Although numerous studies support the applications of organic semiconductors, the fundamental aspects of charge transport through organic materials are not yet well understood. With this motivation, we sought to explore how the structural components (molecular and packing) affect charge transport in organic single crystals. Our research is focused on rubrene derivatives, as rubrene is the benchmark organic semiconductor in single crystal devices. Through our studies we successfully discovered structural modifications that would alter certain packing aspects while maintaining the key packing aspects thought to enhance charge mobility.

ORGN 41

Hypersensitive thermally-activated molecular machines: Anisotropic rotational dynamics within hierarchically ordered periodic mesoporous p- divinylbenzenesilica

Cortnie S. Vogelsberg1, [email protected], Silvia Bracco2, Mario Beretta2, Angiolina Comotti2, Piero Sozzani2, Miguel A. Garcia-Garibay1. (1) Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California 90034, United States (2) Materials Science, University of Milano-Bicocca, Milan, Italy

The dynamics of p-phenylene-d4 rotators in hierarchically ordered periodic mesoporous p-divinylbenzenesilica have been elucidated by deuterium solid-state NMR spectroscopy. The mesoporous material, characterized by a honeycomb lattice structure, has arrays of alternating p-divinylbenzene and siloxane layers forming the ordered walls of the mesoscopic channels. NMR experiments revealed a non-Arrhenius temperature dependence of the rotator dynamics, with rates ranging from 103 to 108 Hz between 215 K and 305 K. The regime of motion changes drastically at ~280 K, indicating a dynamical transition with a corresponding change in heat capacity. At room temperature and above, the rotators comprise a highly mobile fluid-like rotational phase within the organic layers of the walls. However, cooling slightly below room temperature results in rigid glass-like organic layers with markedly slower dynamics. Exploiting the rotational behavior, above and below the transition, represents a means to elicit a very significant thermal response within a narrow temperature range.

ORGN 42

Chemically functionalized nanomaterials based nerve agent sensors: From the receptor synthesis to an autonomous prototype

Alexandre Carella, [email protected], Caroline Celle, Jean-Pierre Simonato. Department of Nanomaterials Technologies, CEA, Grenoble, France

The ability to detect traces of chemical warfare agents is mandatory both for military forces and homeland security. Organophosphorus compounds represent one of the most important and lethal classes of chemical warfare agents (e.g. Sarin, Soman, Tabun). These agents have been used for terrorist attacks in the past (e.g. 1995 Japanese subway attack). Differents strategies have been developed for the detection of organophosphorus compounds (OPs) using nanomaterials based field effect transistors functionalized with a tailor-made chemical receptor specific to traces of organophosphorus agents. We demonstrated that chemically functionalized silicon nanowire field-effect transistor (SiNW-FET) and carbon nanotubes field effect transistor with functionalized electrodes (CNTFET) are suitable for the a sensitive and selective electrical detection of OPs.

These devices have been integrated in a portable, battery-operated, microprocessor- based prototype sensor system for the detection of nerve agents, exhibiting a high sensitivity and selectivity on complex mixtures and on contaminated materials.

Carella, A. et al. Angew. Chem. Int. Ed. 2010, 49, 4063-6; Chem. Commun. 2011 , 47, 6048-6050; Electron Device Letters, IEEE, 2011 32, 979-982; Talanta, 2011 , 85, 2542- 2545

ORGN 43

Materials with singlet oxygen-responsive energy transfer

Samuel W. Thomas, [email protected], Jingjing Zhang, Syena Sarrafpour, Damla Koylu. Department of Chemistry, Tufts University, Medford, MA 02155, United States

This talk will describe new materials that show a ratiometric fluorescent response to 1 singlet oxygen ( O2). These materials comprise a blue-emitting conjugated polymer (CP) and a lower-energy acene that can both accept energy from the conjugated polymer and react with singlet oxygen by a [4+2] cycloaddition reaction. The cycloaddition interrupts the polymer-to-acene energy transfer, which results in a ratiometric response: the emission intensity from the acenes decreases while polymer backbone emission intensity increases. In solution, the acene and CP must be linked to 1 respond to O2, while CP thin films need only be doped with acenes to show a similar fluorescent response. This talk will also summarize structure-property relationships of the acenes used, including the synthesis and characterization of new sterically-crowded red-emitting tetracene derivatives. Applications of these new materials for multiplicative amplification in sensing and in photochemcially tunable solid-state emissive layers in electroluminescent devices will be discussed. ORGN 44

Towards a fluorescent photoswitchable probe to image gold nanoparticles in mammalian cells

Jort Robertus1,2, [email protected], Wim Velema2,1, Derk-Jan van Dijken2,1, Wesley R Brown2,1, Ben L Feringa2,1. (1) Stratingh Institute for Chemistry, University of Groningen, Groningen, Groningen 9747 AG, The Netherlands (2) Zernike Insitute for Advanced Materials, University of Groningen, Groningen, Groningen 9747 AG, The Netherlands

Nanoparticles are increasingly finding applications in sensors, food, cosmetics, and medicine. Consequently, human exposure to nanoparticles is ever increasing. Recently, gold nanoparticles of distinct sizes have been found to accumulate in mammalian cells and cause cell death through apoptosis or necrosis depending on size. However, determining the location of small nanoparticles (< 2 nm) in cells is challenging.

Herein, we describe a fluorescent probe to image Au-nanoparticles in mammalian cells. The fluorescent probe is based on a fluorescent photochromic switch. The fluorescence of the probe can be controlled by using light to switch between the open (fluorescent) and closed (non-fluorescent) state. By assembling the probe onto the surface of Au- nanoparticles we can monitor nanoparticles accumulation in cells by fluorescence microscopy. The fluorescent probe allows us not only to determine the presence of fluorescence, but also allows the verification of the fluorescence source by on–off–on switching of the fluorescence.

ORGN 45

Application of side chains to tune properties of thieno[3,4-b]pyrazine-based polymers

Michael E Mulholland, [email protected], Sean J Evenson, Seth C Rasmussen. Chemistry and Biochemistry, North Dakota State University, Fargo, North Dakota 58104, United States

Due to their unique combination of plastic and semiconductor properties, conjugated polymers have become an interesting new class of materials for technological devices, with applications including light emitting diodes, photovoltaics, and near IR sensors. Low band gap thieno[3,4-b]pyrazines have demonstrated potential in several device applications and thus development of new methods toward tuning their electronic properties is of great interest. In 2008 the Rasmussen group produced a series of new thieno[3,4-b]pyrazine monomers which allow an increased control of the electronic properties by varying the side chains at the 2- and 3- positions. The use of side chains, rather than modification of the polymer backbone, should allow tuning of electronic properties while minimizing changes to bulk physical properties such as pi-stacking and morphology. Preparation and characterization of new series of thieno[3,4-b]pyrazine- based polymers will be presented in an attempt to illustrate potential tuning effects.

ORGN 46

Enhancing the rotation rate of unidirectional molecular motors

Jurica Bauer1,2, [email protected], Lili Hou1,2, Ben L Feringa1,2. (1) Stratingh Institute, University of Groningen, Groningen, Groningen 9747 AG, The Netherlands (2) Zernike Institute for Advanced Materials, University of Groningen, Groningen, Groningen 9747 AG, The Netherlands

Synthetic molecular motors play a potentially important role in the development of nanoscale mechanical devices, and draw inspiration from the many fascinating natural systems that use nanometer-sized motors to drive fundamental biological processes. Our group has developed light-driven rotary molecular motors based on sterically overcrowded alkenes. In the present work we investigate a new structural motif for these motors, in order to tune the rate of rotation with the goal of enhancing it. The new design is expected to give the fastest unidirectional rotary molecular motor to date. The synthesis of the molecule is described as well as some preliminary photochemical measurements. Given the high rotation rate of the motor, the rotary process is followed by microsecond transient absorption spectroscopy.

ORGN 47

Photo-switch on gold nanoparticles

Liangliang Zhu, Hong Yan, Kim Truc Nguyen, Yanli Zhao, [email protected] of Chemistry and Biological Chemistry, Nanyang Technological University, Singapore, Singapore

Pt(II)-bridged multi-[3]rotaxane functionalized gold nanoparticles Au@[Pt-2L(α- CD)2][NO3]4 were developed through a stepwise introduction of Pt(II) coordination and gold-thiol binding in turn. Such sequential self-assembly, which is fast responsive and can be quantitatively controlled, is utilized to mimic a nanoscale security logic monitored by the surface plasmon resonance as well as the color change of solution. The stable nanoparticle hybrid can serve as a novel photo-switch since the α-cyclodextrin rings in the [3]rotaxane can be reversibly switched by the photoirradiation of the azobenzene units, thus realizing the concatenation of the security logic with the [3]rotaxane-based photo-switch.

This work was supported by the National Research Foundation Fellowship (NRF2009NRF-RF001-015).

ORGN 48

External stimuli responsive gelation by low molecular weight gelators

Jochem T van Herpt, [email protected], Marc C A Stuart, Wesley R Browne, Ben L Feringa.Stratingh Institute for Chemistry, University of Groningen, Groningen, The Netherlands

The self-assembly of low molecular weight gelators (LMWGs) into a fibrous gel network is a remarkable phenomenon. Even though the mechanisms and dynamics of these gelating systems are still not fully understood, gels find use in many fields, including medicine, food, controlled cell growth and functional materials. Gaining control over these gel systems, both their properties and their formation, is among the greater challenges in this field, especially using active reversible switching.

Here, we describe the development of gelating systems, both for organic solvents and water, which respond to ultrasonic treatment or irradiation with UV-light, respectively. These organo gelators have the remarkable property that they are tunable to gelate a wide range of solvents.

ORGN 49

Nitrogen-doped graphene for high performance ultracapacitors and the importance of nitrogen-doped sites at basal-planes

Hyungmo Jeong, [email protected]. Department of Material Science and Engineering, KAIST, Daejeon, Republic of Korea Although various carbon nanomaterials have been successfully demonstrated for high performance ultracapacitors, their capacitances need to be improved further for wider and more challenging applications. Herein, using nitrogen-doped graphene produced by a simple plasma process, we developed ultracapacitors whose capacitances (~280 F/gelectrode) are about four times larger than those of pristine graphene based counterparts without sacrificing other essential and useful properties for ultracapacitor operations including excellent cycle life (>200,000), high power capability, and compatibility with flexible substrates.

While we were trying to understand the improved capacitance using scanning photoemission microscopy with a capability of probing local nitrogen-carbon bonding configurations within a single sheet of graphene, we observed interesting microscopic features of N-configurations: N-doped sites even at basal-planes, distinctive distributions of N-configurations between edges and basal-planes, and their distinctive evolutions with plasma duration.

The local N-configuration mappings during plasma treatment, alongside binding energy calculated by density functional theory, revealed that the origin of the improved capacitance is a certain N-configuration at basal-planes.

ORGN 50 Lithium amide-mediated lithiations under non-equilibrium conditions: Aggregates gone wild

David B. Collum, [email protected]. Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, United States

Recent progress in understanding the reactivity of lithium diisopropylamide in tetrahydrofuran at -78 oC. The reaction rates under these synthetically important conditions are dominated by the rates that aggregates exchange. The incomplete aggregate equilibrations cause autocatalysis and related feedback loops to be prevalent. The mechanistic complexity ramps up considerably. Reactions are hypersensitive to trace impurities, causing the source of lithium diisopropylamide to be important.

ORGN 51

Organic reactive intermediates and the chemistry of harsh environments

Robert J McMahon, [email protected]. Department of Chemistry, University of Wisconsin, Madison, WI 53706, United States

Our research efforts focus on elucidating the photochemistry and spectroscopy of organic species that are postulated to play a role in harsh environments (e.g. combustion, planetary atmospheres, interstellar space). These environments contain a remarkable diversity of organic functionality, including reactive intermediates such as anions, radicals, and carbenes. We have drawn on our knowledge of mechanistic and structural organic chemistry to identify chemically-significant targets for detection and characterization. Many of these investigations are made possible through our ability to prepare specific chemical precursor molecules via synthetic organic chemistry. I will present case studies that exemplify how modern physical-organic chemistry bridges the disciplines of organic chemistry and chemical physics.

ORGN 52

Lewis base activation of Lewis acids: A new paradigm for catalysis in main group chemistry

Scott E Denmark, [email protected]. Chemistry, University of Illinois, Urbana- Champaign, Urbana, IL 61801, United States

The field of chemical catalysis has grown immensely in the past century. However, catalysis of reactions of the p-block elements is almost non-existent. Over the past decade, we have investigated reactions based on elements in Groups 14, 16 and 17, under the newly developed paradigm of “Lewis-base activation of Lewis acids”. This lecture will describe our most recent efforts to design, understand and apply synthetically useful cyclofunctionalization reactions of the chalcogens and halogens the under catalysis by Lewis bases.

ORGN 53

Award Address (James Flack Norris Award in Physical Organic Chemistry sponsored by the ACS Northeastern Section). Structure and reactivity of organolithium reagents

Hans J. Reich, [email protected]. Chemistry, University of Wisconsin, Madison, Madison, WI 52706, United States

The majority of C-C bond forming reactions involve the interaction of electrophilic carbon species with carbanionic centers, of which organolithium reagents are probably the most important source. The vast organolithium literature provides a great deal of empirical information, but firm mechanistic and structural insights have been difficult to achieve. We have attempted to understand in detail the properties and reactions of organolithium reagents using reactivity, kinetics, stereochemical and selectivity studies, as well as multinuclear NMR spectroscopic studies using Rapid Injection NMR. Our efforts have focused on the role played by the various aggregates and mixed aggregates of lithium reagents which are now known to be almost invariably involved in their reactions with electrophiles.

ORGN 54

Catalyts for the selective construction of olefins

Robert H. Grubbs, [email protected] of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, United States

Ruthenium based olefin metathesis catalysts have provided new routes to olefins that appear in a variety of structures. Their functional group tolerance and ease of use allow their application in the synthesis of multifunctional bioactive molecules that are being explored as pharmaceutical agents. The same systems are also useful for the synthesis of an array of new materials from multifunctional polymers to supramolecular systems. Underlying these developments has been the discovery of active catalysts with controlled selectivity through the synthesis of new ligands that control the geometry of the intermediate carbene and metallacycle complexes. A recent finding has been a ligand system that controls the geometry of the double bond that is formed in the metathesis process. A particularly efficient catalyst that will dimerize olefins to the Z geometry in high yields has been developed. These systems also generate a family of high Z polyolefins.

ORGN 55

Stereochemical and mechanistic probes for understanding the stereoselectivity of addition to alkenes in the Wacker reaction

Othman A Hamed, [email protected], Partrick M Henry, Daniel P Becker. Chemsitry, Loyola University, Chicago, IL 60626, United States

Catalytic oxidation of olefins with Pd(II) complexes has generated considerable controversy concerning the stereochemistry of hydroxypalladation (mode of addition of Pd(II) and OH to the olefin double bond). Several mechanistic and stereochemical probes were designed and applied to gain a more detailed insight into the stereochemistry of hydroxpalladation. Results showed that the mode of addition is different under different reaction conditions. Thus, Wacker reaction of olefins proceeds through two possible mechanistic pathways: 1) anti-oxypalladation; or 2) syn- oxypalladation. The results were confirmed by a stereochemical probe involving chirality transfer. These results were the initiative in designing new asymmetric synthetic tools for the formation of optically active chlorohydrins, β-substitued ketones, and optically active diesters containing three contiguous chiral centers shown in the following scheme. In the current presentation an overview of all the mechanistic and stereochemical tools that are in support of the dependence of the mode hydroxypalladation addition on the reaction conditions will be presented. [Figure 1]

ORGN 56

Patterns in additions to alkenes

Donna J. Nelson, [email protected]. Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, United States

Patterns in reactions and mechanisms across many additions to alkenes will be presented. Electrophilic additions and nucleophilic additions will be compared and contrasted, both with and without significant steric effects.

ORGN 57

Philicity of heterocarbenes and heterocyclic carbenes: Mechanisms of 1,2- cycloadditions to alkenes

Fillmore Freeman1, [email protected], Damilola A. Adepegba2, Vickie T. Bui3, Gabriela Fernandez-Cuervo4, Dung J. A. Pham5, Stacia A. Sherry6, Keisha T. Watt7. (1) Department of Chemistry, University of California, Irvine, Irvine, CA 92697-2025, United States (2) University of Maryland, Eastern Shores, Princess Anne, Maryland 21853, United States (3) Department of Chemistry, University of California, Irvine, Irvine, CA 92697-2025, United States (4) Department of Chemistry, University of Puerto Rico, Rio Piedras, San Juan, Puerto Rico 00931-3346, Puerto Rico (5) Department of Chemistry, University of California, Irvine, Irvine, CA 92697-2025, United States (6) Santa Rosa Junior College, Santa Rosa, CA 95401, United States (7) Saint Thomas University, Miami Gardens, FL 33054, United States

The mechanisms of the cycloadditions of singlet heterocarbenes and heterocyclic carbenes to alkenes to form heterocyclopropanes and spirocyclopropanes, respectively, have been investigated using CBS-QB3, Density Functional Theory (B3LYP, B3PW91, PBE1PBE) with the 6-311+G(d,p) basis set, and coupled-cluster theory [CCSD(T) and quadratic configuration interaction method [QCISD(T)] with the cc-pVDZ and cc-pVTZ basis sets. Among the carbenes studied are substituted aminocarbenes, 1,2-dihydro- 3H-pyrazol-3-ylidene, 1,2,4,5-tetrahydro-3H-pyrazol-3-ylidene, 1,3-dioxa-2-ylidene, 1,3- dithia-2-ylidene, 1,3-diselenol-2-ylidene, 1,3-oxazol-2-ylidene, 1,2,4-azadiphosphol-3- ylidene, and 1,3-dihydro-1,3-diphosphol-4-azol-2-ylidene.

ORGN 58

Hydrochlorination of alkenes and alkynes

David R. Dalton1, [email protected], Linda M Mascavage2, John Tierney3, Fan Zhang-Plasket4, Francis Costello1, Philip E Sonnet1, Michael Haugh1. (1) Department of Chemistry, Temple University, Philadelphia, PA 19122, United States (2) Department of Chemistry, Arcadia University, Glenside, PA 19038, United States (3) Department of Chemistry, Pennsylvania State University, Brandywine, Media, PA 19063, United States (4) Merck Sharp and Dohme Co., West Point, PA 19148, United States

Mixtures of gaseous alkyl substituted alkenes and alkynes react with gaseous hydrogen chloride, at low to modest pressures and temperatures, to produce chlorine-containing products. The simultaneous disappearance of reactants and the appearance of products have been followed by gas-phase NMR and IR spectroscopies. In the absence of a “wall-less” reactor, it has become clear that the walls and/or wall-adsorbed species play a critical role. Assumptions about wall adsorbed species permit computational analyses that reproduce products obtained experimentally.

ORGN 59

Enantiomerically pure electrophiles for alkene functionalization

Thomas Wirth, [email protected]. School of Chemistry, Cardiff University, Cardiff, United Kingdom

We have developed electrophile-mediated tandem biscyclisation reactions consisting of a sequence of carboannulation and a second cyclisation. Depending on the substrate, the electrophile and the reaction conditions, indanes, indenes, tetrahydronaphthalene derivatives, dihydronaphthalenes and benzofluorenes are easily accessible. These novel methodologies provide fast access to polycyclic ring systems in a single step. Enantiomerically pure electrophiles based on selenium and iodine have been used for the stereoselective functionalization of alkenes. Development of novel reagents as well as their application towards natural products will be discussed.

ORGN 60

Enigmatic reactions of ketenes with tertiary-amines

Thomas T. Tidwell, [email protected], Annette Allen, Sinisa Vukovic. Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada

Ketenes are among the most reactive alkenes, and are known in certain cases to react with tertiary amines such as triethylamine forming observable zwitterionic intermediates that lead to amides of dialkylamines (Fig. 1). Our studies of the mechanisms of these processes reveal that conventional 1,6-intramolecular eliminations are not sufficient to explain formation of these products. Possible pathways for these reactions will be presented.

ORGN 61

Role of distortion energies in alkene cyloaddition reactivities

K. N. Houk, [email protected]. Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA 90095, United States

For many years, the nucleophilicity and electrophilicity of alkenes have been classified according to frontier molecular energies, or by derived quantities like IPs and IAs, or through the conceptual DFT equivalent. Following pioneering work of Morokuma, Ziegler, Guthrie, and Bickelhaupt, we have found that the distortion of alkenes to transition state geometries is the major factor determining activation energies, and thus the controller of cycloaddition reactivity.

ORGN 62

Diversity-oriented synthesis of macrocyclic scaffolds Henning S. G. Beckmann, [email protected], David R Spring. Department of Chemistry, University of Cambridge, Cambridge, United Kingdom

Diversity-oriented synthesis (DOS) aims at the efficient synthesis of structurally diverse compound collections. Macrocycles represent an underexplored structural class in drug discovery although having shown high affinity and selectivity for protein targets as well as suitable pharmacokinetic properties.

Here we report the diversity-oriented synthesis of a diverse collection of novel macrocyclic scaffolds comprising heterocyclic moieties such as hydantoins, dihydrouracils, oxalylureas, and triazoles. These compounds were prepared from a common precursor in not more than three steps.

ORGN 63

Polyglycerol-dendronized fluorophores

Si Kyung Yang1, [email protected], Xinghua Shi2,3,4, Taekjip Ha2,3,4,5, Steven C. Zimmerman1. (1) Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States (2) Department of Physics, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States (3) Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States (4) Howard Hughes Medical Institute, University of Illinois at Urbana- Champaign, Urbana, Illinois 61801, United States (5) Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States

Water-soluble and biocompatible dendritic polyglycerol is an ideal structure for solubilizing and protecting fluorescent dyes for fluorescence microscopy. Attachment of polyglycerol dendrons to water-insoluble dyes such as perylenediimides and boron- dipyrromethenes provides highly stable, water-soluble fluorescent dyes. We have developed clickable, monofunctional, uncharged, water-soluble polyglycerol- dendronized fluorophores that can be singly linked to biomolecules in a specific fashion. The design, synthesis, single-molecule study and target-specific biolabeling will be discussed in this talk.

ORGN 64 Investigating the protein-nucleic acid interactions of RISC using xRNA-containing siRNAs as steric probes in RNA interference

Armando R Hernandez, [email protected], Larryn W Peterson, Eric T Kool. Department of Chemistry, Stanford University, Stanford, CA 94305, United States

Understanding the intricate interactions between small interfering RNAs (siRNAs) and the RNA-induced silencing complex (RISC), the key protein complex of the gene silencing mechanism of RNA interference (RNAi), is of great importance to the development of siRNAs with improved biological (and potentially therapeutic) function. In earlier studies of these interactions, the use of various chemically-modified siRNAs has been reported; however, few examples using nucleobase modifications exist. Here we describe the synthesis and use of siRNAs bearing size-expanded RNA (xRNA) analogues as a novel set of steric probes. xRNA nucleobases are expanded by 2.4 angstroms and retain canonical Watson-Crick base-pairing groups. Their use in a dual- reporter luciferase assay in HeLa cells has revealed sites on the antisense strand where larger-than-natural nucleobases are tolerated, including positions where activity is higher than that of natural RNA. Melting temperature and serum stability data provide further insights into RNAi-based gene silencing.

ORGN 65

Analyte-triggered antenna synthesis as a general method to access responsive lanthanide-based luminescent probes

Elias Pershagen, Csongor Szijjarto, Eszter Borbas, [email protected]. Department of Organic Chemistry, Stockholm University, Stockholm, Sweden

Lanthanide-based responsive luminescent probes are well-suited to the sensitive detection of analytes in challenging media due to to their long excited state lifetimes, which makes the time-gated removal of sample autofluorescence possible. Here we present a general design for the rapid generation of responsive luminescent probes. The strategy entails in situ chemical synthesis of a light-harvesting antenna from a suitable, non-sensitizing precursor. Antenna formation is initiated by an analyte-specific reaction. The scope of analytes is exceptionally broad, and includes small molecules and transition metals. Furthermore, the design is readily adapted to the monitoring of enzymatic activity. The narrowness of the emission bands enables the simultaneous detection of several analytes.

ORGN 66

Design, synthesis and qualitative structure activity evaluations of novel b- secretase inhibitors as potential Alzheimer's drug leads

Taleb H. Al-Tel, [email protected]. Department of Pharmacy Practice, University of Sharjah, Sharjah, Sharjah 27272, United Arab Emirates We have identified highly selective small molecules substituted imidazopyridine armed with benzimidazol and/or aryl imidazole as potent b-secretase inhibitors. The most effective and selective analogs demonstrated low nano-molar potency for the BACE1 enzyme as measured by FRET and a cell-based (ELISA) assays and exhibited comparable affinity (KI) and high ligand efficiency (LE). In addition, these motifs were highly selective (>200) against the structurally related aspartyl protease BACE2. Of the most potent compounds, 34, displayed an IC50 value for BACE1 of 18 nM, and exhibited cellular activity with an EC50 value of 37 nM in the cell-based ELISA assay, high affinity (KI = 17 nM) and ligand efficiency (LE = 1.7 kJ/mol). Compound 34 was found to be 204-fold more selective for BACE1 compared to the closely related aspartyl protease BACE2.1

1. Al-Tel, T. H. J. Med. Chem., 2011, accepted for publication

ORGN 67

Site selective enzymatic protein modification for defined polypeptide functionalization

Mark D. Distefano, [email protected], Mohammad Rashidian, Santoshkumar Khatwani, Jonathan K. Dozier, David M. Hanna. Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, United States

Proteins possess a wide range of functional properties that are useful in bioengineering applications. Hence, new methods to create protein conjugates are desirable. Recently, we have developed a method for incorporating azides, alkynes and aldehydes into proteins using protein farnesyltransferase. This approach involves the use of azide-, alkyne- and aldehyde-containing analogues of farnesyl diphosphate which serve as alternative substrates for protein farnesyltransferase. This enzyme catalyzes the S- alkylation of a specific cysteine residue imbedded in a tetrapeptide sequence positioned at the C-terminus of a protein. Since that sequence can be appended to the C-terminus of virtually any protein, this enzyme can be used to incorporate azides, alkynes and aldehydes into a broad range of proteins. Using this approach, we have prepared conjugates between green fluorescent protein and surfaces, fluorescent dyes and other polymers including DNA and PEG. ORGN 68

Modulating protein-protein interactions with small molecules

Cornelius J O' Connor, [email protected], David R Spring. Department of Chemistry, University of Cambridge, Cambridge, United Kingdom

Protein-protein interactions (PPIs) regulate a host of critical cellular functions, from DNA replication and repair to intracellular communication and programmed cell death. Aberrant or malfunctioning PPIs can cause a plethora of diseases and as such are a very attractive target for therapeutic intervention.

Here, we describe the development of small-molecules designed to modulate interacting proteins, based on computational inspection of the protein interface. A modular synthetic approach was employed, wherein individual building blocks were coupled together to form a scaffold, from which appropriate functionality can be appended in order to target 'hot-spot' residues on the protein surface.

ORGN 69

Novel synthesis of O-protected 4-hydroxybicyclo[2.2.1]heptane-1-carboxylic acid

Xinhua Qian, [email protected], Michael K. Wong, Rita Fox, Matthew R. Hickey, Zhiwei Guo, Kana Yamamoto, Bharat Patel, Reginald Cann, Antonio G. Ramirez, Jollie Godfrey, Richard Mueller, Rajendra P. Deshpande, David R. Kronenthal. Chemical Development, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903, United States

4-Hydroxybicyclo[2.2.1]heptane-1-carboxylic acid and its O-protected derivatives (1 ) has been increasingly utilized in potential therapeutics. However, there is limited information regarding practical syntheses of 1 , primarily due to the challenges of generating the O-substituted bridgehead on a highly constrained [2.2.1]bicyclic scaffold. Starting from norbornene, we have significantly improved a reported 4-step synthesis of 4-(methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid (2 ). Conversion of the carboxylic acid function in 2 to a ketone sets the stage for the key Baeyer-Villiger oxidation to install the bridgehead hydroxyl functionality. Development of the highly regioselective Baeyer-Villiger oxidation will be presented. The final saponification of the methyl ester provided the target molecule 1 with an overall 25% yield in 8 steps. We will also present details of process development work to enable this synthesis on kg-scale.

ORGN 70

Singlet oxygen generation by novel NIR BODIPY dyes

Samuel G Awuah1,2, [email protected], Youngjae You1,2. (1) Department of Chemistry and Biochemistry, University of Oklahoma, Oklahoma City, Oklahoma 73019, United States (2) Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73117, United States

Photodynamic therapy (PDT) is a non-invasive treatment modality widely used in the treatment of cancer. The mechanism of PDT relies on three elements namely: light, oxygen and a photosensitizer (drug). The photosensitizer should possess inherent properties to generate singlet oxygen upon light illumination – a cytotoxic agent. In this study, five novel near-infrared BODIPY dyes were synthesized for improved singlet oxygen generation using thiophene and bromine. Theoretical, optical, photostable and singlet oxygen generation characteristics of these dyes were accessed. Predicted excitation energies by TDDFT calculations were in good agreement (∆E ∼ 0.06 eV) with experimental data. All five dyes showed both excitation and emission in NIR range. In particular, two dyes having sulfur and bromine atoms showed efficient singlet oxygen generation with high photostability. The superior NIR absorption for deep tissue penetration and singlet oxygen generation of these dyes make them promising photosensitizers for use in PDT over clinical ones.

ORGN 71

Synthesis of unnatural amino acids with new function and their incorporation into proteins

Rajendra Uprety, [email protected], Chungjung Chou, Alexander Deiters. Department of Chemistry, North Carolina State University, Raleigh, NC 27695, United States

The complex nature of biological processes such as protein function and signaling pathways are regulated with high spatio-temporal control. The site-specific incorporation of unnatural amino acids (UAA) with unique functionalities such as caging groups, photo-reactive linkers and fluorescent probes into proteins is a powerful technology for the study of protein structure, dynamics, localization and biomolecular interactions in a real-time fashion. We report the development of efficient routes for the synthesis of a variety of unique unnatural amino acids based on the tyrosine and lysine core structure.

ORGN 72

Oxanorbornadiene derivatives as thiol-reactive degradable linkages for the release of molecular cargo Cody J Higginson, [email protected], Alexander A Kislukhin, Vu P Hong, M.G. Finn. Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, United States

7-oxanorbornadiene-2,3-dicarboxylates (ONDs) are easily prepared by Diels-Alder cycloaddition from furans and electron-deficient alkynes, often in a single high-yielding step. These linkers have recently been reported as potent and selective Michael acceptors toward thiol nucleophiles and have been used to label thiol-containing biomolecules. A unique feature of the resulting thiol conjugates is the tunable degradation by a retro-Diels-Alder reaction, the rate of which varies with the OND substitution pattern with half-lives ranging from hours to days under simulated physiological conditions. We have engaged this reactivity to directly label serum albumins in vitro with OND reagents bearing molecular cargos for exploration as drug carriers. The preparation and properties of albumin-OND-cargo conjugates and in vivo evaluation of payload release will be described.

ORGN 73

Investigation of pyrimidine adducts formed by the diazonium ion derived from the carcinogen N-nitrosomorpholine

Niti H Shah, [email protected], James C Fishbein. Department of Chemistry and Biochemistry, University of Maryland Baltimore County, Baltimore, Maryland 21250, United States

N-nitrosomorpholine (NMOR) is a potent carcinogen and mutagen that has been detected in tobacco products, ground water, various foods (dairy products, cured meat, alcoholic beverages), industry of tire, rubber and, leather. The metabolism of NMOR occurs by CYP450 enzymes predominantly through α-hydroxylation. The resulting α- hydroxynitrosomorpholine readily decomposes to a highly reactive diazonium ion which can alkylate DNA or react with solvent water producing 2-ethoxyacetaldehyde. Pyrimidines are alkylated to a significant extent by simple nitrosamines and in some cases subsequent AT to GC transition base substitutions have been observed. The spectrum of pyrimidine alkylation adducts of NMOR was studied. The proposed adduct standards were chemically synthesized, purified by HPLC and fully characterized using 2D NMR, UV-Vis and, HRMS. The results obtained may help in the determination of the sites which are critical for carcinogenesis by N-nitrosomorpholine.

ORGN 74

Carbon dioxide mediated stereoselective coupling of alkynes and thiols

Siti Nurhanna Riduan, [email protected], Yugen Zhang, Jackie Y. Ying. Institute Of Bioengineering and Nanotechnology, Singapore, Singapore 138669, Singapore

A simple procedure for the stereoselective coupling of terminal alkynes and thiols has been developed under carbon dioxide atmosphere. To the best of our knowledge, this is the first instance of determining stereoselectivity with carbon dioxide as the mediator. The reaction system is robust and utilizes inexpensive, readily available catalysts and substrates. Under the optimum reaction conditions, good to high yields and excellent stereoselecitvities are achieved for a broad range of aryl alkynes and thiols.

ORGN 75

Hypervalent iodine reagents in the green synthesis of bioactive compounds

Buchi Reddy Vaddula, [email protected], John Leazer, Rajender S Varma.Sustainable Technology Division, National Risk Management Research Laboratory, U.S. Environmental Protection Agency, Cincinnati, Ohio 45268, United States

Diaryliodonium salts, an important class of trivalent iodine reagents with two carbon ligands, are well known for their potential applications in photochemistry, organic chemistry and medicinal chemistry. The ability of diaryliodonium salts to form Cu(III) intermediates with Cu(I) catalysts in C-N cross coupling reactions pave the way for the rapid N-arylation of sulfoximines under eco-friendly conditions. The transformation was achieved by the reaction of sulfoximines with diaryliodonium salts in aqueous polyethylene glycol-400 with CuBr as the catalyst using ultrasound. The protocol was optimised by exploring different Cu(I) catalysts and green solvents (water, polyethylene glycol-400 etc.). The substrate scope, which was studied with various substituted sulfoximines and diaryliodonium salts, shows the generality of this procedure.

ORGN 76

Catalysis by gold(I) complexes encapsulated in a supramolecular host Zhan J. Wang, [email protected], Casey J. Brown, Robert G. Bergman, Kenneth N. Raymond, F. Dean Toste. Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, United States

Supramolecular host-guest chemistry has emerged as a promising method for performing organic transformations. We have used tetrahedral Ga4L6 clusters to encapsulation of a variety of gold(I)-phosphine complexes. The resulting complex readily catalyzes the intramolecular hydroalkoxylation of allenes in water and shows an 8-fold increase in catalytic activity relative to the unbound catalyst.

Furthermore, the hydroalkoxylation reaction with encapsulated gold catalysts can be employed in parallel with enzymatic processes. Preliminary results suggest that supramolecular encapsulation can prevent undesired interactions between gold and biological enzymes, preserving the activity of both catalysts.

ORGN 77

Borate-catalyzed kinetic resolution of terminal aziridines

Jennifer Cockrell, Christopher Wilhelmsen, Heather Rubin, Allen Martin, Jeremy B. Morgan, [email protected]. Department of Chemistry and Biochemistry, University of North Carolina Wilmington, Wilmington, NC 28403, United States

The ability to efficiently produce single enantiomer compounds has become a problem of increasing importance over the past few decades as the number of enantiopure pharmaceuticals has grown. Aziridines are reactive intermediates for the chemical synthesis of nitrogen-containing molecules; however, rapid access to enantiopure aziridines remains a synthetic challenge. The borate-catalyzed kinetic resolution of N- acylaziridines will be presented. Methods for utilization of the enantiopure aziridines in synthesis and the reaction mechanism will be examined.

ORGN 78

Iodide catalysed acylations by acid chlorides

Russell J Wakeham, [email protected], Jonathan M J Williams. Department of Chemistry, University of Bath, Bath, United Kingdom

Acylations of sulfonamides and amides are typically carried out by using acid chlorides and one equivalent of a strong base. Here we show initial studies into the use of lithium iodide as a catalyst for the coupling of acid chlorides to sulfonamides or amides to form the corresponding N-acyl product, eliminating the need for additional base.

ORGN 79

Synthesis and studies of novel NHC intermediates

Christopher J Collett1, [email protected], Richard S Massey2, Andrew D Smith1, AnnMarie C O'Donoghue2. (1) School of Chemistry, University of St Andrews, St Andrews, Fife KY16 9ST, United Kingdom (2) Department of Chemistry, University of Durham, Durham, United Kingdom

A range of novel NHC (N-heterocyclic carbene)-aldehyde adducts from the benzoin and Stetter reactions have been synthesised and studied in order to relate catalyst structure to activity. Studies on these compounds allow a correlation between stabilites and reactivites for a series of NHC precursors to be made.

ORGN 80 Squaric acid mediated bioconjugation: 20 years after

Tobias Steinbach1,2, Carsten Dingels2, Frederik Wurm1,2, [email protected]. (1) Institut des Matériaux and Institut des Sciences et Ingénierie Chimiques, Laboratoire des Polymères, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland (2) Institut für Organische und Makromolekulare Chemie, Johannes Gutenberg-Universität Mainz, Mainz, Germany

Squaric acid (SA) mediated coupling reactions are well-known since the early 1990s. We have developed novel strategies for the sequential amidation of SA diesters to generate glyco- and polymer-protein conjugates. The extraordinary hydrolytic stability of SA-esters and ester-amides and their selectivity to amine groups are the main features which make this protocol very attractive for selective protein conjugation. Investigations for protein PEGylation proved the selectivity for lysine residues without any side- reactions to other nucleophilic amino acids. The talk will also present novel water- soluble SA diesters and macromolecular building blocks based on SA which can be used for further coupling reactions.

ORGN 81

Preparation of allyl and vinyl silanes via the palladium catalyzed silylation of terminal olefins

Donald A Watson, [email protected], Jesse R McAtee, Sara E. S. Martin, Derek T Ahneman. Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19711, United States

A high-yielding protocol for the palladium-catalyzed silylation of terminal alkenes using silyl halides will be discussed. This method allows facile conversion of styrenes to E-b- silyl styrenes using either TMSI, or TMSCl with LiI. Terminal allyl silanes with good E:Z ratios are also readily accessed from a-olefins by this method. When combined with existing technology, this transformation provides a powerful strategy to selectively functionalize the vinyl or allylic position of terminal alkenes.

ORGN 82

Silanols and silanediols as hydrogen-bonding organocatalysts

Sean O Wilson, [email protected], Ngon T Tran, Annaliese K Franz. Department of Chemistry, University of California, Davis, Davis, CA 95616, United States

The search for small-molecule organocatalysts is valuable due to their non-toxic, inexpensive, and moisture/air stable properties with respect to metal-based catalysts. Hydrogen-bonding interactions play an important role for organocatalysis and molecular recognition based on the catalytic activity observed for thioureas and phosphoric acids. Silanols and silanediols are known for their strong hydrogen-bonding capabilities and are frequently used for analytical separations and heterogeneous catalysis. We have demonstrated the catalytic activity of discrete, organic silanediols in carbon-carbon bond forming reactions. Based on this activity, we are studying the mechanism and important role of cooperative hydrogen-bonding in these systems. Discussion will focus on the synthesis of silanols and silanediols as well as their application in the field of organocatalysis.

ORGN 83

Organophosphorus catalysis by in situ reduction of phosphine oxide

Henri A. van Kalkeren, [email protected], Floris P. J. T. Rutjes, Floris L. van Delft. Institute for Molecules and Materials, Radboud University Nijmegen, Nijmegen, The Netherlands

Several important reactions in organic chemistry thrive on stoichiometric formation of phosphine oxides from phosphines. To avoid the resulting burden of waste and purification, cyclic phosphine oxides were evaluated for new catalytic reactions based on in situ regeneration. Therefore, the ease of silane-mediated reduction of cyclic phosphine oxides was explored.

Dibenzophosphole oxides were found to be reducible under mild conditions and were selected for further applications in organophosphorus catalysis such as the catalytic Appel reaction and the Staudinger reduction.

ORGN 84

WITHDRAWN

ORGN 85

Novel routes to dihydropyridine systems

Ricardo Girling, [email protected], Andy Whiting. Department of Chemistry, Durham University, Durham, Durham DH1 3LE, United Kingdom

As part of a programme to examine new catalytic asymmetric routes to dihydropyridones of type 4, we were examining an alternative to the formal aza-Diels- Alder approach, i.e. via a direct route using enone derivatives 6 in place of dienes 2 by using a Mannich-Michael pathway.[1] This led to the discovery of two novel reactions: formal [2+2+2]- and [1+2+1+2]-cycloadditions to form dihydropyridine derivatives 7 and 8 respectively.

This presentation will discuss possible mechanisms and reasons for these different reactions. [1]Girling, P. R.; Kiyoi, T.; Whiting, A. Org. Biomol. Chem., 2011 , 96, 3105.

ORGN 86

Metal catalyzed enantioselective diethylzinc addition to enones using FAM and PFAM ligands

Ozdemir Dogan, [email protected]. Department of Chemistry, Middle East Technical University, Ankara, - 06800, Turkey

Asymmetric diethylzinc addition to enones have been carried out by using newly developed FAM (ferrocenyl aziridinyl methanol) and PFAM (phosphino ferrocenyl aziridinyl methanol) ligands. One of the FAM ligands formed the product in up to 96% yield and 80% ee. In the case of the PFAM ligand, the product was obtained in up to 96% yield and 92% ee. The results obtained from different substrates using both ligands will be presented in details.

ORGN 87

N-Hydroxymethyl group of α-amino aldehydes for two-step stereoselective synthesis of β–amino-α-hydroxy acid derivatives

Youngran Seo, [email protected], Hyeonjeong Kim, Young Gyu Kim. Department of Chemical and Biological Engineering, Seoul National University, Seoul, Republic of Korea

We have reported efficient and stereoselective synthetic methods for γ-amino-β-hydroxy acids, which utilize the N-hydroxymethyl group attached to α-amino aldehydes as an internal nucleophile in the intramolecular conjugate addition. Some biologically active natural products such as (-)-statin, 3-aminodeoxystatine and threo-β-hydroxyglutamic acid have been successfully synthesized via the intramolecular conjugate addition between the N-tethered hydroxymethyl group and the unsaturated ester of γ-amino-α,β- unsaturated esters.

As an extension of the above method, effective synthesis of β-amino-α-hydroxy acids has been studied because they are more frequently found in biologically active natural products. For example, a mitotic inhibitor paclitaxel, an immune response modifier bestatin, and an aminopeptidase inhibitor amastatin have the β-amino-α-hydroxy acid unit as a key pharmacophore. The nitroolefin functionality is chosen as a carboxylic acid equivalent as well as a Michael acceptor. A cascade reaction involving the Henry reaction, the nitroolefin formation and the intramolecular conjugate addition produced the nitromethyl intermediates I effectively and with excellent stereoselectivity. Further oxidation of I gave the desired β-amino-a-hydroxy acids derivatives in two steps with 65- 72% yields from a-amino aldehydes II.

ORGN 88

Catalytic enantioselective synthesis of 3-hydroxy-2-oxindoles and 3-spirocyclic-2- oxindoles

Nadine V. Hanhan, [email protected], Nicolas R. Ball-Jones, Annaliese K Franz. Department of Chemistry, University of California, Davis, Davis, California 95616, United States

Here we describe the development of synthetic methods for direct and efficient enantioselective additions of diverse nucleophiles to isatins, including the first asymmetric indole addition to isatins and also the first catalytic asymmetric [3+2] allylsilane annulation reaction. These methods provide access to highly enantiomerically enriched 3-substituted-3-hydroxy-2-oxindoles, and 3-spirocyclic-2-oxindoles that are potential pharmaceutical leads or backbones of natural products. These catalytic methods utilize either neutral or cationic scandium (III)-pybox complexes with catalyst loading as low as 1 mol% to obtain oxindole products of up to 99% yield and up to 99% ee. Investigation of the effects of various chiral Lewis acid catalysts, counterions, additives, temperatures, solvents, and substrates will be discussed.

ORGN 89

Metal-catalyzed enantioselective additions to oxocarbenium ions

Mary P. Watson, [email protected], Prantik Maity, Harathi D. Srinivas. Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, United States

We have developed an enantioselective, copper(I)-catalyzed alkynylation of racemic isochroman and chromene acetals. This method is one of the first transition metal- catalyzed approaches to enantioselective additions to prochiral, cyclic oxocarbenium ions. In these reactions, Lewis acid is used to form the oxocarbenium ion under conditions compatible with formation of the copper acetylide. By using a bis(oxazoline) ligand, good yields and enantioselectivities were observed for a variety of alkynylethers. Our working mechanistic proposal and model for enantioinduction will also be presented.

ORGN 90

Metal catalysed asymmetric hydrogenation reactions

Katherine E Jolley, [email protected], Martin Wills. Department of Chemistry, University of Warwick, Coventry, West Midlands CV4 7AL, United Kingdom

This talk will feature aspects of metal catalysed asymmetric hydrogenation reactions for ketones including: i) Use of KOtBu with tetradentate ligands for hydrogenation.1 ii) Iron-based catalysts with novel ligands for asymmetric transfer hydrogenation.2 iii) Use of tethered ruthenium catalysts for asymmetric hydrogenation.3

Related references:

1) Walling, C. and Bollyky, L., J. Am. Chem. Soc. 1964, 86 , 3750-3752.

2) Morris, R. H., Chem. Soc. Rev. 2009, 38 , 2282-2291. 3) Soni, R., Collinson, J-M., Clarkson, G. C. and Wills, M., Org. Lett. 2011, 13 , 4303- 4307.

ORGN 91

N-Prolinylanthranilamide pseudopeptides as bifunctional organocatalysts for asymmetric aldol reactions

Santanu Panda, [email protected], Anthony J. Pearson. Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, United States

Organocatalysis is currently one of the most rapidly growing areas of organic synthesis research, and one entire recent issue of Chemical Reviews was devoted to this topic.1 We recently reported the use of N-prolinylanthranilic acids,2 which are very effective catalysts for aldol reactions of cyclic ketones with aromatic aldehydes, in most cases giving >95% ee. However, for aldol reactions of acetone those catalysts were marginally better than proline itself (80% vs 75% ee). Consequently, we examined modifications of this system in which the anthranilic carboxyl terminus is modified by attaching an additional amino acid to create a pseudotripeptide. We anticipated that such a structure would show a preferred conformation that results from intramolecular hydrogen bonding as shown Figure 1a. Proline anthranilamide-based pseudopeptides were shown to be effective organocatalysts for enantioselective direct aldol reactions of a selection of aldehydes with various ketones with excellent yield, enantioselectivity up to 99% and anti to syn diastereoselectivity up to 25:1(Figure 1b).3 Further progress on the catalyst system will be reported in this presentation.

1) List, B., Ed. Chem. Rev. 2007 , 107(12), 5413-5883.

2) Pearson, A. J.; Panda, S. Tetrahedron 2011 , 67, 3969.

3) Pearson, A. J.; Panda, S. Org. Lett. 2011 , ASAP

ORGN 92

Structure-selectivity relationships in asymmetric carbonyl propargylation via iridium catalyzed coupling of 1,3-enynes and alcohols Laina M. Geary, [email protected], Michael J. Krische. Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712, United States

Homopropargylic alcohols are very useful and versatile intermediates in modern organic synthesis. It is not surprising then that there have been several methods developed for the synthesis of these compounds. Despite decades of research, asymmetric propargylation not only relies heavily on stoichiometric metals and/or organometals, but few systems have been optimized for good selectivity and the substrate scope remains narrow. In contrast, we have recently developed a method of carbonyl propargylation that utilizes hydrogen transfer to couple alcohols and 1,3-enynes in the presence of catalytic amounts of iridium. Similarly, aldehydes and enynes may also be coupled in the presence of formic acid as the hydrogen source. Homopropargyl alcohols have been assembled in these manners with both high diastereo- and enantioselectivies from simple and inexpensive materials. The results of these studies, as well as the relationship between substrate and ligand structures and selectivity will be presented.

ORGN 93

Pd-catalyzed conjugate additions: Formation of asymmetric all-carbon quaternary centers and addition of aryl halides to enones

Aditya L Gottumukkala1, [email protected], Adriaan J Minnaard1, Johannes G de Vries1,2. (1) Stratingh Institute for Chemistry, University of Groningen, Groningen, Groningen 9747 AG, The Netherlands (2) DSM Innovative Synthesis BV, Geleen, The Netherlands

Conjugate addition reactions are a convenient route to stereoselective carbon-carbon formation. Palladium catalyzed conjugate addition is becoming an increasingly popular method to this end, owing to mild reactions condtions, good selectivities and facile manipulation of reactants.

In this oral communication, two advances are presented. The first deals with the challenging asymmetric all-carbon quaternary stereocenter formation, by conjugate addition of arylboronic acids. The catalyst can be conveniently synthesized from PdCl2 and commercially available bisoxazoline ligands. This catalyst (1 ) affords quaternary all-carbon stereocenters in up to 99% ee and 97% yield (Scheme1) for a variety of substrates. The approach has been successfully exploited in the synthesis of enantiopure α – cuparenone in two steps from 3-methyl-cyclopentenone, which represents the shortest-synthesis-to-date of this natural product, which bears two vicinal quaternary centers. In the second part, the conjugate addition of aryl halides to enones is described. Conventionally, organometallics such as Grignard reagents, organozinc or organoboron reagents are employed for this purpose, which in turn are obtained from the corresponding halides. Herein, we discuss a novel catalyst system that allows the selective conjugate addition of iodoarenes to enones. Using only 1.5 mol% of a commerically available Pd-N-Heterocyclic carbene catalyst, conjugate addition of aryl iodides was achieved for a variety of cylic, linear and subsitituted enones(Scheme2). Furthermore it has been demonstrated that these reactions can be performed diastereoselectively, and under microwave-irradiation without the loss of selectivity or yield.

ORGN 94

NHCs in organocatalysis: Recent advances of d2 enolate synthons

James J Douglas, [email protected], Andrew Smith. Department of Chemistry, University of St Andrews, St Andrews, Fife KY16 9ST, United Kingdom

Since its recent birth organocatalysis has grown to become one of the most desirable methods for the expedient synthesis of complex functionality. Within this field N- Heterocyclic carbenes (NHCs) are recognised to promote a range of diverse reaction types. This talk summarises recent advances in the applications of d2 enolate synthons, generated via addition of NHCs to ketenes.

ORGN 95

Harnessing the power of chirality transfer in oxindole synthesis Edward Richmond, [email protected], Andrew D Smith. Department of Chemistry, University of St Andrews, St Andrews, Fife KY16 9ST, United Kingdom

An efficient, enantioselective route to 3,3-disubstituted oxindoles from chiral nitrones (e.g. 1 ) and disubstituted ketenes (2 ) has been developed, allowing access to an array of acyclic 3,3-oxindole species (3a ) and oxindoles bearing an asymmetric spirocyclic quaternary centre (3b ) with excellent enantiocontrol (up to 99% ee).

ORGN 96

Asymmetric organocatalysis using N-heterocyclic carbenes

Stuart M Leckie, [email protected], Andrew D Smith. Department of Chemistry, University of St Andrews, St Andrews, Fife KY16 9ST, United Kingdom

This talk will describe the use of NHCs as organocatalysts. NHC 1 , formed by the deprotonation of the corresponding triazolium salt, can add to alkylarylketenes to form azolium enolates (2 ). These enolates can be trapped by a range of β,γ-unsaturated-α- keto-acceptors (3 ) to give the corresponding dihydropyranones with the diastereoselectivity determined by the nature of the γ-substituent. A range of derivatisation strategies for these dihydropyranones will also be presented.

ORGN 97

Preparation of chiral propargyl and homopropargyl alcohols via Nozaki-Hiyama type reactions mediated by chromium complexes of TBOx family

Dmitry L. Usanov, [email protected], Hisashi Yamamoto. Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, United States The interesting yet poorly discovered potential of the cis-β geometry of chiral metal complexes in asymmetric catalysis has been exemplified by new entries in chromium- mediated chemistry; the derivatives of TBOx ligand have been successfully used in asymmetric Nozaki-Hiyama propargylation of aldehydes, which allowed preparation of a range of homopropargyl alcohols with up to 93% ee. A novel partially reduced H8-TBOx ligand was developed, which appeared to be superior to the parent system in the context of enantiocontrol. Compromise of enantioselectivity associated with the background process was detected, which was successfully overcome by the introduction of cobalt porphine co-catalysts (conventional cobalt additives appeared inefficient). TBOxCrCl was also used in the first example of enantioselective alkynylation of aldehydes with iodo- and bromoacetylenes (with cobalt co-catalysis being beneficial for the latter group of substrates). A range of propargyl alcohols were obtained with up to 92% ee.

ORGN 98

Light controls light: An organic optical transistor operated under ambient conditions

Martti Pärs1, [email protected], Christiane C. Hofmann1, Katja Willinger2, Peter Bauer2, Mukundan Thelakkat2, Jürgen Köhler1. (1) Department of Experimental Physics IV, University of Bayreuth, Bayreuth, Germany (2) Department of Applied Functional Polymers, University of Bayreuth, Bayreuth, Germany

An optical transistor is a device that is operated with photons instead of electrons as signal carriers. Recently we demonstrated that the key functionalities of an optical transistor, i.e gating and amplification can be accomplished by a molecular triad (figure left) that consists of a photochromic unit (dithienylcyclopentene, DCP) and two highly efficient fluorophores (perylenebisimide, PBI). While the DCP unit can be reversibly interconverted between two bistable forms by light, the fluorescence intensity of the PBI shows a strong modulation as a function of the state of the DCP (figure right). Hence light controls light. In the presentation we will discuss the performance of the triad from the viewpoint of an optical transistor.

Reference:

M. Pärs, C. C. Hofmann, K. Willinger, P. Bauer, M. Thelakkat, J. Köhler, Angew. Chem. Int. Ed. 2011, 50, DOI: 10.1002/anie.201104193 (online) ORGN 99

Benzodithiophene semiconducting polymers for organic solar cells

Mihaela C Stefan1, [email protected], Prakash Sista1, Ruvini Kularatne1, Michael C Biewer1, Paul Dastoor2, Mitchell Wilson2, Natalie Holmes2, Warwick Belcher2. (1) Chemistry, University of Texas at Dallas, Richardson, TX 75080, United States (2) Centre For Organic Electronics, The University of Newcastle, Callaghan, Australia

The synthesis and opto-electronic properties of homopolymer and alternating copolymers of benzodithiophene with decyl phenylethynyl substituents are reported. The introduction of thiophene, bithiophene, and terthiophene spacers into alternating copolymers allowed the systematic variation of the spacing between the decyl substituents of benzodithiophene. The influence of spacing between the decyl substituents on the performance of bulk heterojunction solar cells with PCBM is investigated.

ORGN 100

Versatile and tunable thieno[3,4-b]pyrazine-based terthiophenes as polymeric precursors

Ryan L Schwiderski, [email protected], Jon P Nietfeld, Seth C Rasmussen. Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 58108, United States

Polythiophene-based polymers have been shown to be highly versatile and allow the ability to tune their physical, electronic and optical properties at the molecular level, allowing their application to a variety of technological devices. This research group has previously demonstrated the tunability of thieno[3,4-b]pyrazine monomers as a function of side chain functionality and their initial applications to thieno[3,4-b]pyrazine-based, low band gap materials. This approach has now been expanded to include synthetic routes for new terthiophenes utilizing central 2,3-dibromo- and 2,3- bis(bromomethyl)thieno[3,4-b]pyrazine units as common precursors to families of thieno[3,4-b]pyrazine-based terthienyls. Synthetic details for the preparation of these precursors and their optical and electronic characterization will be presented to illustrate the extent in which choice of side chains can dictate HOMO and LUMO energy levels. Initial incorporation of these new terthienyls into copolymeric materials will also be presented to illustrate potential tuning in the resultant polymeric systems.

ORGN 101

Synthesis of a novel "meso" molecular motor and prediction of its rotational behavior by DFT Jos CM Kistemaker, [email protected], Johan Visser, Ben L Feringa.Stratingh Institute for Chemistry, University of Groningen, Groningen, Groningen 9747AG, The Netherlands

A wide variety of chiral molecular motors has been developed for the purpose of nanoscale devices. These devices have been able to induce the movement of objects a hundred thousand times their size. However, unidirectional movement under ambient conditions of this new class of nanomotors still has to be proven.

Here we present a novel type of 'meso' molecular motors that are designed to function as a unidirectional molecular walker. These 3rd generation molecular motors were synthesized and their behavior was investigated. In a theoretical study their rotational behavior was studied and the effect of various substitution patterns investigated. In this presentation a combined theoretical/experimental study will be presented.

ORGN 102

Supramolecular ss-DNA templated assemblies of new photochemical switches

Paula de Mendoza, [email protected], Ben L. Feringa.Synthetic Organic Chemistry, Rijksuniversiteit Groningen, Groningen, Groningen 9747 AG, The Netherlands

Dynamic self-assembly processes are essential for the organization of functional organic molecules and a variety of other phenomena in nature.[1] The design of new dynamic molecular switches in which supramolecular assembly together with essential electronic functions can be triggered by an external signal, is a major challenge for the development of new artificial systems and the construction of electronic nano-devices following a bottom-up approach.

Recently, several examples have been reported in which single-strand DNA acts as a template for the organization of p-conjugated organic molecules via hydrogen bonding.[2] Here we present several synthetic approaches for the preparation of dithienylethene switches incorporating nucleotide base pair moieties and their supramolecular organization in the presence of a DNA-template. Moreover, the transfer of chirality from the oligonucleotide-template to the photochemical switch will be discussed.

[1] Lehn, J.-M. Supramolecular Chemistry: Concepts and Perspectives; VCH: Weinheim, 1995

[2] Ruiz-Carretero, A.; Janssen, P. G. A.; Kaeser, A; Schenning, A. P. H. J. Chem. Commun. 2011 , 47, 4340-4347.

ORGN 103 Photoinduced amplification of chirality in the gel state

Derk Jan van Dijken, [email protected], John M. Beierle, Wesley R. Browne, Ben L. Feringa.Synthetic Organic Chemistry, Rijksuniversiteit Groningen, Groningen, Groningen 9747 AG, The Netherlands

In nature, important molecular processes such as replication, enzyme catalysis and communication rely on the balance between supramolecular and molecular chirality and their interplay. For the design of nanostructured materials, such as sensors and memory systems, controlling chirality at different hierarchical levels by an external source is of major importance.[1] In this context, chiral self-assembling optical molecular switches offer great opportunities because both molecular and supramolecular chirality are addressable by light.[2]

Recently, chiral dithienylethene molecules that exert nearly absolute stereocontrol upon irradiation with light in the gel state have been reported.[3] Here we present a molecular system based on a dithienylethene photochromic 'open' switch and its diastereomerically pure 'closed' analogue. The closed analogue amplifies the chirality of its own formation upon photochemical ring closing of the open switch by acting as a chiral template in a supramolecular assembly

[1] Lehn, J.-M. Science, 2002 , 295, 2400

[2] Feringa, B.L., Ed., Molecular Switches (Wiley, Weinheim, Germany, 2001 )

[3] de Jong, J.J.D.; Lucas, L.N.; Kellogg, R.M.; van Esch, J.H. and Feringa, B.L. Science 2004 , 304, 278

ORGN 104

Developing a smart surface based on a photo- and electroactive dithienylethene switch

Hella Logtenberg, [email protected], Paula de Mendoza, Jasper van der Velde, Jetsuda Areephong, Ben L. Feringa, Wesley R. Browne. Department of Synthetic Organic Chemistry, University of Groningen, Groningen, Groningen 9747 AG, The Netherlands

Here we report the synthesis and electropolymerization of a dithienylethene containing monomeric unit, used to make a switchable surface. The system is based on the diarylethene photochromic switches, which show excellent electrochromism and photochromism.

Using a phenyl spacer allows the dithiophene polymerizable unit and dithienylethene switch unit to function independently. Thick polymer layers are formed on several electrode surfaces by electropolymerization. Switching between open and closed forms of the photochromic unit alters the conductivity of the polymer film.

ORGN 105

Towards applications of carborane-containing conjugated polymers

Andrew R Davis, [email protected], Joseph J Peterson, Kenneth R Carter. Department of Polymer Science and Engineering, University of Massachusetts, Amherst, MA 01003, United States

Icosohedral carboranes (C2B10H12) have been under investigation for a number of years due to a number of factors including their thermal and chemical stability, unusual geometry, interesting electronics, and high neutron capture cross-section. Recently, incorporation of carboranes into conjugated polymers has revealed interesting effects on optoelectronic behavior. In particular, ortho-carborane has led to aggregation induced emission whereby the photoluminescent properties of the carborane-containing polymer are enhanced in both intensity and and efficiency when in aggregation regimes (i.e., solid state or poor solvent). There has been little work in adapting these unique properties to application-based studies of carborane-containing conjugated polymers. Here we show newly observed solvochromatic behavior of carborane-containing poly(fluorene)s in which thin films of the polymers display characteristic shifts in photoluminescence when exposed to common solvent vapors. Additionally, certain amine vapors were found to completely quench polymer emission. The effects of carborane incorporation on electronic polymer device behavior were also investigated.

ORGN 106

Synthesis, characterization, and solvent-independent photochromism of spironaphthooxazine dimers

Davita L. Watkins, [email protected], Tomoko Fujiwara. Department of Chemistry, University of Memphis, Memphis, TN 38152, United States The use of spirooxazine based materials has become of increasing interest due to their excellent photostability, compatibility in a variety of matices, and distinctive changes in structure and absorption spectra upon irradiation. In this work, the synthesis, photochromism, and application of conjugated spirooxazine dimers are discussed. The two spirooxazine monomers are connected so that the structure produced has a fixed angle between the two monomers therefore acting as an ionic cavity for interactions with guest molecules. The photochromic reactions of the dimers are studied under continuous UV irradiation in solvents of different polarity. The photomerocyanine isomers show positive solvatochromism. The thermal closing rate at 25oC varied depending on the compound and solvent. To effectively utilize photochromic properties, dimers were coupled onto varying polymeric substrates. Preliminary results of the photo-switchable surfaces indicate potential use as stimuli responsive materials for selective recognition

ORGN 107

Intramolecular charge transfer in symmetrical BODIPY dyads

Kathryn Allen, [email protected], Sean Roberts, Sarah Conron, Matthew Whited, Niral Patel, Peter Djurovich, Stephen Bradforth, Mark Thompson. Chemistry, University of Southern California, Los Angeles, CA 90089, United States

Symmetry breaking intramolecular charge transfer (ICT) that is stabilized in polar environments has been observed in systems ranging from the photosynthetic reaction center to 9,9'-bianthracene. The ability to charge transfer is important for high efficiency photovoltaic (PV) devices, making ICT systems interesting candidates for understanding and improving PV performance. Unfortunately, due to its absorption profile, 9,9'- bianthracene is not suitable for solar applications. However, boron-dipyrromethenes (BODIPYs) are excellent fluorescent dyes, strongly absorbing visible light. We describe the synthesis of symmetrical BODIPY dimers linked at the meso positions with various functionalities at the 3,5-, 2,6- and/or 1,7- positions. The photophysical analysis of these dyads reveals solvent dependent ICT similar to that observed in 9,9'-bianthracene. Varying the substitution of the dyads positively or negatively affects the ICT and is evidenced by a change in the emission and transient absorption properties. The properties of these dyads as thin films will also be presented.

ORGN 108

Smart biphenyl lactone containing a nitro acceptor and methoxy donor capable of pH-driven dihedral angle switching

Asia M Riel, [email protected], Bart J Dahl. Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, WI 54702, United States

Biphenyl has a solution-phase equilibrium dihedral angle of 30-40°. Although biphenyl achieves excellent extended conjugation when planar, the steric hinderance of the ortho hydrogens prevents this geometry from being an energetic minimum. The dihedral angle of biphenyl-containing compounds greatly affects physical properties such as electronic absorption, emission, and conductance. Most biphenyl-containing compounds have a fixed dihedral angle and thus fixed physical properties. However, we have synthesized a reversible lactone “tether” between the two rings that should force a planar geometry. This “smart” biphenyl lactone contains a methoxy donor and a nitro acceptor at the 4 and 4' positions to affect charge transfer through the ring system. By varying the pH, we can reversibly open and close the lactone which should switch the molecule in and out of planarity. The design, synthesis and characterization of this “smart” biphenyl will be presented.

ORGN 109

Synthesis and study of methoxy‐donor cyano‐acceptor biphenyl and terphenyl lactones

Erick J Carlson, [email protected], Bart J Dahl. Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, WI 54702, United States

The goal of this project is to explore methoxy-donor/cyano-acceptor arenes capable of dihedral angle modification through a reversible tethered lactone bridge. These compounds can exist in two states: open and planar. In the open state, pi-orbital overlap is minimized due to an increased dihedral angle. However, the substantial pi-orbital overlap when the tether is closed enhances some properties including conductance, quantum yield and UV-vis absorption. An efficient switching mechanism must be implemented to survey these changes. The compounds should switch conformation based on pH with the open conformation prevailing at alkaline pH, and the closed conformation at acidic pH. The overall goals of the research described are: The synthesis of the ring-closed donor-acceptor compounds, the determination of the efficacy of pH as a means to switch between the two conformations, and the detection of a unique UV-vis or fluorescence signal associated with each state.

ORGN 110

Synthesis and characterization of N-functionalized dibenzothieno[3,2-b:2',3'- d]pyrroles

Rylan Wolfe, [email protected], Sean J Evenson, Seth C Rasmussen. Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 58108, United States

Conjugated materials are of special interest due to the control over their electronic properties through synthetic modifications at the molecular level. Materials incorporated fused-ring dithieno[3,2-b:2',3'-d]pyrroles (DTPs) have been previously investigated by our group and shown to have interesting properties applicable to OLEDs and OPVs. A new class of DTP analogues incorporating additional fused rings has been synthesized from benzo[b]thiophene. Enhanced conjugation and greater pi-stacking interactions are expected due to increased backbone planarity. Further modifications can be made through multiple N-functionalized side chains, including aryl, alkyl, or acyl groups. Synthetic methods, as well as structural and electronic characterization, will be reported.

ORGN 111

Applications of dithieno[3,2-b:2',3'-d]pyrroles and its analogs to conjugated materials

Casey B McCausland, [email protected], Sean J Evenson, Seth C Rasmussen. Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 58108, United States

Interest in conjugated polymers has been growing in recent years due to their unique ability to adjust their optical and electronic properties at the molecular level, as well their potential ease of manufacture in electrical devices. A main axis of research in our lab has been the development of a class of polythiophenes utilizing fused-ring dithieno[3,2- b:2',3'-d]pyrroles (DTPs). Through work in our laboratory and others, DTP-based materials have been shown to give high carrier mobilities, enhanced fluorescence, and reduced or low band gaps. Recent work has shown that the addition of an electron- withdrawing N-acyl group affords stabilization of the DTP HOMO and LUMO. Using DTP as a template, we are currently investigating additional related analogues to explore the relation between structure and electronic properties. The synthesis, characterization and material applications of DTPs and related analogues analogs will be presented.

ORGN 112

Synthesis of dithieno[3,2-b:2'3'-d]pyrrole-based poly(arylenevinylene) materials

Dillon T Hofsommer, [email protected], Sean J Evenson, Seth C Rasmussen. Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 58108, United States

Polythiophenes are a class of conjugated polymers having good environmental stability which, due to their ease of synthetic modification, are thought to be one of the most versatile of this class of polymers. A class of modified polythiophene materials utilizing dithieno[3,2-b:2',3'-d]pyrroles (DTPs) have been shown to exhibit improved electronic and optical properties in comparison to poly(3-alkylthiophene)s. The addition of ethylene units to the polymer backbone has been shown to be a successful approach to the lowering of the polymer band gap, and thus efforts to combine this approach with our previous application of the fused-ring DTPs is a current goal. The synthesis and characterization of DTP-based arylenevinylene polymers will be presented. ORGN 113

Redox-controlled gating of a water soluble hemicarcerand

Kendall N. Houk, Roger C Helgeson, Amy E Hayden, Fang Liu, [email protected]. Department of Chemistry and Biochemistry, University of California, Los Angeles, LOS ANGELES, CA 90095, United States

We designed and synthesized water soluble gated hemicarcerands in which the complexation and release of guests is controlled by disulfide-dithiol interchange.

We also applied computational methods to predict the rates of guest binding and release in open and closed forms as well as intrinsic binding energies that were used to select the most promising candidates for experimental study. Our decomplexation experiment showed that the “disulfide gate” opening depends upon added thiol concentrations. This implies that if applied as an anticancer-drug-carrier, the water- soluble redox-gated hemicarcerand could selectively release the drug in cancerous tissue due to the fact that the glutathione (GSH) concentration in human cancer cells is often two to five times higher than that in normal cells. Increasing the size of the cavity of a water soluble hemicarcerand may lead to encapsulation of small therapeutic peptides.

ORGN 114

Metal chelating crosslinkers and their application in hydrogels and hydrogel nanoparticles for non-invasive imaging Minnie Chan, [email protected], Jagadis Sankaranarayanan.Skaggs School of Pharmacy and Pharmaceutical Science, University of California San Diego, San Diego, California 92122, United States

We have developed a hydrogel based delivery systems that can be traced non- invasively in vivo by Magnetic Resonance Imaging (MRI). This was accomplished with a metal chelating crosslinker to form hydrogels that are able to form both bulk hydrogels as well as hydrogel nanoparticles. When chelated with Gadolinium (Gd), these gels become active MRI contrast agents, and enjoy a high relaxivity that can be altered through different crosslinking densities. Gd and Eu (Europium), a luminescent lanthanide, can also be concurrently chelated, giving these nanogels dual modality imaging properties. Hydrogel nanoparticles can also function as theranostic delivery vehicles when formulated to contain biomolecules. Incorporation of an acid-degradable crosslinker allows for release of these contained biomolecules. We are investigating the in vivo applications of these gel systems as trackable imaging systems and non- invasive monitoring of gel integrity.

ORGN 115

Emission spectroscopy as a tool to study the dynamics of spiropyran photochromism in the ionic liquid [BMIM][BF4]

Robyn M. Gaudet, Anne A. Leslie, Sean P. Naughton, Amy E. Keirstead, [email protected]. Department of Chemistry and Physics, University of New England, Biddeford, ME 04005, United States

Ionic liquids continue to be an intriguing medium in which to study the function and dynamics of switches, sensors, and other molecular electronic devices. Spiropyrans are particularly interesting, as the dynamics of their photochromism could be strongly affected by the viscosity of the solvent as well as electrostatic interactions between the spiropyran and the ionic medium. In this work, emission spectroscopy was used to study spiropyran photochromism in the ionic liquid [BMIM][BF4]. In addition to the expected fluorescence from the merocyanine (open) form, phosphorescence from the spiro (closed) form was observed. This is the first known example of spiropyran phosphorescence in ionic liquids, and suggests that the ring-opening reaction is slowed in the ionic liquid compared to traditional solvents such that phosphorescence becomes competitive with the ring-opening process. This type of two-color emission could find applications in molecular switches or devices where two measurable outputs are desired.

ORGN 116

Visualization of the rotary motion of a molecular motor

Jiawen Chen, [email protected], Ben L. Feringa.Stratingh Institute for Chemistry, University of Groningen, Groningen, The Netherlands Nature has many nanoscale molecular motors. The direct observation of rotary motion of F1-ATP synthase has been achieved. However, visualizing rotation of a synthetic molecular motor remains a major challenge.

Here we describe a highly functionalized light-driven molecular motor. The stator can be attached to a surface and the rotor is connected via a long rigid arm to a fluorescent group that is used for visualization.

ORGN 117

Synthesis of host and guest molecules for knot preparation using the thread-link- cut method

Elizabeth A Margolis, [email protected], Stephen D Lockey, Rebecca J Keyes, Edward E Fenlon. Department of Chemistry, Franklin and Marshall College, Lancaster, Pennsylvania 17604, United States

This research involves synthesizing a small trefoil knot and the first ever small-molecule Figure Eight knot. Our Thread-Link-Cut (T-L-C) approach involves an electron-rich host molecule binding an electron-poor guest molecule(s). Synthetic progress towards several Guests will be presented. One Guest (1 ) has been successfully synthesized in five steps (32%). Synthesis of the first generation Host (2 , R= H) will be discussed. Second generation Hosts contain solubilizing groups (R) to aid T-L-C experiments.

ORGN 118

High-contrast reversible fluorescence photoswitching of dye-crosslinked dendritic nanoclusters in living systems

Yoonkyung Kim, [email protected], Hye-youn Jung, Yun Hui Choe.Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea The diarylethene derivative, known as one of the most efficient photochromic species for reversible photoswitching, has been used in the reversible quenching of the fluorescence of a fluorophore through FRET. Here, we synthesized a biocompatible reversible photoswitch by oligomerizing the dendrimers with a diarylethene derivative (FRET acceptor) as a crosslinker, followed by the attachment of a fluorophore (FRET donor). The fluorescence of these dendritic nanoclusters inside the living cells and zebrafish was switched off and on by alternate irradiation with UV and visible light, respectively. Interestingly, of the two surface modifications applied (anionic vs. neutral) to enhance the biocompatibility, the nanocluster with a neutral surface showed higher cell viability, superior cellular uptake, and higher on-off contrast (up to 19 folds) in photoswitching. We envision that our relatively nontoxic dendritic nanoclusters may facilitate fluorescence imaging in living systems by enhancing its resolution through the reversibly controlled exhibition of high on-off contrast.

ORGN 119

3-Nitro-7a,15-methanonaphth[1',2':6,7][1,3]oxazepino[3,2-a]indoles as new ultrafast photochromic switches

Greta Ragaite1, Vytas Martynaitis1, Kipras Redeckas2, Mikas Vengris2, Algirdas Sackus1, [email protected]. (1) Department of Organic Chemistry, Kaunas University of Technology, Kaunas, Lithuania (2) Department of Quantum Electronics, Vilnius University, Vilnius, Lithuania

Organic photochromic compounds have attracted significant attention for their potential applications in optoelectronic devices such as photoinduced molecular switches.

We designed new ultrafast molecular switches by the transformation of spiro[indole-2,3'- naphth[2,1-b]pyrans] 1 to the compounds cis/trans-2 , possessing the rigid bridged naphth[1',2':6,7[1,3]oxazepino[3,2-a]indole ring system.

Nanosecond flash-photolysis measurements on a new type of photochromic molecules 2 have been performed. Irradiation of 2 solutions in acetonitrile with nanosecond laser pulses (355 nm wavelength) has yielded a cleavage of the C-O bond and subsequent formation of the 6-nitro-2-naphtholate chromophores 3 (absorption peaks at 430 and 515 nm), which reverted back thermally to their initial state 2 within tens of nanoseconds.

ORGN 120 Tuning of charge balance in bipolar host materials for highly efficient solution- processed phosphorescent devices

Wei Jiang1, [email protected], Yong Qiu2. (1) School of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu 211189, China (2) Key Lab of Organic Optoelectronics and Molecular Engineering of Ministry of Education, Department of Chemistry, Tsinghua University, Beijing, China

A novel bipolar host material, which meets the requirements of high triplet energy, good charge carrier transport properties, high solubility, and film-forming ability at the same time, has been designed and synthesized.

Utilizing a new compound as host material, high-efficiency solution-processed blue and white phosphorescent organic light-emitting diodes (PHOLEDs) have been achieved.

ORGN 121

Synthesis and characterization of a novel alkyl main chain pendant biphenyl carbazole and triphenylamine unit as host for polymer light emitting diodes

Ching-Nan Chuang1, [email protected], Man-kit Leung1,3, Kuo-Huang Hsieh2,1. (1) Institute of Polymer Science and Engineering, National Taiwan University, Taipei, Taiwan 106, Taiwan Republic of China (2) Department of Chemical Engineering, National Taiwan University, Taipei, Taiwan 106, Taiwan Republic of China (3) Department of Chemistry, National Taiwan University, Taipei, Taiwan 106, Taiwan Republic of China

Three novel vinyl polymers, containing pendant carbazole and triphenylamine chromophores attached with diphenyl group, were synthesized by radical polymerization to investigate the optoelectronic properties

. The new polymers showed wide band gaps (3.17-3.20 eV) and had good thermal stabilities. Three new polymers were studied as electrophosphorescent host materials in PLED devices. Electrophosphorescent devices with the configuration of ITO/PEDOT:PSS/polymers:Ir(ppy)3:PBD/Mg/Ag were fabricated. The polymer SCzCz based device showed a maximum current efficiency of 17.5 cd/A and maximum brightness of 15800 cd/m2. When we blended with different ratios of electron transport materials (TRZ and PBD) in the same system, the brightness was enhanced to 23400 cd/m2, and the maximum efficiency of 12.3 cd/A.

ORGN 122

Synthesis of 5,15-meso π-extended porphyrins for surface adsorption studies

Mothi M Ebrahim1, [email protected], Mathias O Senge1, Attilio A Cafolla2. (1) School of Chemistry, Trinity College Dublin, Dublin, Ireland (2) School of Physical Sciences, Dublin City University, Dublin, Ireland

Molecular self assembly of porphyrins on surfaces has been a subject of intense research activity not only for their technological value but also for their fundamental implications. These surface-supported systems represent a promising class of materials for applications in nanopatterning, surface templating, molecular data storage, quantum computing, solar cells, sensors etc. 5,15-A2B2-type porphyrins flanked on both sides by long π-conjugated arms are attractive class of target compounds. Bromination of free meso positions in 5,15-diarylporphyrins followed by transition metal catalyzed C-C bond forming reactions provide rapid access to such hugely π-conjugated molecular systems with potential applications in molecular electronics.

ORGN 123

Formation of poly(isopropyl glycolide) stereocomplexes

Georgina A Comiskey, [email protected] of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States

Polylactide stereocomplexes and their properties have been widely explored throughout the years. It is known that the melting temperaure (Tm) of the stereocomplex is higher than the homopolymer Tm. However, stereocomplexes of poly(isopropyl glycolide) have not been explored. Herein we report the synthesis and characterization of isotactic poly(isopropyl glycolide) and the formation of its stereocomplexes. Crystallinity and thermal properties are studied.

ORGN 124

Formation and testing of atropisomeric rhodamine derivatives for chiral sensing

Justin Romaire1, [email protected], Kevin Yehl3, Mike Maher2, Jeff Weihe2, Grant Seiler2, Clifton J. Stephenson1, [email protected], Ken D Shimizu3. (1) Department of Chemistry, Loyola University New Orleans, New Orleans, LA 70118, United States (2) Department of Chemistry, Carthage College, Kenosha, WI 53140, United States (3) Department of Chemistry and biochemistry, University of South Carolina, Columbia, SC 29208, United States

An atropisomeric xanthene dye derivative was used to develop a simple yet highly sensitive enantioselective flouroescent assay. The biological activity of enantiomers can vary greatly, thus, making chiral sensing important for the pharmaceutical industry and organic synthesis. Fluorescent atopisomers are advantageous for chiral sensing applications as they can be highly sensitive and easily monitored by UV-Vis or fluorescent spectroscopy. Herein, the development of a new atropisomeric fluorescent probe is described for potential enantiomeric sensing applications. The chiral sensor was formed by modifying the xanthene dye, Rhodamine B (RB ). RB derivatives are desirable as molecular probes due to their ability to undergo an off/on sensing mechanism. This discussion will include the synthesis, resolution, and testing of the atropisomeric RB derivatives.

ORGN 125

Derivatives of polyfuran copolymers for organic-based solar cells

Malcolm R Davidson II1, [email protected], Jenna Binion2, Hemali Rathnayake3. (1) Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803, United States (2) Department of Chemistry, Western Kentucky University, Bowling Green, KY 42101, United States (3) Department of Chemistry, Western Kentucky University, Bowling Green, KY 42101, United States

With growing constraints on natural resources making classical energy sources uneconomical, the U.S. has need of a multifaceted of energy alternatives for the future. Here we synthesize and characterize an organic-based conductive material, having implementations in energy production and conservation. This will reduce the energy we consume by improving efficiencies of existing LED based electronics and inorganic semiconductors. We have synthesized a polyheterocyclic conductive polymer known as polyfuran (PFu) by Grignard Metathesis. The polymer was characterized by 1H-NMR and UV-visible spectroscopy. The polymer morphology was examined under TEM and SEM. The electronic properties of the polymer thin-films were studied by applying the voltage from -1 to +1 V.

ORGN 126

Redox-active stimuli-responsive drug delivery system

Rasika Ranatunga Nawimanage, [email protected], Robin L McCarley. Chemistry, Louisiana State University, Baton Rouge, LA 70803, United States

A goal of our research program is the development of NADH quinone oxidoreductase type1 (NQO1) enzyme-triggered liposome delivery agents with highly controllable stimuli-responsive behavior for eventual use in tumor-directed drug delivery systems (DDS). One direction for such triggered liposomal DDS is use of trigger groups that self- eliminate from the lipid head groups of the liposome upon activation (triggering) by an enzyme, such as those we have reported on that use quinone propionic acid trigger groups that take advantage of the Thorpe-Ingold Effect. In this presentation, we investigate a new group of potential trigger groups for liposomal DDS based on 2- hydroxymethyl-3,5,6-trimethyl-1,4-benzoquinone (HMBQMe), a compound that upon derivatization at the 2-hydroxymethyl site can undergo 1,4-elimination reactions as a result of quinone methide formation. The synthesis of novel HMBQMe-primary amine derivatives is presented, and the formation of quinone methides from them upon quinone group reduction is investigated using spectroscopic methods. ORGN 127

3D microvascular gas exchange unit for carbon capture

Du T Nguyen, [email protected], Y Leho, Aaron Esser-Kahn. Department of Chemistry, University of California, Irvine, Irvine, CA 92697, United States

Carbon capture and sequestration (CCS) technologies are receivingconsiderable attention as a means of reducing CO2 emissions. For thecapture of CO2 from mixed gas streams, materials for increased gasexchange are necessary. Efficient gas exchange systems already exist in theform of vascularized lung-tissue. These tissues createthree- dimensional solid/liquid composites with high surface areas,continuous flow, and intimate contact between gasses and capture fluids.We will discuss a method for the synthesis of three-dimensionalmicrovascular gas exchange units capable of removing CO2 from flowing gasstreams. We will illustrate a newly observed spatiotemporal pattern of CO2reactivity in the microvascular gas exchange unit using colorimetric, pHsensitive dyes. Control over three-dimensional geometry is shown to increasecapture efficiencies. We have developed and will disclose a computationalfinite element model that validates and explains the experimental observations.

ORGN 128

Syntheses and photophysical/electrochemical characterizations of phosphole containing thiophene oligomers

Steven R Ruark, [email protected], Kenneth F Cooper, [email protected], Katsu Ogawa. Department of Chemistry & Biochemistry, California State University Northridge, Northridge, California 91330-8262, United States

Oxidatively polymerizable thiophene oligomers have been important precursors for conjugated polymeric materials. Such thiophene oligomers containing phosphole moiety have been known in the literature. However, the phosphole rings of these oligomers are typically functionalized at 3 and 4 positions. The α-unit of the side chain are known to cause steric interactions with the polymer back bone. On the other hand, a variety of 1,2,5-triphenylphosphole derivatives with unfunctionalized central phosphole rings are known but they are not feasible for oxidative polymerization. In order to reduce steric hindrance between backbone and the α-unit of sidechains without losing oxidative polymerization capability, 1-phenyl-2,5-bis(2-thienyl)phosphole and its derivatives were synthesized as monomeric precursors for conjugated polymeric materials. Photophysical and electrochemical properties were investigated.

ORGN 129

Electron transport laterally across a monolayer of fullerenes and application to hybrid photovoltaics Keith M Haynes, [email protected], William J Youngblood. Department of Chemistry, University of North Texas, Denton, TX 76210, United States

Hybrid solar cells (HSCs) are similar to organic solar cells (OSCs), but they also contain inorganic components which are often metal oxide films. These films can serve as a substrate to attach a monolayer of fullerene molecules that can function as the acceptor component together with a 'donor' semiconductive polymer. Transport of electrons through the fullerene monolayer on the oxide support then works by 'hopping' from fullerene to fullerene, laterally across the oxide support. Several different fullerene molecules were synthesized; the electron transport affinity of each fullerene derivative was then quantified using chronocoulometry. These electrochemical experiments look at the concentration of the attached monolayer and the surface area to determine how efficiently electrons can be transported across the monolayer of acceptor molecules.

ORGN 130

Nerve agent simulant sensors using oligoanilines synthesized directly from aniline dimer

Srikanthrao Agnihotra1, [email protected], Sumedh P. Surwade1, Marisely De Jesus Vega2, Anita Vaidya1, Akshay Phulgirkar2, Srikanth Ammu2, Dr. Sanjeev K Manohar2. (1) Department of Chemistry, University of Massachusetts Lowell, Lowell, MA 01854, United States (2) Department of Chemical Engineering, University of Massachusetts Lowell, Lowell, MA 01854, United States

We describe a one-step synthesis of oligoanilines having pre-selected molecular weight, such as, aniline hexamer, octamer, dodecamer, hexadecamer, etc., by chemical oxidative coupling of N-phenyl-p-phenylenediamine (4-ADPA, or aniline dimer) in dilute aqueous acids (HCl, CSA) using ammonium peroxydisulfate as the oxidant. Oligoaniline films show robust, reversible chemiresistor response when exposed to volatile organic compounds (VOCs) and are particularly effective in detecting nerve agent stimulants DMMP and DIMP at room temperature in ambient air.

ORGN 131

Synthetic metals: New functionalized TCNQ and precursors for donor-sigma- acceptor materials

Edward J Parish1, Jiann-Tsyh Lin2, Hiroshi Honda3, Yuchen Lo4, [email protected]. (1) Department of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849, United States (2) Department of Crop Improvement & Utilization Research, Agricultural Research Services, USDA, Albany, CA 94710, United States (3) Department of Bioengineering, Northwestern Polytechnic University, Fremont, CA 94539, United States (4) Department of Biomedical Engineering, University of California, Los Angeles, CA 90095, United States The p-nitrophenylethyl and TCNQ 3-perylenyl carbamates were prepared and purified by their spectral properties. Fluorescence lifetime measurement have been determined. Two Perylene derivatives have been prepared in which the polycyclic electron-donor was substituted on the carbamate ester.

ORGN 132

Evaluation of kinetics of reduction and lactonization of quinone propionic acid ethanolamine derivatives – a study using 1H NMR

K. L. Iresha S Perera, [email protected], Robin L McCarley. Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803, United States

Stimuli-responsive liposome systems based on trimethyl-lock quinone propionic acid lipid derivatives seems highly promising because these liposome systems have the potential to release high drug concentrations upon reduction (by reductase enzyme) at the tumor site. The reduced quinone (hydroquinone) intermediate undergoes facile lactonization leading to liposome rupture, and thereby cargo unloading. Thus the evaluation of kinetics of quinone reduction and subsequent lactonization is of utmost important. In order to investigate the kinetics, five water-soluble model trimethyl-lock quinone propionic acid ethanolamine derivatives were synthesized with different substituents on the quinone ring. Studies were carried out by 1H NMR spectroscopy in D2O medium at several temperatures with sodium dithionite as the reducing agent. 1 Time-resolved H NMR spectra were used to evaluate the rate constant and t½ values for the lactonization reaction. We observed that the substituents on the quinone ring significantly affect the rate of lactonization.

ORGN 133

Selective fast flux of organic liquids and solids using nanoporous membranes of polydicyclopentadiene

Abhinaba Gupta, [email protected], Ned Bowden. Chemistry, University of Iowa, Iowa City, Iowa 52242-1292, United States

Membranes were fabricated from the ring opening metathesis polymerization of dicyclopentadiene with the Grubbs first generation catalyst, and the permeability of organic molecules through them was studied. Both polar and apolar molecules with molecular weights from 101 to 583 g mol-1 permeated these membranes with values for flux of 10-5 to 10-6 mol cm-2 h-1 but selected molecules did not permeate them and had flux 10^4 to 10^5 times slower. The difference in flux was large between molecules that permeated and those that did not permeate, but no trend was observed that correlated flux with molecular weight or hydrophobicity. Rather, molecules that did not permeate the membranes had large cross-sectional areas that led to low rates of diffusion within the highly cross- linked polydicyclopentadiene membranes. The degree of cross-linking within the polydicyclopentadiene membranes was measured using infrared spectroscopy and approximately 84% of the dicyclopentadiene monomer had reacted to form cross-links. These are the first organic solvent nanofiltration membranes that separate molecules with molecular weights from 100 to 600 g mol-1 based on cross-sectional areas.

ORGN 134

Electrical conductivity of surfactant modified carbon nanotube thin film

Juliet Hahn, [email protected]. Department of Chemistry, New Mexico Tech, Socorro, NM 87801, United States

Electrical conductivity of surfactant modified carbon nanotube thin films is being investigated. Spectroscopic techniques including FT NMR, and FT IR to quantify the surfactant content is being developed. Optimal surfactant content for electrical conductivity will be discussed.

ORGN 135

Computer-aided design of receptors for mustard molecules

Janos Nadas, [email protected], Benjamin P Hay. Department of Chemical Sciences, Oak Ridge National Laboratory, Oak Ridge, TN 37831, United States

We present computational methods used to design receptors for mustard blister agents, molecules composed of a central heteroatom, either S or N, decorated with two 2- chloroethyl substituents. Following evaluation of geometric and energetic aspects of X– H···Cl [X = C, N, O] interactions, the de novo design of the receptors containing three hydrogen bonding sites was performed using our in–house software, HostDesigner (HD). Progress on the synthesis and testing of the top scoring receptor candidates will be discussed.

ORGN 136

Synthesis, structure and metal ion binding of di-(1,8-naphtho)-16-crown-4 compounds

Lokman Torun1, [email protected], Peter Mueller2, Xiaodan Cao3, Richard A Bartsch3. (1) Chemsitry Department, TUBITAK MAM, Gebze, Kocaeli 41470, Turkey (2) Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139-43, United States (3) Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, United States

Crown ethers are well known for their strong interactions with alkali metal and alkaline earth metal cations. Small-ring crown ethers with four oxygens often exhibit selective complexation of Li+. In this report, we describe the results of the synthetic endeavors, as well as the solid-state structure of di-(1,8- naphtho)-16-crown-4 and its alkali metal cation selectivity in synthetic polymeric membrane electrodes.

ORGN 137

Progress toward the synthesis of fluorescent organic macrocycles

Nicole Cook, [email protected], Mindy Levine. Department of Chemistry, University of Rhode Island, Kingston, RI 02881, United States

Various biphenyl precursors and alkynyl-substituted anthracenes have been synthesized, and the reaction conditions necessary to link these precursors to form an all-organic macrocycle are being optimized. We are utilizing flow chemistry to effectively achieve high dilution conditions, which will favor the formation of the target macrocycle over the competing polymer. The use of flow chemistry will also limit the buildup of potentially explosive organic azides. Once synthesized, these macrocycles will be used for a fluorescence-based assay for the detection of TNT. We will utilize an array-based detection scheme, which will allow us to discriminate between TNT and other structurally similar but benign nitroaromatics such as dinitrotoluene and nitrobenzene. Using the array, each analyte will have a unique range of interactions with the various macrocycles, thereby enabling selective detection.

ORGN 138

Novel and efficient approach for chromogenic and spectroscopic detection of nerve agent mimics

Vinod Kumar, [email protected]. Chemistry and Biochemistry, The University of Texas at Austin, Austin, Texas 78712, United StatesProcess Technology Development Division, Defence Research and Development Establishment, Gwalior, MP 474002, India A novel and chromogenic protocol has been developed for rapid and selective detection of nerve agent mimic (diethyl cyanophosphate). The chromogenic sensor 1 displayed drastic color change from its colorless solution to yellow instantaneously with 89 nm bathochromic shift. No inference of other chemical warfare mimics such as diisopropyl fluorophospahte, malathion, dimethyl methyl phosphonate, chloroethyl phenyl sulfide, was observed either with naked-eye or by UV-Vis spectroscopy

ORGN 139

Introduction of active functionality to self-assembled nanostructures

Amber M Johnson, [email protected], Richard J Hooley. Department of Chemistry, University of California Riverside, Riverside, CA 92521, United States

Self-assembled nanostructures of an M4L6 tetrahedral geometry were targeted from bi- or tridentate chelators and octahedral metals or lanthanides. Introverted functional groups such as amines and carboxylic acids were introduced to control guest binding and reactivity. The introduction of different groups allows for tuning of the complex to different guests, and modular synthesis allows for variety in chelator geometry.

ORGN 140

Conjugated oligomer sensor array for aliphatic amines

Xiaoning Li, [email protected], John J Lavigne, Min Cai. Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208, United States A cross-reactive sensor array based on conjugated oligomers of thiophene containing diboronate esters was synthesized to differentiate Lewis basic analytes such as aliphatic amines. By altering substituents on the diol portion of the boronate esters the Lewis acidity and steric accessibility of the boron binding site is significantly impacted, which results in different, unique and reproducible responses towards different amine analytes with varied structures and basicity. Multiple wavelengths from the absorption spectrum for each diester host responding to a particluar amine were used to create a unique pattern for that analyte. Statistics analysis was applied to differentiate the analytes with relatively high classification accuracy. Single crystal x-ray diffraction and binding studies were used to understand the binding mechanism. To amplify the sensory response and further diversify the sensor array, the development of conjugated polymer sensors with boron-heteroatom bonds in the main-chain were also developed and will be discussed.

ORGN 141

Water soluble synthetic receptors as metalloenzyme mimics

Katherine E Djernes, [email protected], Orly Moshe, Magi Mettry, Richard J. Hooley. Chemistry, University of California, Riverside, Riverside, CA 92507, United States

Cavitands provide an alluring scaffold for metalloenzyme mimics because they are capable of displaying four rigid coordinating motifs at defined distances around a cavity. We discuss novel metallocavitands featuring an active metal oriented toward a cavity, where the cavity acts as a size-selective recognition motif. The size and shape of the recognition motif are controlled by coordinating metals either above or at the sides of the cavity. The potential for the cavitands to act as site-selective oxidation catalysts is discussed.

ORGN 142

D2-Symmetric macrocycles as enantioselective fluorescence sensors Shaun Ben-Ari, [email protected], J. Frantz Folmer-Andersen, [email protected]. Department of Chemistry, The State University of New York at New Paltz, New Paltz, NY 12561, United States

We have developed an efficient synthesis of series of enantiomerically pure, large-ring macrocycles containing trans-1,2-diaminocyclohexane and 1,1'-bi-2-naphthol subunits. The structures contain three mutually perpendicular two-fold rotational symmetry axes, and belong to the D2 point group. Because the macrocycles are chiral, they are in principle capable of preferentially binding one enantiomer of a guest molecule over the other within their interior cavities. This phenomenon was demonstrated towards several chiral carboxylic acid derivatives in aprotic solvents by both 1H NMR and fluorescence spectroscopies. In particular, the macrocycles display enantioselective fluorescence quenching in the presence of dibenzoyl tartaric acid (DBTA), thus giving an optical signal that is dependent on the enantiomeric excess (ee) of the DBTA sample. We hope to extend these systems to achieve a general method of photometrically quantifying the ees of various chiral carboxylic acid samples.

ORGN 143

Encapsulation of redox-active guests inside a dimeric molecular capsule

Yanhua Qiu, [email protected], Angel E Kaifer. Department of Chemistry, University of Miami, Miami, Florida 33146, United States

In general terms, an isolated redox-active guest will undergo substantial attenuation of electrochemical kinetics, reflected on the reduced current response at potentials at which oxidation or reduction would happen. In this poster, we will present a series of guests (ferrocene-derivatives, tetrathiafuvalene and benzoquinone-derivatives) encapsulated inside a molecular capsule formed by two deep-cavity cavitands and discuss how the electrochemistry of the guests is affected in each case.

ORGN 144

Molecular torsion balances for probing the distance dependency of CH-pi interactions

Timothy Grabnic1, [email protected], Mark R Ams1, Brijesh Bhayana2. (1) Chemistry, Allegheny College, Meadville, PA 16335, United States (2) Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, United States

Torsion balances are minimal folding models that can measure CH-pi interactions within a single molecule. We have found that decreasing the hinge angle of the torsion balance increases the CH-pi interaction distance and has a dramatic effect on the in versus out folding ratio. In our poster, we discuss the synthesis of torsion balances with varying hinge angles and CH-pi gaps. The folding data from these models will be used to help determine the relationship between CH-pi strength and distance.

ORGN 145

Synthesis and characterization of mechanically interlocked cucurbit[n]uril receptors

Vijayakumar Ramalingam, [email protected], Adam R Urbach. Chemistry, Trinity University, San Antonio, Texas 78212, United States In the field of supramolecular chemistry, the structure and properties of the receptor (host) dictate its binding to guest molecules. Approaches to chemically modifying receptors are very attractive because they can be used to tailor the binding affinity and selectivity to different guest molecules and under different conditions. The vast majority of macrocyclic receptors (e.g., cucurbiturils, cyclodextrins, crown ethers, and calixarenes), however, are difficult to modify due to their repeating structures and/or undesirable solubility properties. We have circumvented this problem using the two- guest binding property of the macrocyclic cucurbit[8]uril (Q8) to modify the physical properties of the receptor without performing any synthetic modification of the macrocycle itself. Q8 is unique in that it can bind two different guest molecules simultaneously. Threading a viologen derivative (as the first guest) through the Q8 receptor and stoppering produces a Q8-rotaxane that can bind a second guest as an inclusion complex. The resulting rotaxane is a new receptor with intrinsic solubility and binding properties that derive both from Q8 and from the threaded and stoppered first guest. The synthesis and characterization of Q8-rotaxanes and their applications will be described.

ORGN 146

Conformational freezing of fluorine-substituted di- and tribenzylammonium cations in Cucurbit[8]uril: Unusual regio- and stereochemical outcomes

Xiaoyong Lu, [email protected], Eric Masson. Department of Chemistry & Biochemistry, Ohio University, Athens, Ohio 45701, United States

The interaction between CB[8] and a series of fluorine-substituted di- and tribenzylammonium cations was monitored by 1H nuclear magnetic resonance spectroscopy. CB[8] encapsulation triggered significant rotational freezing, and allowed the characterization of very unusual conformers in its cavity. In the case of tribenzylammoniums, CB[8] encapsulated regioselectively two of the three aromatic units. Also, CB[8] displayed remarkable diastereoselectivity towards ammonium cations bearing a chiral group and three different benzyl substituents, the nitrogen atom thus becoming the second stereocenter.

ORGN 147

Cucurbituril slippage: Metallic cations as supramolecular lubricants

Xiaoxi Ling, [email protected], Eric Masson. Department of Chemistry and Biochemistry, Ohio University, ATHENS, Ohio 45701, United States

We show that Cucurbit[7]uril (CB[7]) can slip over motifs as large as 21-crown-7, and that unexpectedly, CB[7] dethreading is promoted by metallic cations, which stabilize intermediate(s) and transition state(s) along the slippage pathway by interacting with both the crown ether unit and the carbonylated portal of CB[7]. Rate enhancements of up to 500-fold have been measured. To the best of our knowledge, this “lubricating” effect of metallic cations on the motion of CB[n]s along an axle is unprecedented.

ORGN 148

Conjugated bis(dioxaborole)s for optically sensing fluoride by an integral sensory approach Min Cai, [email protected], John J Lavigne. Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, United States

Conjugated polymers have been investigated for sensing, in large part due to their signal amplification. We reasoned that the borole linkage could be incorporated into a polymer main-chain and these materials used as optical sensors. Boronate ester formation, with its covalent yet reversible nature, provides advantages including facile synthesis, good stability and extended π-conjugation for the creation of sensitive conjugated polymer sensors. Herein, bis(dioxaborole)s were used as models for poly(dioxaborole)s, creating an integral sensory approach for elucidating the mechanism of binding and signal transduction based on optically sensing fluoride. This sensing mechanism was intensively studied by UV-Vis, fluorescence, NMR spectroscopy as well as computational methods. It was found that the recognition of fluoride by bis(dioxaborole)s was sensitive, reversible and cross-reactive with other Lewis bases. These results provide insights into the development of conjugated poly(dioxaborole)s further amplifying the optical signals to increase sensitivity.

ORGN 149

Atropisomerism in confined space: The impact of cucurbit[8]uril on the torsional barrier of biphenyl units

Roymon Joseph, [email protected], Eric Masson. Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio 45701, United States

Biphenyl atropisomers are well-known scaffolds for chiral ligands used in enantioselective organometallic reactions, and the effect of ortho substituents on the torsional barrier along the biphenyl axis has been assessed on several occasions. Yet, would activation barriers be altered upon encapsulation of the biphenyl unit into a macrocyclic host? In this study, we show that CB[8] behaves as a molecular brake upon encapsulation of substituted biphenyl units flanked by a sulfonium group at their 3- position.

ORGN 150

Fine tuning the pH dependence of self-assembly in peptide amphiphiles for cancer imaging Arijit Ghosh, [email protected], Joshua E Goldberger. Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, United States

The creation of smart self-assembling materials that undergo morphological transitions in response to specific physiological environments can allow for the enhanced accumulation of imaging or drug delivery agents based on differences in diffusion kinetics. Here, we have developed a series of self-assembling peptide amphiphile molecules that transform from isolated molecules or spherical micelles to nanofibers when the pH is slightly reduced from 7.4 to 6.6, in isotonic salt solutions that simulate the acidic extracellular environment of tumor tissue. This transition is rapid and reversible, indicating that the system is under thermodynamic equilibrium. The concentration-pH self-assembly phase diagrams have been mapped out for peptide systems with and without imaging labels. By fine-tuning the balance of attractive hydrophobic and hydrogen bonding, repulsive electrostatic and steric forces, the self assembly morphology (isolated molecules, spherical micelles and nanofibers) and the pH of transition can be systematically controlled.

ORGN 151

Anions detection and their selectivity tuning by hydrogen-bond donor ensemble through fluorescence dye displacement assay

Punidha Sokkalingam, [email protected], Chang-Hee Lee. Department of Chemistry, Kangwon National University, Chun-Chon, Republic of Korea

A Series of calix[4]pyrrole-based supramolecular host-guest complexes have been synthesized and studied for selective recognition of anions through fluorescent dye displacement assay (FDDA). The strong fluorescence of the dye, chromenolate anion, was completely quenched upon complexation with calix[4]pyrrole derivatives. Exposure of these supramolecular complexes with anionic analytes, whose binding affinities were greater than the dye with receptor, resulted in complete displacement of the dye with the full restoration of fluorescence. While fluoro-substituted receptor showed greater affinity towards only fluoride anions, the iodo-substituted one exhibited relatively high selectivity for both acetate and fluoride anions. On the other hand, the pyridinium substituted calix[4]pyrrole displayed preferential selectivity for pyrophosphate over phosphate and other anions. We expect that the present work could provide structural foundation for selective sensing of various anions through an ON-OFF-ON fluorescence mechanism with a visual change in fluorescence intensity by introducing suitable substituent in the receptor.

ORGN 152

Multienzyme responsive polymeric micelles Ti-Hsuan Ku, [email protected], Miao-Ping Chien, Nathan Gianneschi. Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, United States

In biology, stimuli-responsive multisubunit assemblies are ubiquitous, and mimicking these systems via synthetic approaches is of increasing interest. Interfacing such synthetic materials with biological systems is particularly promising for a range of biomedical applications including targeted drug delivery and molecular diagnostics. Within this class of materials are particles capable of changing morphology in response to stimuli. Enzymes are attractive and unique stimuli with great potential in this regard, as they propagate an amplified response via catalytic reactions, can be highly substrate specific, and have expression patterns sometimes associated with disease states. Nanoscale assemblies of block copolymer amphiphiles are well-suited for the development of functional, stimuli-responsive systems because changes in the chemical or physical nature of the amphiphile can lead to formation, destruction, or morphological transformations. Here, the first example of enzymatic switches of micellar morphology will be demonstrated that polymer-peptide micellar nanoparticles were utilized in responsive to multiple. Reversible switching of the morphology and nanoparticle aggregation induced by specific enzymes will be described.

ORGN 153

New fluorescent sensors based on various fluorophores and their biological applications

Ji Young Choi1, [email protected], Ying Zhou2, Xiaoqiang Chen2,3, Juyoung Yoon1,2. (1) Department of Bioinspired Sience, Ewha Womans University, Seoul, Republic of Korea (2) Department of Chemistry and Nano Science, Ewha Womans University, Seoul, Republic of Korea (3) College of Chemistry and Chemical Engineering, Nanjing University of Technology, Nanjing, Jiangsu, China

Fluorescent sensors which sense ions or neutral analytes demonstrate their potential roles in a variety of fields, such as biological sensors, environmental sensors, molecular devices, nerve gas sensor, etc. The selective binding of chemical species upon molecular recognition can lead to large perturbations in the host environment, particularly when the guest is ionic. These sensors based on the analyte-induced changes in fluorescence are particularly attractive due to their simplicity and in vivo/in vitro imaging. Various fluorophores such as rhodamine, pyrene, and naphthalimide derivatives are used as a probe for many ions or biological molecules. Thus, we designed various fluorescent chemosensors containing these fluorophores and those sensors showed excellent selectivity for certain analytes. For example, Rhodamine derivative was reported as a HOCl sensor which emits strong fluorescence when it reacts with the HOCl. In addition, pyrene based sensors were designed as probes for lysine. Gold ion sensor based on a naphthalimide derivative was designed and showed high selectivity toward Au3+ ions. Some of these sensors were successfully applied in cell imaging showing their potentials for biological applications. ORGN 154

Novel conjugated polydiacetylenes as effective colorimetric and fluorometric sensors for metal ions

Songyi Lee1, [email protected], Juyoung Yoon1,2, Kyung Mi Lee1, Qingling Xu1, Hye Ryeong Jeong2. (1) Department of Bioinspired Science, Ewha Womans University, Seoul, Republic of Korea (2) Department of Chemistry and Nano Science, Ewha Womans University, Seoul, Republic of Korea

Polydiacetylene(PDA) is a colorimetric polymer owing to a brilliant blue-to-red color transition that takes place in response to environmental perturbations. Also, it already has been known that “blue-phase” PDAs are nonfluorescent while their “red-phase” counterparts fluorescence. Owing to the color (blue-to-red) and fluorescence (non-to- fluorescent) changes, PDA is an ideal choice for use as a chemosensor. PDAs have been actively used as sensory materials for the detection of biologically, environmentally, and chemically-important target molecules. Diacetylene amphiphiles are self-aseembled into a variety of forms that can be modified for various detection applications, and be photopolymerized to generate PDA in situ. PDA provides optical signal generation arising from changes in the absorption and emission spectra of the conjugated backbone caused by interaction with the target materials. PDA is made by 1,4-addition between neighbored diacetylenic monomers, initiated by ultraviolet(UV) irradiation. The polymer which is formed by exposure to UV irradiation is intensely blue to the eye, because of electronic delocalization within the conjugated framework, generating absorption at around 650nm in the visible region to electromagnetic spectrum.

It would be meaningful to detect many harmful metals like lead and copper ions with naked eyes. Among the metal ions, Pb2+ is one of the important targets because of the adverse health effects of lead exposure, particularly in children. It is reported that lead exposure can cause memory loss, irritability, anemia, muscle paralysis, and mental retardation. However, there are few reports on the use of fluorescence or UV changes to detect these harmful metal ions. And a new method for visual detection of Cu2+ based on azide- and alkyne-functionalized polydiacetylene (PDA-aa) vesicles has been developed. This method provides a naked eye detection of Cu2+ in water without the aid of complex instruments.

ORGN 155

Molecular assembly of perylenediimide derivatives controlled by hydrophobic cavities in nucleic acid

Tadao Takada, [email protected]. Department of Materials Science and Chemistry, University of Hyogo, 2167 Shosha, Himeji, Hyogo 671-2280, Japan DNA is a unique yet useful material to construct nanoscale molecular arrays along the helix axis. In this work, we show a new approach to create molecular assembly within DNA. Abasic sites were introduced into both strands of DNA to generate a hydrophobic cavity that serves as a host. A planar hydrophobic molecule (water-soluble perylenediimide derivatives, PDI) was used as the ligand molecule. In the presence of the DNA with the cavity, the binding of the PDI was found to site-specifically occur in the hydrophobic cavity. The molecular assembly and arrangement of more than two PDI molecules was performed by changing the sizes and positions of the cavities.

ORGN 156

Design and synthesis of organic nanotubes

Bo Liu, [email protected], Joseph W Lauher, Frank W Fowler. Department of Chemistry, Stony Brook University, Stony Brook, NY 11790, United States

Carbon nanotubes are the center of the nanotechnology revolution due to their potential applications in biochemical sensors, electronics, and medical deliveries. Based on our experience on polydiacetylenes (PDAs), our goal is to prepare synthetic nanotubes by using diacetylene topochemical polymerizations. Compared to the widely studied carbon nanotubes, a potential advantage of these synthetic organic nanotubes is their unlimited potential for modification by organic synthesis as needed for different applications.

Here, we designed and synthesized a series of macrocyclic diacetylenes and assembled them into columns by using intermolecular π - π stacking forces. Different functional groups were introduced into the macrocycles to achieve the ideal packing distances needed for the polymerization. X-ray crystallography clearly shows the formation of tubular structures.

ORGN 157

Evaluation of the catalytic potency of cucurbit[7]uril on benchmark substitution reactions Lawrence Kyeremeh-mensah, [email protected], Eric Masson.department of chemistry, ohio university, athens, ohio 45701, United States

The catalytic properties of Cucurbit[7]uril (CB[7]) on benchmark nucleophilic substitution reactions have been investigated by 1H NMR spectroscopy. The effect of CB[7] on competitive reactions involving one electrophile and two or more nucleophiles has been assessed, and notable variations in the product distributions have been observed. Encapsulation of substrates, key intermediates and transition states within the cavity of CB[7] has been found to have a significant effect on reaction rates and product distributions.

ORGN 158

Advanced diazaperylenium derivatives for use in solar harvesting and nanoscale sensors via mechanostereochemistry

Ashish N. Basuray, [email protected], J. Fraser Stoddart. Department of Chemistry, Northwestern University, Evanston, IL 60208, United States

We are currently developing a library of compounds that incorporates the highly fluorescent, photo-stable diazaperylenium core for use in organic photovolatics and nano-scale sensors. Based on our previous work with viologen-based host-guest chemistry[1], we have evolved the complexity and functionality to incorporate the perylene-derivatized core to participate in similar pseudorotaxanation events. We have completed the synthesis and crystallographic determination of the N,N′-dimethyl- diazaperylenium (DDP2+) compound (Fig. 1). We are finalizing work on the binding studies of DDP2+ with the 1,5-dinaphtho-[38]crown-10 (DNP38C10) macrocycle (Fig. 2), which shows strong binding as well as quenching of fluorescence upon the host-guest complexation event, building upon previous work based on N,N′-dimethyl- diazapyrenium.[2]

[1] P. R. Ashton; J. F. Stoddart; et.al. Complexation of diquat and paraquat by macrocyclic polyethers incorporating two dihydroxynaphthalene residues. Tetrahedron Lett. 1987 , 28, 6367−6370.

[2] P. R. Ashton; J. F. Stoddart; et.al. Molecular meccano. Part 50. Diazapyrenium- containing catenanes and rotaxanes. New J. Chem. 1999 , 23, 587−602.

ORGN 159

Host-guest dynamics of self-assembled M8L6 cubes

John D Thoburn1, [email protected], Wenjing Meng2, Jack K Clegg2, Jonathan R Nitschke2. (1) Department of Chemistry, Randolph-Macon College, Ashland, VA 23005, United States (2) Department of Chemistry, Cambridge University, Cambridge, United Kingdom

A series of self-assembled M8L6 cubic cages has recently been synthesized from tetraaminophenyl porphyrin, pyridine aldehyde, and iron(II) sub-components.

The large void space (>1300Å) and porphyrin faces of the cage make it an ideal host for large aromatic molecules. The focus of this presentation is on the dynamics of host– guest interactions. This cubic host sequentially encapsulates three coronenes guests. We have modelled the kinetics of coronene binding to eludicate possible mechanisms of encapsulation.

ORGN 160

Stimuli responsive boronic acid containing amphiphilic block-copolymers

Matthew P Thompson, [email protected], Nathan C Gianneschi. Chemistry and Biochemistry, University of California San Diego, La Jolla, California 92093, United States

The ability of boronic acids to form reversible bonds with molecules containing diols has led to their wide use as sensors for glucose and other biologically relevant molecules as well as in other applications such as separations, flame retardants and as delivery agents. Polymers containing boronic acid functionalities are expected to have a large impact in the above mentioned areas. We have synthesized a number of amphiphilic block copolymers via Ring Opening Metathesis Polymerization (ROMP) incorporating boronic acids, hydrophobic and hydrophilic norbornene units that form well defined nanoparticles in aqueous solution. The formation/degradation of boronic esters can be controlled with various stimuli such as pH and additives (diols). This allows us the ability to control the not only the morphology of the nanoparticles but also to explore their function as sensors, delivery agents and crosslinkers.

ORGN 161

Crystal engineering of new cocrystals of pyrazinamide using benzamides and benzoic acids

Jesús Meléndez, [email protected], Devon Cocuzza, Heba Abourahma. Chemistry, The College of New Jersey, Ewing, New Jersey 08628, United States

Research in the area of pharmaceutical cocrystals has sparked much interest in recent years. Cocrystallization of an active pharmaceutical ingredient (API) with a cocrystal former (a coformer) generates a new solid phase, which may have improved properties over existing solid phases of the API. Our research focuses on the API pyrazinamide (PZA), an antibiotic used in the treatment of tuberculosis. We will present a series of PZA cocrystals that have been prepared employing substituted benzamide and benzoic acid coformers (substituent group = -OH, -NH2, -NO2). Synthesis of the cocrystals was achieved by solvent-drop grinding, slow evaporation, slurry and the melt. Characterization was accomplished using PXRD, DSC, TGA and single crystal X-ray crystallography, when possible. The impact of the electronic effect of the coformer substituent on cocrystal formation will be addressed.

ORGN 162

Structural studies of pyrogallol[4]arenes supramolecular architectures: Bilayers, nanocapsules and nanotubes

Oleg V. Kulikov, [email protected]. Chemistry, Yale, New Haven, CT 06511, United States

Over the years, self-assembled supramolecular species derived from pyrogallol[4]arenes, such as nano-capsules 1 , nano-tubes 2 and bilayers 3 , have attracted much attention from researchers due to their ability to incase the small molecular guests and conduct the ions across the membrane. In furthering our goals to study these unique hydrogen-bonded arrangements, we have prepared a number of pyrogallol[4]arenes bearing various side chains and investigated their solid state structures.

ORGN 163

Rotational dynamics in self-assembled nanostructures

Michael C Young, [email protected], Richard J. Hooley. Department of Chemistry, University of California - Riverside, Riverside, North Carolina 92507, United States

A variety of ligands have been synthesized with arene cores connected to different metal-chelating groups via acetylenes. These ligands can be treated with metals to induce self-assembly to form discrete structures in solution. Changes in the rotational dynamics have been studied by changing the size of core-substituents, by changing the geometry of the assembly, and as a consequence of potential guest binding. Addition of interactive functional groups is expected to further change the observed rotational phenomena.

ORGN 164

Evaluating the stability of pharmaceutical cocrystals in the solid state

Jennifer M Urban, [email protected], Heba Abourahma. Department of Chemistry, The College of New Jersey, Ewing, New Jersey 08628, United States The study of pharmaceutical cocrystals is an emerging area of research that has gained a lot of interest in recent years for the potential to easily modify poor physical properties of an active pharmaceutical ingredient (API) without altering its therapeutic effect. However, if a cocrystal were to make it to the market, it has to withstand formulation conditions and the grinding into a tablet with other materials. The goal of our study is to assess the stability of pharmaceutical cocrystals in the solid state in the presence of other materials that can potentially affect the integrity of the cocrystal. Specifically, we will address the solid state stability of theophylline and caffeine cocrystals in the presence of molecules known to cocrystallize with each. We will present results from the solid state grinding experiments of theophylline and caffeine cocrystals in the presence of substituted benzoic acids (substituents = -OH, -NO2, -N(CH3)2).

ORGN 165

Hydrophobic modulation of lower critical solution temperature of nonpolymeric thermosensitive supramolecules

Yazmary Melendez-Contes, [email protected], Luis M Negrón, Jose M Rivera. Department of Chemistry, University of Puerto Rico, Rio Piedras Campus, San Juan, Puerto Rico 00931, Puerto Rico

Many supramolecular naturally occurring machines can self-assemble into nanostructures that sense environmental changes and respond to them accordingly. In thermosensitive materials, when hydrophilic substances are modified to increase their hydrophobicity, the resulting material reaches a composition where it shows a lower critical solution temperature (LCST) before becoming entirely insoluble. Most examples of this are polymers that experience a coil to globule shift and/or self-assembling into aggregates upon reaching a transition temperature (Tt). It's essential that we modulate the three-dimensional configuration of said systems in order to create a selection of Tt's. Recently, we discovered non-polymeric supramolecular G-quadruplexes made from 8- aryl-2'-deoxyguanosine (8ArG) derivatives that show this phenomenon. Our interest is to control the three-dimensional distribution of hydrophobic patches affecting the LSCT by using constitutional isomers of 8ArG derivatives. We will present the synthesis and characterization of two isomeric 8ArG derivatives via Differential Scanning Calorimetry, Dynamic Light Scattering, Mass-Spectrometry, IR and NMR.

ORGN 166

Toward anion sequestration via thiourea-functionalized phase tags

Christopher Daczkowski, [email protected], Mark R Ams. Chemistry, Allegheny College, Meadville, PA 16335, United States

Precipitons are molecular phase tags that can be photochemically switched from a high- solubility to a low-solubility state for the purpose of isolating desired compounds from a mixture. We discuss our investigation of thiourea-functionalized precipitons for the purpose of anion sequestration in DMSO solvent. The synthesis of these precipitons will be discussed, in addition to the binding and isomerization rate constants for complexes formed with various anions.

ORGN 167

G-quartet formation from N9-modified guanine derivatives

Jeremy E.B. McCallum, [email protected], Taylor Fletcher, [email protected]. Chemistry and Biochemistry, Loyola Marymount University, Los Angeles, CA 90045, United States

With the recent interest in the anticancer potential of G-quadruplexes, the need exists for understanding the self-assembly of G-quadruplexes and G-quartets. Several N9- modified guanine derivatives were synthesized to examine their self-assembling properties. N9-(3,5-di-tert-butylbenzyl)-guanine, N9-(3,5-bis(tert-butyldimethylsilyloxy) benzyl)-guanine, N9-(3,5-bis(pent-4-enyloxy)benzyl)-guanine, N9-(3,5-bis(hex-5- enyloxy)benzyl)-guanine, N9-(3,5-bis(hept-6-enyloxy)benzyl)-guanine, and N9-(3,5- bis(oct-7-enyloxy)benzyl)-guanine were synthesized in good yields via coupling reactions involving 2-N-acetylguanine and benzyl bromide derivatives followed by amide deprotection. The self-assembling properties of these derivatives to form G-quartets were studied through the addition of various metals and determined by NMR and molecular modeling studies.

ORGN 168

Dimetallated cage macrocycles: Molecular recognition and catalysis

Ana S. Gamboa, [email protected], Richard J. Hooley. Department of Chemistry, UC Riverside, Riverside, CA 92521, United States

A series of dimetallated cage macrocycles (where M= Fe(II), Cu(I), and Ni(II)) with ditolyl and terphenyl spacers and an ellipsoidal cavity have been synthesized. This family of cages with their unique shape, size, and electronic properties provide high degree of selectivity of suitably substituted guest molecules. Their molecular recognition properties and catalytic activity are currently being studied. ORGN 169

Application of dynamic combinatorial chemistry to identify new compounds that bind G-quadruplex DNA

Elizabeth Cline, [email protected], Marcey Waters. Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States

Cyclic peptides are considered “privileged structures” for drug design due to the number of natural and synthetic cyclic peptides that exhibit biological activity. These macrocyclic scaffolds are advantageous because they mimic native protein structure, exhibit enhanced metabolic stability, and are structurally preorganized, which reduces the entropic cost of binding. Despite their therapeutic potential, the options for synthesizing structurally diverse libraries of cyclic peptides in a high-throughput format are limiting. To this end, a strategy has been developed in our laboratory utilizing thioester exchange for generating solution-phase cyclic thiodepsipeptide libraries via dynamic combinatorial chemistry. We wish to exploit this method to identify acridine-cyclic peptide conjugates that binds selectively for G-Quadruplex DNA. An acridine moiety, known to bind to G-Quadruplex DNA selectively over duplex DNA, is incorporated at the N-terminus of tetrapeptides containing cysteine while a thioester group is installed at the C-terminus. This allows for thioester exchange with the cysteine moiety and reversible formation of a library of cyclic peptides. G-Quadruplexes are a desirable target for binders due to their possible formation in the promoter region of several human genes and oncogenes, as well as their role in chromosomal maintenance at the single stranded end of telomeres. Cyclic peptides have been known to interact with the wide grooves of G-Quadruplex DNA better than linear peptides, thus it is our goal to employ those methods developed in our laboratory to identify potential binders through dynamic combinatorial chemistry.

ORGN 170

Far-red to near-infrared fluorescent dye synthesis for fluorogenic CuACC reactions

Honglin Li, [email protected], Qian Wang. Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208, United States

We have developed a series of fluorogenic CuAAC reactions

based on coumarin, anthracene and BODIPY fluorophores in which non- or weakly- fluorescent reagents meet each other to generate highly fluorescent compounds. These fluorescence-generated reactions have emerged as a powerful tool for bioconjugation, materials science, organic synthesis and drug discovery. However, almost all the available fluorescent dyes used in the Cu(I) catalyzed azide-alkyne cycloaddition (CuAAC) reactions display the absorption wavelengths varied in the visible light region. Since far-red to near-infrared fluorescent dyes are expected to be superior because the light in this wavelength region shows greater tissue penetration, has less overlap with the spectrum of background auto-fluorescence and exhibits less phototoxicity, we here report our design and synthesis of novel far-red to near-infrared fluorescent dyes and their applications in cell biology.

ORGN 171

Context-dependent determination of hydrogen bond strength

Brian R Linton, [email protected], Anthony J Metrano, Justin R DeFrancisco, Benjamin D Brink, Christopher R Shugrue, Rio S Nomoto, Stephen C Hahneman. Chemistry, College of the Holy Cross, Worcester, MA 01610, United States

A series of derivatives were synthesized with varying positioning of hydrogen bond donor and acceptor. The strength of the hydrogen bond interaction was determined in comparison with controls that exhibit similar electronic and steric environment. This approach permits a quantitative assessment of hydrogen bond strength.

ORGN 172

Adenylate kinase recognition using peptide imprinted QCM chip

Cheng Hsin Wu, Tzu-Chien Lin, Dar-Fu Tai, [email protected]. Department of Chemistry, National Dong-Hwa University, Hualien/Shoufeng, Taiwan Republic of China

Adenylate kinase (EC 2.7.4.3) senses cellular energetic imbalances and modulated cellular, interstitial and blood AMP levels. There is a direct relationship between defects in adenylate kinase and AMP metabolic signaling and human diseases. Novel binding materials for adenylate kinase (AdK) were thus constructed using six pentadecapeptides as templates to fabricate molecularly imprinted polymers (MIPs) on QCM chip. Although the infrastructure of each molecularly imprinted cavity is different, AdK was captured in the complementary cavity with different conformations. The binding ability of AdK with each MIPs chip was recorded and the use of these materials as a tool to explore protein function will be demonstated.

ORGN 173

Study of chiral recognition in amino acid based chiral ionic liquid solvents Daniel Kroupa, [email protected], Todd Hopkins. Department of Chemistry, Bulter University, Indianapolis, Indiana 46208, United States

In this study, amino acid based chiral ionic liquids were prepared and their chiral recognition ability probed using a model system. Potential applications of amino acid based chiral ionic liquids include enatioselective catalysis and chiral resolution. The chiral ionic liquids under study were prepared from amino acid methyl ester cations and bis(trifluoromethane)sulfonamide (TF2N) anions, specifically l-alanine methyl ester , d- alanine methyl ester, l-leucine methyl ester, l-proline methyl ester, l-serine methyl ester, and d-serine methyl ester. The model system used to quantify chiral recognition of each chiral ionic liquid consisted of dissolving a chiral luminescent probe, racemic Eu(2,6,- 3- pyridine dicarboxylate)3 , in the ionic liquid and measuring the ratios of left versus right- handed circularly polarized luminescence emitted from the sample. The role of intermolecular interactions and stereochemistry of the amino acids in chiral recognition of the luminescent probe will be discussed.

ORGN 174

Convenient synthesis of cyclic oligopeptides by Staudinger ligation-mediated ring-closure

Charles E Ocampo, Khanh Ha, [email protected], Byron Williams, [email protected]. Department of Chemistry, University of Florida, Gainesville, Florida 32611, United States

Ring size is the most significance factor that governs the success of cyclic peptide synthesis. The cyclization of large peptides containing more than seven amino acids is not challenging, however 7_15-membered cyclic peptides are inaccessible or can only be synthesized with great difficulty. We report a novel atom-economic and mild approach for the preparation of cyclic oligopeptides containing β- or γ-amino acid residues via solution phase Staudinger ligation. The study includes 7-, 8-membered cyclic dipeptides and 10-, 11-membered cyclic tripeptides.

ORGN 175

Convenient synthesis of CML, a key advanced glycation endproduct (AGE) biomarker Jeanette M Andersen1, [email protected], Thomas Hjelmgaard1, John Nielsen1, Lars O. Dragsted2. (1) Department of Basic Science, LIFE, Copenhagen University, Copenhagen, Denmark (2) Department of Human Nutrition, LIFE, Copenhagen University, Copenhagen, Denmark

Advanced glycation endproducts (AGEs) are formed when sugars react with peptides and proteins without the help of enzymes, and by thermal processing of food such as baking and frying. AGEs and especially CML has been used as general key biomarkers for oxidative stress and a number of diseases associated with poor lifestyle. Herein we present the first synthetic pathway to the free zwitter ion of CML via a protected intermediate, which allows for future incorporation of CML in peptide chains.

ORGN 176

WITHDRAWN

ORGN 177

Concise synthesis of the thiazole-thiazoline fragment of largazole

Frederik Diness1,2, [email protected], Daniel S. Nielsen1,2, David P. Fairlie2. (1) Department of Medicinal Chemistry, University of Copenhagen, Copenhagen, Denmark (2) Institute of Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia

We here present a novel method for the synthesis of amino acid derived thiazole-4- carbonitriles. The method presents a facile alternative to existing protocols and allows quicker access to compounds with a thiazole-thiazoline motif including the potent natural histone deacetylase inhibitor largazole. Furthermore it is demonstrated that amino acid derived thiazole-4-carbonitriles serve as superior starting materials in the synthesis of other azole-azoline ring systems which are found in a range of biologically active natural products including the antibiotics GE2270A.

ORGN 178

Turn mimetic cyclic tetrapeptides (CTPs) via copper-tris(triazole) ligand complex catalyzed macrocyclization

Gagan Chouhan, [email protected], Keith James. Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92014, United States

Protein-protein interactions (PPIs) regulate most of the biological processes in the cell and the modulation of such protein-protein interactions (PPIs) represents a large and important class of targets for human therapeutics. Proteins are comprised of three ordered secondary structures (helices, sheets, and reverse-turns), of which reverse- turns are common recognition domains for protein-protein interactions. Thus, synthetic mimics of the reverse-turn structures have potential as therapeutics. Macrocyclization of short sequences of amino acids represents an attractive strategy for achieving the conformational constraint necessary to stabilize secondary structural motifs such as reverse-turns, thereby locking the molecule into a bioactive conformation. In order to establish an optimum conformation for such macrocyclic-peptides, access to libraries of structures is usually necessary. This requires synthetic methodologies which are efficient, versatile and compatible with a range of functional groups. Herein we have described a simple and efficient copper-tris(triazole) ligand complex catalyzed- macrocyclization strategy for the synthesis of 1,2,3-triazole-containing turn mimetic cyclic tetrapeptides (CTPs).

ORGN 179

Peptide macrocyclization via Pd-catalyzed chemoselective indole C-2 arylation Huijun Dong, [email protected], Keith James. Chemistry, The Scripps Research Institute, La Jolla, CA 92037, United States

Peptide based macrocycles have found wide application, from therapeutic agents to biomaterials. Among various strategies for generating macrocyclic peptides, creation of side-chain to side-chain bridges has the advantage of not disrupting potential interaction between the N- or C-termini and the target receptor. Depending on the functional groups in the side chains, the established macrocyclization reactions have included ring-closing metathesis, amide-coupling reactions, and azide-alkyne cycloadditions. The use of transition-metal catalysts for C–C bond formation between aromatic rings constitutes an attractive way to construct biaryl-macrocycles, which represent a carbogenic fusion of naturally occurring aromatic amino acid side-chains. Here we present a macrocyclization between the side chains of tryptophan and phenylalanine derivatives through a palladium-catalyzed C–H activation reaction. This macrocyclization features a chemoselective C–H arylation of indole derivatives. The scope and the future direction of this chemistry will be discussed.

ORGN 180

Synthesis of drug-like macrocycles and bridged peptides as modulators of protein-protein interactions

James Collins, [email protected], Keith James.The Scripps Research Institute, La Jolla, CA 92037, United States

Protein-protein interactions (PPIs) represent a large and critically important sub-set of molecular interactions, integral to both extra-cellular and intra-cellular signalling pathways, typically involving large, shallow protein surface area contacts. The modulation of PPIs within cells is a largely unexploited area in drug discovery that offers huge therapeutic potential. Macrocyclic systems represent a compelling strategy for addressing intracellular PPIs, since the intrinsic conformational constraint imposed by their cyclic structure offers the prospect of improved physicochemical behaviour and lower entropic losses on binding.

We will describe our results in two related areas of research: 1. Development of novel macrocyclization reactions and optimized conditions that allow efficient generation of libraries of drug-like macrocycles 2. Application of these reactions to the synthesis of side-chain to side-chain bridged macrocyclic peptides that can exhibit a stabilized bioactive conformation or secondary structure, along with reduced susceptibility to protease cleavage

ORGN 181

Azide-based macrocyclisation strategies towards functionalised stapled peptides

Yu Heng Lau, [email protected], David R Spring. Department of Chemistry, University of Cambridge, Cambridge, United Kingdom

Stapled peptides are conformationally restricted peptides which adopt well-defined secondary structures due to the cross-linking of unnatural amino acid side chains. These cyclic peptides are strong candidates for addressing traditionally 'undruggable' drug targets such as protein-protein interactions due to their inherent binding selectivity, enhanced cell permeability and proteolytic resistance.

We report the efficient synthesis of a range of diazidopeptides, their macrocyclisation with external linkers using either a double Staudinger ligation or Cu-catalysed azide- alkyne cycloaddition, and the resulting secondary structures induced by the macrocyclisations. This synthetic approach enables the conjugation of other functional domains to stapled peptides in a convergent route, ranging from simple fluorescent tags to organelle-targeting motifs.

ORGN 182

Derivatives of a highly fluorinated and achiral α,α-dialkylated amino acid

Adria A Lombardo1, [email protected], Xi Zeng1, Douglas B Grotjahn1, Eric C Wiener2. (1) Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182, United States (2) Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, United States

The highly fluorinated, achiral, hindered amino acid α,α-bis-[3,5- bis(trifluoromethyl)phenylmethyl]glycine has been made for the first time. Synthetic methodology to overcome challenges presented by the high degree of steric hindrance at the α carbon has been investigated, including formation of the related azido acid for use in click chemistry and dendrimer formation.

ORGN 183

Solid phase synthesis of lysobactin and analog studies Edward A Hall, [email protected], Michael S. VanNieuwenhze. Department of Chemistry, Indiana University Bloomington, Bloomington, IN 47403, United States

According to a recent estimate, 70% of the bacteria that give rise to hospital infections are resistant to one or more common antimicrobial agents. With this is mind, we have chosen to investigate Lysobactin, a depsipeptide antibiotic which shows marked activity against both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin- resistant enterococci (VRE). To facilitate our synthetic studies, a high yielding solid phase approach has been developed allowing rapid access to a variety of Lysobactin analogues.

ORGN 184

Synthesis of meso-15N-2,6-diaminopimelic acid via the homologation of Ni(II) complexed nucleophilic 15N-glycine equivalents derived from a 2-[N-(α- picolyl)amino]-benzophenone ligand

Trevor K Ellis1, [email protected], Charles V Rice2. (1) Department of Chemistry and Physics, Southwestern Oklahoma State University, Weatherford, OK 73096, United States (2) Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, United States

An effective approach to the preparation of meso-15N-2,6-diaminopimelic acid (15N- DAP) will be presented. The synthetic procedure employed for the preparation of the 15N-DAP is based on the dimerization of 15N-glycine residues of two Ni(II) complexed glycine Schiff Bases of 2-[N-(α-Picolyl)Amino]-benzophenone with 1,3-diiodopropane under basic conditions in DMF. The diastereomers that result from the previous reaction are separated before the Ni(II)complexes are disassembled with dilute acid in methanol and the 15N-DAP is recovered utilizing ion exchange chromatography.

ORGN 185

Block copolypeptides with hemostatic and antimicrobial activity

Diego Benitez, [email protected], Jarrod A. Hanson, Janet Chow, Kevin R. Ogilby, Michael P. Bevilacqua. Amicrobe, Inc., Pasadena, CA 91106, United States

Amicrobe is developing new biomaterials that combine hemostatic and antimicrobial properties. It is anticipated that products utilizing Amicrobe's hemostatic / antimicrobial biomaterials will become valuable aids in the treatment of life-threatening traumatic wounds. These simple biocompatible materials are long-chain, block copolypeptides, composed of two or three different amino acids. They can be designed to self-assemble into hierarchical structures that may facilitate application and improve wound coverage, as well as improve efficacy and reduce toxicity. Selected block copolypeptides demonstrated procoagulant activity in vitro (i.e., platelet aggregation and whole blood clotting) and hemostatic activity in pilot studies in vivo (bleeding wound assay). In addition, initial data suggest that our lead copolypeptides are broadly antimicrobial, effective in wound infection models, and biocompatible with tissues. Direct application to wound cavities could improve hemostasis and reduce infection.

ORGN 186

Design and application of unnatural supramolecular amino acids as templates for peptide folding

Davoud Mozhdehi, [email protected], Zhibin Guan. Chemistry, University of California, Irvine, Irvine, CA 92697-2025, United States

Designing functional proteins and enzymes has proven to be very challenging. Many of the reported examples in literature utilize strategic placement of hydrophobic residues to direct the tertiary folding of designed proteins in water. This strategy, however, fails in nonpolar solvents as hydrophobic collapse can no longer provide cue to the folding sequence.

We propose to take a different approach to this problem in which strong and specific hydrogen bonding units, introduced in the primary sequence of peptides, replace the hydro-phobic collapse. We envision that large enthalpic gain from pairing of these strong hydrogen bonding units in a nonpolar environment can control and guide the folding process. Herein, we report the synthesis and incorporation, of two supramolecular unnatural amino acids with specific array of hydrogen bonding acceptors and donors in a series of peptides and peptoids and their effect on the secondary structure.

ORGN 187

Self-destructing latent fluorophores for dynamic biological imaging

Toshia R Zessin, [email protected], Shaina E Ives, Arthur H Winter. Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States

Bioimaging has been a powerful tool in unraveling the molecular origins of disease by determining the locations and interactions of biomolecules in cells or in living animals. The major roadblock that has prevented bioimaging from reaching its full potential is the lack of chemical probes that permit dynamic imaging as a function of time. To address this problem, I have developed a new class of small-molecule fluorescent chemical probes, termed 'self-destructing fluorophores', which are redesigned to meet this critical need. These reagents are based on latent fluorophores, which are masked fluorescent dyes that get transformed into their bright form by a mask-removing reaction with a biomolecule. To permit dynamic bioimaging, we have incorporated a molecular 'suicide switch' moiety into the chemical structure of the dyes that is responsible for switching off the dye's fluorescence, leading to transient fluorescence of the unmasked probe rather than a persistent fluorescence.

ORGN 188

Nucleophilic additions to a p-benzyne intermediate derived from an enediyne: Exploring relative reactivity of nucleophiles

Gabriel J Reyes-Rodríguez, [email protected], Charles L Perrin. Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, United States

A new mechanism for haloaromatic formation involves Bergman cyclization of enediyne 1 to a p-benzyne (2 ), which is attacked by a halide nucleophile, leading to 4 . We now report the use of other nucleophiles. Insights into nucleophilic additions to an enediyne, the role of solvation, competition experiments, and alternative capture of the aryl anion will also be reported.

ORGN 189

Rotational barriers of atropisomeric biphenyls: Kinetic and computational studies of configurationally labile ortho,ortho'-difunctionalized biphenyls

Frank Sartorius, [email protected], Reinhard Brückner. Institute of Organic Chemistry and Biochemistry, University of Freiburg, Freiburg, Germany

Atropisomerism is the basis for many design motives in asymmetric catalysis.1 Mixtures of atropisomers, the existence of which has been unraveled rather recently,2 are being sold as pharmaceuticals although the human body may respond differently to such species3 and although two-thirds of the drugs released between 2004 and 2006 were single enantiomers. This is because atropisomerism can be caused by more scaffolds than “the usual suspects”. The existence of rotational barriers in ortho,ortho'- di(!)substituted biphenyls, which we happened to find for Rortho = Rortho' = CH2Br raises awareness of that fact.

From the mentioned compound we synthesized a series of ortho,ortho'-bis(CH2X)- substituted biphenyls. We investigated the impact of X on the height of the rotational barrier using dynamic NMR spectroscopy and dynamic GLC. These results and their analysis by calculations should help to develop new atropisomeric biphenyl ligands.

1 BINOL et al., BINAP et al., BIPHEP et al., etc.

2 Clayden, J.; Moran, W. J.; Edwards, P. J.; LaPlante, S. R. Angew. Chem. Int. Ed. 2009, 48, 6398-6401; LaPlante, S. R.; Edwards, P. J.; Fader, L. D.; Jakalian, A.; Hucke, O. ChemMedChem 2011, 6, 505-513.

3 Kania-Korwel, I.; El-Komy, M. H. M. E.; Veng-Pedersen, P.; Lehmler, H.-J. Environ. Sci. Technol. 2010, 44, 2828-2835; Takahashi, H.; Wakamatsu, S.; Tabata, H.; Oshitari, T.; Harada, A.; Inoue, K.; Natsugari, H. Org. Lett. 2011, 13, 760-763.

ORGN 190

Carbon-13 nuclear magnetic resonance spectral properties of cholest-4-en-3-one and cholest-5-en-3-one Edward J Parish1, Yu-Chen Lo2, Wan-Yuan Huang3, [email protected], Hiroshi Honda3. (1) Department of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849, United States (2) Department of Biomedical Engineering, University of California, Los Angeles, Los Angeles, CA 90095, United States (3) Department of Bioengineering, Northwestern Polytechnic University, Fremont, CA 94539, United States

This paper represents carbon-13 nuclear magnetic resonance spectral properties of cholest-4-en-3-one and of the isolated reaction intermediate cholest-5-en-3-one. A DEPT experiment made it possible to distinguish the carbon resonances of secondary carbons from those of primary and tertiary carbons.

ORGN 191

Computational study of the Formose reaction in aqueous solution

Christopher G Lee, [email protected], Jeremy Kua. Department of Chemistry and Biochemisty, University of San Diego, San Diego, CA 92110, United States

The oligomerization of formaldehyde in the Formose reaction has implicit importance in the study of the origin of life. Ribose, the sugar in RNA is a pentameric oligomer of formaldehyde, but only one among a variety of pentoses and hexoses synthesized in the unselective formose reaction. We use Density Functional Theory (B3LYP//6-311G**) to study the formose reaction in aqueous solution. Specifically, we calculate the solution free energies and activation barriers of a range of intermediates and products formed in the oligomerization reaction. This allows us to identify the low-barrier pathways and the thermodynamic sinks in the reaction. In doing so, we hope to obtain a better understanding of the complex product distribution found in the Formose reaction and elucidate conditions by which certain products may be selected for over others.

ORGN 192

Multidimensional tunneling effects on nitrogen inversion in aziridine, diaziridine, and bis-aziridine

Ian E Stewart, [email protected], John D. Thoburn. Department of Chemistry, Randolph-Macon College, Ashland, VA 23005, United States

Quantum mechanical tunneling plays a role in many reactions involving hydrogen transfer, yet it is often difficult to determine how much tunneling contributes to the overall rate because it usually competes with the quasi-classical rate of reaction. If tunneling is significant however, it will affect observable parameters such as the kinetic isotope effect (KIE), Arrhenius parameters (A and Ea), and Swain-Schaad exponents (SSE). This poster will explore multidimensional tunneling effects on the rates of nitrogen inversion. First, the rates and H/D KIE will be calculated using POLYRATE and GAUSSIAN03 with mPW1K/6-31+G(p,d) methodology for nitrogen inversion in aziridine since its rates and H/D KIE have been measured experimentally and calculated with various tunneling models. Then we will present results on the effect of tunneling on the double nitrogen inversion in diaziridine and bis-aziridine to see how tunneling affects the KIE for both the concert and stepwise mechanisms of double nitrogen inversion.

ORGN 193

Computational investigations of coarctate and pseudocoarctate rearrangements

James A. Duncan, Hillary A. Henthorn, [email protected], Sarah H. Sandholtz, [email protected], Cassandra A. Settle. Chemistry, Lewis & Clark College, Portland, OR 97219, United States

A CASSCF computational investigation was conducted on two sets of reactions, some of which are depicted below. The first set served as a model study of the partial mechanism of the known conversion of (2-ethynylphenyl)triazines and (2- ethynylphenyl)diazines into their corresponding heterocycles, while the second set provided further insights. The results of this mechanistic study, which focused on whether a particular reaction proceeded via a fully coarctate mechanism (no orbital disconnections) or via a pseudocoarctate mechanism (one or more orbital disconnections), are reported.

ORGN 194

Modulating Fermi resonance through isotopic editing

Rui Song, [email protected], Edward E. Fenlon, Scott H. Brewer. Chemistry, Franklin & Marshall College, Lancaster, PA 17603, United States

The azido group (R-N3) has great potential as a sensitive, site-specific vibrational probe in proteins and nucleic acids. However, the utility of some azide probes is hindered by accidental Fermi resonance. The syntheses and IR spectra of six 15N and 2H isotopomers of 3-azidopyridine (1 ), a model system, will be presented. In addition, syntheses of unlabeled and 15N middle labeled isotopomers of azidohomoalanine (2 ) will be presented. Finally, attempts to make 15N middle labeled 2'-azido-2'-deoxyuridine (3 ) will be presented.

ORGN 195

Halocarbene additions to strained C-C pi bonds: Mechanistic surprises

Viktoriya Rutkovskaya, [email protected], Aliza Stein, [email protected], Marina Orman, Ul Weena, Dina C. Merrer, [email protected]. Department of Chemistry, Barnard College, New York, NY 10027, United States

Dihalocarbene additions to C-C π systems with ≥55 kcal/mol of strain energy are affected by reaction dynamics. Preliminary direct dynamics trajectories of CCl2 + benzocyclopropene (1 ; Estrain = 68 kcal/mol) using restricted DFT proceed via xylylene 2 to benzocyclobutene in <65 fs. In contrast, unrestricted DFT trajectories reveal novel reaction path 1 →7 . Adamantene (9 ; Estrain = 37 kcal/mol) is reacted photochemically with chlorocarbenes to form 10 . Product studies will elucidate the mechanisms of addition.

ORGN 196

Kinetic studies of oxygen atom transder reaction from trans-dioxoruthenium(VI) porphyrins to sulfides

Chris Abebrese, Yan Huang, Alice Pan, Zhibo Yuan, [email protected], Rui Zhang. Department of Chemistry, Western Kentucky University, Bowling Green, KY 42101, United States The kinetics of the reactions of three trans-dioxoruthenium(VI) porphyrin derivatives with organic sulfides were measured. These trans-dioxoruthenium(VI) species were competent oxidants and reacted rapidly with thioanisoles to generate corresponding sulfoxides. Typical second-order rate constants determined for sulfoxidation reactions are 8-60 M-1s-1, which are 3 orders of magnitude larger in comparison with those of well studied alkene epoxidations and activated C-H bond oxidations by the same dioxo species. Various para-substituted thioanisoles react in a narrow kinetic range with the same dioxo species. The kinetic results obtained in this study indicate a concerted oxygen atom transfer and/or electron transfer followed by oxygen transfer mechanism from oxidant to sulfide. Competition kinetic reactions with a catalytic amount of porphyrin ruthenium(II) species and a terminal oxidant give relative rate constants for sulfoxidation of competing substrates that are consistantly smaller than the ratios of absolute rate constants, implying a multiple oxidant model for sulfoxidation reactions.

ORGN 197

Lewis acid assisted Brønsted acid catalyzed imino-aldol reaction

Anil Kumar Gupta, [email protected], Victor Prutyanov, William Dean Wulff. Department of Chemistry, Michigan State University, East Lansing, MI 48824, United States

In 2001, we developed an unusually robust Zr-VAPOL catalyst for the imino-aldol reaction that could provide high selectivities and maintain practically the same efficiency over a range of temperatures from 25 to 100oC. Prior to our work, Kobayashi and co- workers reported the same reaction using 6,6'-Br2-BINOL derivative in 1997. In literature, two mechanisms have been proposed. One of them involves the presence of imidazole in the transition state whereas the other one assumes no role of imidazole in the transition state. Both reactions were assumed to be Lewis acid catalyzed reactions. Utilizing computational chemistry by means of Gaussian '03, we found that the reaction is actually a Lewis acid assisted Brønsted acid catalyzed reaction. The transition states were located using ONIOM level DFT Calculations.

ORGN 198

Reactivity of vinyl azides in solution and matrix isolation studies

Ranaweera A. A. Upul Ranaweera, [email protected], Jeanette A. Krause, Bruce S. Ault, Anna D. Gudmundsdottir. Department of Chemistry, University of Cincinnati, Cincinnati, OH 45220, United States

Triplet vinyl nitrenes are intermediates that have high spin properties and thus have the potential to be used as building blocks for organic magnets. We investigated the photoreactivity of vinyl azides 5a and 5b , to determine whether it forms triplet vinyl nitrenes upon irradiation. We used laser flash photolysis (LFP, λ=308 nm, 17 ns) of 5a-b , product studies, matrix isolation, and theoretical calculations to identify the triplet vinyl nitrene intermediates and their reactivity. Solution photolysis of 5a and 5b in argon- saturated chloroform-d yielded 6a-b, 7a-b and 8a-b . In comparison, solution photolysis of 5a in oxygen-saturated chloroform-d also yielded 6a , 7a and 8a whereas 5b yields 6b , 7b , 8b and 9b . The mechanism for product formation will be discussed.

ORGN 199

Additive fluorescence color mixing in the solution of excited-state intramolecular proton transfer (ESIPT) dye mixtures showing frustrated energy transfer

Ji Eon Kwon1, [email protected], Sanghyuk Park2, Soo Young Park1. (1) Department of Materials Science and Engineering, Seoul National University, Seoul, Republic of Korea (2) Department of Chemistry, Kongju National University, Gongju, Chungnam 314-701, Republic of Korea

Here, we will report a simple mixture system composed of RGB emitting ESIPT dyes, each of which has delicately tailored Stokes' shift and independent emission without any kind of energy transfer between them. It will be demonstrated that the whole range of emission colors enclosed within the color triangle is conveniently reproducible from the RGB mixture by varying either excitation wavelength or mixing ratios. It must be noted that the exact emission spectrum is easily predictable by the simple sum of three RGB spectra.

ORGN 200 Role of distortion energy on 1,3-dipolar cycloadditions to strained alkenes

Steven A Lopez, [email protected], Kendall N Houk. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, United States

Quantum mechanical calculations were used to investigate the role of strain energy on reactivity in 1,3-dipolar cycloadditions. These reactions with strained alkenes and alkynes have become increasingly important in click chemistry for bioorthogonal reactions. This study reports a computational investigation of azide cycloadditions to various strained and unstrained cycloalkenes, including norbornene derivatives. Quantum mechanical calculations were carried out with B3LYP, M06-2X, and SCS-MP2 methods with several basis sets to benchmark the reaction enthalpies and activation barriers. This study contains the first transition structures for the (3+2) cycloaddition of norbornene and phenyl azide. The calculated reaction barriers are strongly correlated with distortion energy and not with strain release. The stereoselectivity of reactions of norbornene and derivatives was also explored. Significant staggering occurs in the transition structures of exo addition to norbornene, while endo transition structures have appreciable eclipsing.

ORGN 201

Cage opening/rearrangement of cubyl styrene

Christopher J Dietz, [email protected], Ronny Priefer. Department of Chemistry and Biochemistry, Niagara University, Niagara University, New York 14109, United States

Cubane is considered to be very stable even though it possesses very high strain energy. Studies on cubane have revealed that the molecule can undergo intramolecular rearrangement based upon the functionality directly attached to the cage. Cubanol, cubyl amine, and cubane thiol all undergo a spontaneous ring opening by the donation of an electron pair into the cage. In addition, we showed that 4-iodo-1-vinylcubane quantitatively undergoes cage opening under thermo or Lewis acid assisted conditions to initially yield its corresponding cyclooctatetraene and further rearranges to produce 4- vinyl-trans-β-iodostyrene. We felt that styrene derivatives of cubane may deter the possibility of the cage opening by stabilizing the charged or radical intermediate. This was not the case and the cage opening/rearrangement was in fact accelerated. Our goal in this research is to investigate this thermolytic rearrangement and to ascertain its mechanism.

ORGN 202

Solution structures of lithium phenolates: A survey of ligand binding Laura L Tomasevich, [email protected], David B Collum. Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States

Reactions involving lithium enolates have proven over the years to be reliable methods for forming carbon-carbon bonds. Despite their importance, the characterization of lithium enolates in a reaction mixture has not been thoroughly explored, as gaining structural information has proven to be a difficult task for several reasons. The method of Continuous Variation applied to lithium-6 NMR spectroscopy has been used to gain structural insight into organolithium reactions. Lithium phenolates offer the opportunity to serve as a proxy for lithium enolates while also enabling the study of ligands which are not compatible with enolate chemistry. A survey of various ligands with phenolates of different steric demands is described, with a semi-quantitative assessment of the relative binding strengths of the various ligands.

ORGN 203

Mechanism and rate of thermolytic fragmentation of substituted benzylic dialkoxy disulfides

Eric G Stoutenburg, [email protected], Ronny Priefer. Department of Chemistry and Biochemistry, Niagara University, Niagara University, New York 14109, United States

Previous work has shown that dialkoxy disulfides fall apart under thermolytic conditions to yield trappable S2. Two possible mechanisms have been proposed for this process. In an effort to further ascertain the fragmentation of this moiety a library of benzylic dialkoxy disulfides were synthesized and subjected to thermo-stability studies. This was performed in solution, as well as neat using TGA and DSC. Each derivative had different substituents in the para position which was shown to influence both the method and rate of fragmentation. The presence of a distinctive AB-quartet was used to monitor the rate of deterioration. In addition, the coupling constant of the AB-quartet for each benzylic dialkoxy disulfide was solvent dependent. Upon heating, the derivatives decomposed into distinctive ratios of alcohol to aldehyde. This data was used to discern between Harpp's and Thompson's proposed mechanisms of fragmentation.

ORGN 204

Theoretical evaluation of two and three-center intramolecular hydrogen bonds in 2-(R-anilino)-1,4-naphthoquinones

Sarai Vega Rodríguez, [email protected], Rogelio Jiménez Cataño, Elisa Leyva, Silvia E Loredo Carrillo.Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí, San Luis Potosí, San Luis Potosí 78210, Mexico

Density functional theory calculation at BP86/6-311G(d, p) level of theory was realized to determine the existence of two and three-center intramolecular hydrogen bond in a series of naphthoquinone derivatives. The characteristic features of hydrogen bond formation (geometric changes and vibrational frequency shift), suggest the formation of two and three-center intramolecular hydrogen bonds in molecules theoretically evaluated.

ORGN 205

Cyclization of o-alkynyloxime derivatives under photooxidative conditions

Wanshin Kim, [email protected], Peter de Lijser. Department of Chemistry and Biochemistry, California State University, Fullerton, Fullerton, CA 92834, United States

Synthesis of heteroaromatic ring systems is of particular interest in natural product chemistry. Previous studies have revealed that ortho-alkynyloxime derivatives can undergo efficient electrophilic cyclization, yielding isoquinoline or isoquinoline N-oxide derivatives. However, not much attention has been focused on the oxime radical cation or iminoxyl radical cyclization processes of ortho-alkynyloxime derivatives. Our previous studies have shown that oxime derivatives can form reactive radical species under photooxidation, which suggests that cyclization might be possible in the case of o- alkynyloximes. In order to study this possibility as well as the regioselectivity of these cyclization processes, we prepared a series of o-alkynylbenzaldehyde and acetophenone oximes. The oximes were subjected to photooxidation or thermal oxidation in different solvents and the product formation was followed by GC/MS and NMR. The results obtained so far suggest that cyclization does indeed occur, although the process is not selective. This presentation will discuss the influence of substituents, solvent, oxidizer and other factors on the cyclization and other reactions of the reactive intermediates derived from the o-alkynyloximes.

ORGN 206

Elucidation of the intramolecular Diels-Alder reaction of tryptamine-derived Zincke aldehydes

Hung V. Pham1, [email protected], David B. C. Martin2, Christopher D. Vanderwal2, Kendall N. Houk1. (1) Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, United States (2) Department of Chemistry, University of California, Irvine, Irvine, CA 92697, United States

Computational studies show that the base-mediated intramolecular Diels–Alder reaction of tryptamine-derived Zincke aldehydes, used as a key step in the synthesis of the Strychnos alkaloids norfluorocurarine and strychnine, proceeds via a step-wise pathway. The experimentally determined importance of a potassium counterion in the base is explained by its ability to preorganize the Zincke aldehyde diene in an s-cis conformation suitable to bicyclization. Computation also supports the thermodynamic importance of the generation of a stable enolate in the final reaction step. The thermal cycloreversion reaction of the Diels–Alder products is also found to proceed in a step- wise manner.

ORGN 207

Theoretical study of cyclohexyne addition to carbonyl-Cα bonds: Allowed vs. forbidden electrocyclic ring openings of strained cyclobutenes

Charles A Sader, [email protected], Kendall N Houk. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, United States

The mechanism of cyclohexyne insertion into a C(O)-Cα bond of cyclic ketones, explored experimentally by the Carreira group, has been investigated using density functional theory. B3LYP and M06-2X calculations were performed in both gas phase and THF (CPCM, UAKS radii). The reaction proceeds through a stepwise [2+2] cycloaddition of cyclohexyne to the enolate, followed by ring opening of the cyclobutene alkoxide to give the product. Surprisingly, our computational results for the model alkoxide and potassium alkoxide systems show that the allowed/forbidden energy gap in the ring opening is less than 1 kcal/mol, which is in sharp contrast to that of simple cyclobutenes. In more complex systems, the barrier of the forbidden disrotatory ring opening is lower in energy than that of the allowed conrotatory ring opening by 4-8 kcal/mol. This suggests that the thermodynamically more stable disrotatory product can be formed directly through a “forbidden” pathway.

ORGN 208

Photolysis of phenylazirine derivatives

Xiaoming Zhang, [email protected], Anna D. Gudmundsdottir. Department of Chemistry, University of Cincinnati, Cincinnati, Ohio 45221, United States

Photolysis of 3-phenyl-2-methyl-2H-azirine (1a ) in dichloromethane yields benzaldehyde (2 ) and 1-chloro-1-phenylpropan-2-one (3 ). Similarly, photolysis of 1a in bromoform yields 2 and 1-bromo-1-phenylpropan-2-one (4 ). However, photolysis of the isomeric 2-phenyl-3-methyl-2H-azirine (1b ) in yields a dimer 2,5-dimethyl-3,6-diphenyl- 2,5-dihydropyrazine (8 ). Laser flash photolysis of 1b in acetonitrile results in a long lived transient absorption with maximum at 335 nm that we assign to ylide formation. In comparison, laser flash photolysis of azirine 1a resulted in a transient absorption with λmax at ~460nm, which has a lifetime of 12 ms. We will present density functional theory calculations to explain the different reactivity of isomers 1a and 1b .

ORGN 209

Anomeric effects in fluoro and trifluoromethylpiperidines

Nathan D. Erxleben1, [email protected], Gary S. Kedziora2, Joseph J. Urban1. (1) Chemistry Department, United States Naval Academy, Annapolis, MD 21402, United States (2) High Performance Technologies, Wright Patterson AFB, OH 45433, United States

The conformational preferences of 2-fluoro and 2-trifluoromethylpiperidine have been investigated with a variety of computational approaches including molecular mechanics, density functional theory, and post-HF ab initio methods. Conformations with the fluoro or trifluoromethyl group axial are found to be stabilized in a manner consistent with a stereoelectronic effect akin to the anomeric effect. Results from a variety of levels of theory including ωB97XD, B2PLYP-D, and CCSD(T) will be compared. Natural bond orbital analysis will be used to provide insight into the conformer relative stabilities. The impact of the stereoelectronic effect on the ability of the X-C-N (X =F, CF3) moiety to engage in intermolecular hydrogen bonding interactions will also be investigated.

ORGN 210

Cysteine-catalyzed enantioselective Rauhut-Currier reaction: A computational study

Silvia Osuna1, [email protected], Scott J. Miller2, K. N. Houk1. (1) Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California 90095, United States (2) Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States

The Rauhut-Currier (RC) and the Morita-Baylis-Hillman (MBH) reactions involve a nucleophilic conjugate addition and latent enolate generation. Both MBH and RC are of interest due to the formation of new C-C bond in an atom economical manner, and actually represent unique and valuable protocols for C-C bond formation. Although the MBH has been widely studied, the RC has received much less attention due to the low reactivity of substrates and the low selectivity of the process. In 2007, Miller and coworkers established a method for affording enantioselective RC reactions using a simple cysteine derivative as an asymmetric catalyst.1,2 The reaction consists of several steps, first the conjugate addition of the thiolate to one of the activated alkenes, then cyclization via Michael addition, and finally proton transfer and elimination of the of the Cys-derived anion (see scheme 1). In this communication, a thorough theoretical investigation of the different steps in the cysteine-based enantioselective RC reaction is presented.

(1) Aroyan, C. E.; Dermenci, A.; Miller, S. J. J.Org. Chem. 2010 , 75, 5784.

(2) Aroyan, C. E.; Miller, S. J. J. Am. Chem. Soc. 2007 , 129, 256.

ORGN 211

Photochemistry of arylazides

Elisa Leyva, [email protected], Edgar Moctezuma, Rogelio Jiménez, Saraí Vega. Centro de Investigación y Estudios de Posgrado, Universidad Autónoma de San Luis Potosí, San Luis Potosí, San Luis Potosí 78210, Mexico

Polyfluorinate arylnitrenes are useful reagents in organic synthesis, for the covalent modification of polymer surfaces and in photoaffinity labeling (PAL). This represents a new way to attach radiotracers to antibody fragments for diagnostic and therapeutic uses, in potential noninvasive imaging and therapy against cancer. The photochemical reactions of arylazides are presented. The desired reactions for PAL are insertion and addition since they result in covalent attachment. However, these particular reactions are not favored for the parent phenyl azide. In biochemistry, arylazides have been the most frequently used photoaffinity labels since they are relative easy to synthesize and to handle and because they are quite stable to physiological pH. Thus, a more complete understanding of photochemistry of a given arylazide is a basic requirement for its use in PAL. We will discuss the reactions and intermediates generated upon photolysis of fluorophenylazides and some examples of the application of these reagents in PAL and organic synthesis will be shown.

ORGN 212 Model studies for elementary steps in carbon condensation mechanisms

Brian J Esselman1, [email protected], Frank L Emmert III2, Andrew J Wiederhold1, Stephanie Thompson2, Lyudmila V Slipchenko2, Robert J McMahon1. (1) Department of Chemistry, University of Wisconsin, Madison, WI 53706, United States (2) Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States

The ring-coalescence and annealing model for fullerene formation postulates a [2+2] cycloaddition of polyynes to produce a polyethynyl-substituted cyclobutadiene which then undergoes a Bergman cyclization to produce a p-benzyne. Computationally, the cyclization of diethynylcyclobutadiene proceeds in the expected manner and is slightly exothermic, but the subsequent ring-opening to produce cyclooctadiendiyne has a vanishingly small barrier. The diradical will thus be short-lived, which appears to be inconsistent with the current model.

ORGN 213

Diazonium ion derived adducts formed in the reaction of cyclic nitrosamines: N- nitrosomorpholine, N-nitrosopyrrolidine and, N-nitrosopiperidine

Niti H Shah, [email protected], Niangoran Koissi, Charles N Zink, James C Fishbein. Department of Chemistry and Biochemistry, University of Maryland Baltimore County, Baltimore, MD 21250, United States

Nitrosamines are an important class of potentially carcinogenic compounds. Metabolic activation of nitrosamines by P-450 catalyzed α-hydroxylation produces α- hydroxynitrosamine which decomposes in aqueous media to a highly reactive diazonium ion. The resulting electrophilic diazonium ion reacts with nucleophilic sites on DNA and forms DNA-adducts. Diazonium ion derived adducts formed in the reaction of cyclic nitrosamines, N-nitrosomorpholine (NMOR), N-nitrosopyrrolidine (NPYR) and, N- nitrosopiperidine (NPIP), are investigated. A detailed comparative study of the alkylation at O6 and N7 guanine and, N3- adenine in the reaction of carcinogens with nucleosides and DNA was done. Identification and quantification of adducts from the reaction of carcinogen with nucleosides and DNA was accomplished by LC-MSMS with the use of synthetic standards.

ORGN 214

Energy transfer in a quantum chain reaction of aryl- and alkyl-linked diarylcyclopropenone dimers takes place through a Dexter or linker-dependent super-exchange mechanism, depending on the nature of the linker

Amy E. Nielsen, [email protected], Miguel A. Garcia-Garibay, Gregory Kuzmanich. Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA 90024, United States

The photochemical decarbonylation of diarylcyclopropenones has been previously shown to proceed adiabatically at 312 nm with quantum yields of up to 3.3±0.3 in the solid state. Aryl- and alkyl-linked diarylcyclopropenone dimers under go the same adiabatic ring-opening reaction, with quantum yields >1 in solution and in solids. Computational analysis of intrachromophore distance and orientation, as well as experimentally determined energy transfer efficiency, reveals that a Dexter or linker- dependent super-exchange mechanism is operative, depending on the nature of the linker.

ORGN 215

Self-assembly and photophysical properties of cylindrical perylene-3,4- dicarboximide-based aggregates

Kelly M. Lefler1,2, [email protected], Dick T. Co1,2, Michael R. Wasielewski1,2. (1) Department of Chemistry, Northwestern University, Evanston, IL 60208, United States (2) Argonne-Northwestern Solar Energy Research Center, Evanston, IL 60208, United States

Natural photosynthesis relies upon non-covalent interactions between chromophores to regulate the direction, yield, and rate of energy and charge flow. We have incorporated perylene-3,4-dicarboximide (PMI) in a covalently linked PMI-melamine (Mel) system with two phenyl spacers. PMI has a ground state dipole that could provide an electrostatic driving force for charge motion in certain aggregate structures. Solution phase small- and wide-angle X-ray scattering experiments in methylcyclohexane indicate that the observed aggregation is a cylindrical structure with a circumference formed by 6 (PMI-Ph2-Mel) monomer units. Transient absorption spectroscopy does not show evidence of charge transfer in the monomer; however, in the aggregated system charge separation is observed on the picosecond timescale with τcs 41±2 ps. Charge recombination occurs with τcr 366±35 ps. This suggests that electron transfer occurs through the shortened intermolecular pathway created by the hydrogen bonding in the aggregate and not through the intramolecular pathway.

ORGN 216

Torquoselectivity in hexatriene electrocyclizations

Ashay Patel1, [email protected], Kendall N. Houk1, Joeeph Vella2. (1) Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, United States (2) Department of Chemical and Biochemical Engineering, Rutgers University, Piscataway, NJ 08854, United States

Hsung and coworkers have developed two 6π electrocyclic ring-closing manifolds involving azatrienes and 2-halo-amidotrienes. In addition, Barcan and Kwon have incorporated a torquoselective ring closing into their total synthesis of reserpine. We have used QM calculations (B3LYP and M062X) to identify the source of torquoselectivity in each of these cases and to characterize the energetics of the relevant reaction pathways. Our computations reveal that both steric and electronic effects can control torquoselectivity in these systems. Stereoselectivity in the electrocyclization of azatrienes is determined by the inside alkoxy effect. Torquoselectivity in both Hsung's 2-haloamidotriene and Barcan/Kwon's electrocyclization is caused by steric effects. In 2-haloamidotrienes, this steric clash manifests itself indirectly through an unfavorable rotation of a key dihedral to alleviate a potential clash in the disfavored TS. Torquoselectivity in the Barcan/Kwon electrocyclization is explained by the presence of allylic strain in one of two diastereomeric transition states. Rhw dog jumps over the fence every time he see a bone in the neighbors yard

ORGN 217

Theoretical modeling of nucleophilic aromatic substitution by glutathione in polychlorinated biphenyls (PCBs)

Donald Boerth1, [email protected], Anthony Arvanites2. (1) Department of Chemistry & Biochemistry, University of Massachusetts Dartmouth, Dartmouth, MA 02747, United States (2) Department of Chemistry & Biochemistry, University of Massachusetts Dartmouth, Dartmouth, MA 02747, United States Bioremediation of halogenated xenobiotic compounds by microorganisms is an important mechanism for the removal of polychlorinated biphenyls (PCBs) and other halogenated pollutants from industrial and agricultural sources. A principal pathway for this detoxification of halogenated aromatic compounds is nucleophilic conjugation of glutathione catalyzed by glutathione-S-transferases. In order to elucidate the fundamental mechanism of these reactions and factors responsible for reactivity, we have studied reactions of planar and non-coplanar PCB congeners with thiomethoxide, a strong nucleophile and model for glutathione. Molecular orbital theory was applied at Hartree-Fock and Density Functional Theory levels of theory to the reaction hypersurface in the gas phase and in aqueous solution using the SM8 method of Cramer and Truhlar. Comparison was made to the nucleophilic reactions of simple chlorobenzenes, which appear to be single-step processes in the gas phase with no sigma-complex or Meisenheimer complex as a true intermediate on the reaction coordinate.

ORGN 218

Organic single-monolayer rectifiers: Preparation and properties of tetracyano-p- quinodimethane derivatives

Edward J Parish1, Yuchen Lo2, Hiroshi Honda3, [email protected]. (1) Department of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849, United States (2) Department of Biomedical Engineering, University of California, Los Angeles, CA 90095, United States (3) Department of Bioengineering, Northwestern Polytechnic University, Fremont, CA 94539, United States

This paper represents the preparation and evaluation of donor-sigma-Acceptor materials which have electron-donor and electron-acceptor moieties covalently bonded through a non conjugated bridge of carbon, nitrogen and/or oxygen atoms.

ORGN 219

Attempted preparation of four-membered ring halonium ions and iodine cation-Π complex study

Nathan Connolly, [email protected], Brian K. Ohta. Department of Chemistry, Villanova University, Villanova, PA 19085, United States

Direct observation of stable four-membered ring halonium ions has eluded researchers. Results from our laboratory suggest that four-membered rings are susceptible to nucleophilic attack by SO2, the typical solvent used to characterize halonium ions under superacidic conditions. Herein, we experimentally and computationally investigate the stability of four-membered ring chloronium, bromonium, and iodonium ions. Experimentally, attempted syntheses of tetramethylene halonium ions showed that the predominant species was 1-methylethylene halonium ion. However, additional signals in the spectrum could be assigned to an alternative structure that suggests nucleophilic 1 addition of SO2 to the ions. In the iodonium ion, the H spectrum of the 1-methylethylene iodonium ion does not exhibit a germinal coupling constant between the diasteriotopic, geminal protons. The absence of a large coupling constant suggests the hybridization of the metyhlene carbon in the 1-methylethylene iodonium ion is sp2 and the molecule resembles a cation-Π complex rather than a sigma complex.

ORGN 220

Photochemical, electrochemical, and computational investigations of perimidinespirohexadienone photochromes, toward photochromic photooxidants

Jason G. Gillmore, [email protected]. Department of Chemistry, Hope College, Holland, MI 49423, United States

We are working to develop a new class of photooxidants based on organic photochromes to add an additional level of gating to the process of photoinduced charge transfer initiation of cation radical reactions of materials relevance. Perimidinespirohexadienone meets the requirements of photochemical coloration, * thermal fade, and more positive excited state reduction potential (E red) for long * wavelength (LW) vs. short wavelength (SW) isomers. However ΔE red is very modest, and LW is only a weak photoxidant. To understand and improve these redox properties, several analogs have been prepared. Electrochemical, photochemical and photophysical measurements help us understand these compounds' photochromic and electrochromic rearrangements. NOE experiments on quinazolinespirohexadienones prove an unexpected structure for LW, and indicate differential spirocyclic ring opening depending on whether this occurs photochromically, electrochromically, or thermally. This newfound structural data explains our interesting electrochemical results, and renders these in agreement with ground-state reduction potentials we are able to predict computationally.

ORGN 221

Structure/Reactivity studies of O-alkyl carbinolamides in water as function of pH

Sarah C. Stewart, [email protected], Richard W. Nagorski. Department of Chemistry, Illinois State University, Normal, Illinois 61790, United States

Carbinolamides are formed by the reaction of an amide and an aldehyde/ketone with an accompanying proton shift. Interest in their chemistry has been fueled by their intermediacy in the enzyme catalyzed synthesis of α-amidated peptides and in many other biological venues. Mechanistic studies of the aqueous reaction of these compounds have produced an interesting spectrum of reactivity. More recently an increasing number of O-alkylated carbinolamides have been isolated that have interesting biological function. The methods by which these compounds accomplish their biological function is unknown and this is, in part, due to a complete lack of knowledge as to the mechanisms by which these compounds react in solution. The purpose of the work presented here was to synthesize a number of O-alkylated carbinolamide derivatives of benzamide and acetamide, and study their breakdown in water as a function of pH. The acid-catalyzed rate constants for the carbinolamide derivatives will be discussed, along with two kinetically viable mechanisms of breakdown.

ORGN 222

Total synthesis of bryostatin 7 via C-C bond forming hydrogenation: Merged redox-construction events for synthetic efficiency

Yu Lu, [email protected], Sang Kook Woo, Michael J Krische. Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, TX 78712, United States

The marine macrolide bryostatin 7 is prepared in 20 steps (longest linear sequence) and 36 total steps. A total of 5 C-C bonds are formed using hydrogenative methods. The present approach represents the most concise synthesis of any bryostatin reported, to date, setting the stage for practical syntheses of simplified functional analogous.

ORGN 223

Synthesis of minimized analogs of the helminthosporols

Jack P Stehman, [email protected], Sveta Shneider, Eduard G Casillas, [email protected]. Department of Chemistry, Villanova University, Villanova, PA 19085, United States

The isomeric natural products, helminthosporol (1 ) and prehelminthosporol (2 ), have shown inhibitory activity against Acyl-CoA Acyltransferase, an enzyme responsible for cholesterol uptake. Several analogs that lack pendant groups from the [3.2.1]- bicyclooctane core are being prepared in order to explore structure activity relationships, featuring deoxyhelminthosporol (3 ) and desisopropylprehelminthosporol (4 ). The syntheses employ a key sequence involving Michael-initiated ring closure of a functionalized cyclopentenone (6 ) followed by divinylcyclopropane rearrangement to provide the appropriate bicyclic ketone (5 ).

ORGN 224

Efforts towards the preparation of a cembrane precursor to sarcoglane

Silviana Ruci, [email protected], Ryan A. Sowers, Eduard Casillas, [email protected]. Department of Chemistry, Villanova University, Villanova, PA 19085, United States

Sarcoglane, a cytotoxic diterpene metabolite produced by the soft coral Sarcophyton glaucum, possesses a unique tricyclo[7,5, 010,14] [7.5.0]tetradecenone ring system, the biogenesis of which could originate from a cembrane precursor. To investigate the chemical (non-enymatic) feasibility of such a transformation, the cembrane is the focus of recent synthetic efforts. The synthetic approach has focused on the preparation of a synthon, similar to geranial, from which both halves of the final macrocycle can be derived.

ORGN 225

Flexible syntheses of isogemichalcones B & C

Drew Brandt, [email protected], Kristina M. Grauer, Eduard Casillas, [email protected]. Department of Chemistry, Villanova University, Villanova, PA 19085, United States

Isogemichalcones B & C, isolated from Hypercum geminiflorum and Broussonetia papyrifera, respectively, have been shown to possess inhibitory activity against aromatase, a cytochrome P450 enzyme responsible for estrogen biosynthesis. These natural products have been synthesized in short preparations (~10 steps) incorporating key Stille, Claisen-Schmidt, and Mitsunobu couplings. The current synthetic route is amenable to providing various substitutions on the three aryl rings for the purpose of exploring early structure-activity relationships (SAR).

ORGN 226

Short and efficient syntheses of oxacyclic natural products-Nodulisporacid A and Urechitol A

Tatsunobu Sumiya1,2, [email protected], Ken Ishigami2, Hidenori Watanabe2. (1) Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., Nogi-Machi, Shimotsuga-Gun, Tochigi 3290114, Japan (2) Graduate School of Agricultural and Life Scieneces, The University of Tokyo, Bunkyo-ku, Tokyo 1138657, Japan

Nodulisporacid A was reported to exist as a 1:1 equilibration mixture of the (E)- and (Z)- isomers. However the stereochemistry at the three asymmetric centers of Nodulisporacid A remained unclear. We report a synthesis of four stereoisomers of Nodulisporacid A by the concise approach which includes the three-component reaction.

Urechitol A has a novel and unique structure, incorporating a highly functionalized cycloheptane ring with two oxygen bridges. Recently, we synthesized racemic Urechitol A using a [4+3] cycloaddition as a key reaction.

ORGN 227

Towards a total synthesis of rhizopodin

Michael Dieckmann, Manuel Kretschmer, Pengfei Li, Sven Rudolph, Daniel Herkommer, Dirk Menche, [email protected]. Department of Organic Chemistry, Universität Heidelberg, Heidelberg, Germany

An efficient strategy towards a total synthesis of the potent natural product rhizopodin is presented. The C2-symmetric macrolide consists of a 38-membered macrolactone with two attached side chains and bears 18 stereogenic centers overall.

The stereocontrolled synthesis of the three key subunits and their successful union is described allowing for rapid access to the macrocyclic core. Attachment of the side chains is possible in a bidirectional manner based on aldol methodology enabling efficient access to the target compound.

ORGN 228

Towards the total synthesis of Parnafungin A

Anna M Linsenmeier, [email protected], Stefan Braese. Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Karlsruhe, Baden-Württemberg 76131, Germany

Parnafungin A (1 ), isolated from the fungus Fusarium larvarum,[i] implies both, a tetrahydroxanthone 2 as well as an isoxazolidinone core 3 .

For the total synthesis of Parnafungin A (1 ) it is planned build up the tetrahydroxanthone core 6 via a domino oxa-Michael-aldol reaction with the functionalized salicylaldehyde 5 and cyclohexenone 4 . After oxidation in benzylic position and hydrogenation of the carbon-nitrogen-bond, we want to finish the total synthesis of Parnafungin A (1 ) by ring-closure of the isoxazolidinone cycle and subsequent deprotection.

[i] Overy, D. Bioorg. Med. Chem. Lett. 2009 , 19, 1224–1227.

ORGN 229

Synthesis and structure elucidation of Ac2SGL: A sulfoglycolipid from Mycobacterium tuberculosis

Danny Geerdink, [email protected], Bjorn ter Horst, Adriaan J. Minnaard. Department of Bio-Organic Chemistry, University of Groningen, Groningen, Groningen 9747 AG, The Netherlands

Tuberculosis (TB) has been one the most infectious and deadly diseases for decades and is nowadays responsible for the death of 1.7 M people annually. The thick hydrophobic cell wall of the microorganism responsible for TB, Mycobacterium tuberculosis (M.tb), is the main reason for its persistence, creating an impermeable barrier for antibiotics.

An interesting compound found only in the cell wall of M.tb is di-acylsulfoglycolipid (Ac2SGL). Ac2SGL was recognized to function as a mycobacterial antigen able to activate T-cells which in turn can release interferon-γ, kill mycobacteria in vitro and recognize infected antigen presenting cells. For these reasons, Ac2SGL could be of interest for a TB vaccine.

In light of all these appealing properties we aimed for the first asymmetric synthesis of Ac2SGL. A prerequisite was to elucidate the absolute stereochemistry of the hydroxyl group at C-17 vicinal to the 1,3-polymethyl array. In the presentation we will present how we unraveled the stereochemistry using NMR and HPLC studies. Additionally, two approaches towards the synthesis of the 1,3-methyl substituted fatty acid (hydroxyphthioceranic acid) and its regioselective introduction to the trehalose core will be discussed.

ORGN 230

Synthetic investigations toward the angucycline antitumor antibiotic galtamycin

Asmita Shrestha, [email protected], John L Davenport, [email protected], Rongson Pongdee. Department of Chemistry, Sewanee: The University of the South, Sewanee, TN 37383, United States

Galtamycin (1 ) is a member of the angucycline family of antitumor antibiotics and displays cytotoxicity against Gram-positive bacteria, human cytomegalovirus, and certain carcinomas. Structurally, galtamycin (1 ) consists of a polyketide-derived tetracycle adorned with a highly deoxygenated tetrasaccharide unit attached via a 2- deoxy-β-C-aryl glycosidic linkage. As part of our program aimed at the development of architecturally novel chemotherapeutic agents based upon natural product scaffolds, we will present our progress toward the construction of the aromatic core of 1 .

ORGN 231

Total synthesis of muironolide A: Efforts toward the isoindolone core

Courtnay E Shaner, [email protected], T. Andrew Mitchell. Department of Chemistry, Illinois State University, Normal, Illinois 61761, United States

Muironolide A was recently isolated by Molinski from the same marine sponge that delivered the potent anticancer natural product, phorboxazole A. Although only 90 µg of muironolide A was isolated; the structure was successfully elucidated. While preliminary biological activity was investigated, the minute quantity obtained leaves total synthesis as the only means of studying its biological potential. Our convergent total synthesis of muironolide A focuses on three strategic disconnections: NHC-mediated ynal redox esterification, EDCI coupling, and HWE olefination toward fragments A, B, and C. Initially, we focused on an intramolecular Diels-Alder strategy which would indirectly access the isoindolone core. However, we have revised our strategy which now utilizes an intermolecular Diels-Alder approach that will provide the isoindolone core directly.

ORGN 232

Total synthesis and biological evaluation of bryostatin 7

Gary E. Keck1, Yam B. Poudel1, [email protected], Thomas J. Cummins1, Arnab Rudra1, Jonathan A. Covel1, Noemi Kedei2, Nancy E. Lewin2, Peter M. Blumberg2. (1) Department of Chemistry, University of Utah, Salt Lake City, Utah 84112, United States (2) NCI, NIH, LCBG, Center for Cancer Research, Bethesda, MD 20892, United States

The bryostatins are a family of highly oxygenated macrolide natural products isolated from the marine bryozoans Bugula neritina. Bryostatin 1, the most thoroughly studied member, has displayed unique and diverse biological activities including reversal of multidrug resistance in cancer cells, synergistic effects with other anticancer agents, stimulation of the immune system, improvement of learning and memory in animal models, and activity against HIV. Very limited biological studies have been carried on other members of this family such as bryostatin 7. We describe here the total synthesis of bryostatin 7 utilizing our pyran annulation strategy and our initial biological evaluations of this congener.

ORGN 233

Studies towards the synthesis of the Amphomycin antibiotics: Total synthesis of Laspartomycin

Randall J Binder, [email protected], Michael S VanNieuwenhze. Department of Chemistry, Indiana University, Bloomington, Indiana 47405, United States The Amphomcins are a family of undecapeptide natural products who share a similar macrocyclic core, possessing interesting antibiotic activity against gram-positive bacteria. They inhibit peptidoglycan assembly during cell-wall biosynthesis, though the exact mechanism and site of action remain unknown. Studies towards the solution- phase total synthesis of Laspartomycin used a convergent route for application to the other members of this family of antibiotics and to generate fluorine labeled analogues for use in REDOR-NMR studies to identify the specific antibiotic mechanism.

ORGN 234

Synthetic study of quinocarcin

Hiroaki Chiba, [email protected], Shinya Oishi, Nobutaka Fujii, Hiroaki Ohno.Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Sakyo-ku 606-8501, Japan

We planned the preparation of 2,5-cis-pyrrolidine 3 , an important building block for the synthesis of quinocarcin, by a cis-selective intramolecular amination of bromoallene 1 develoved by our group. As we anticipated, 2,5-cis-pyrrolidine 2 was obtained with an excellent diastereoselectivity from a diastereomixture of 1 . Next, we embarked model study for construction of the core structure of quinocarcin. Although undesired 5-exo-dig cyclization is generally favored, we found that desired 6-endo-dig product 5 was obtained exclusively when using dihydrobenzofuran 4 .

ORGN 235

Total synthesis of the Aspidosperma indole alkaloid subincanadine E Corinne M. Sadlowski, [email protected], Stephen P. Waters. Department of Chemistry, The University of Vermont, Burlington, VT 05405, United States

The first total synthesis of the indole alkaloid subincanadine E is reported in a 10-step sequence from tryptamine. This natural product was first isolated from Picralima nitida cell suspension cultures by Lim and co-workers in 1982 under the name pericine and again in 2002 by Kobayashi as subincanadine E from Aspidosperma subincanum. It is the most biologically potent member of the subincanadine family of alkaloids with in vitro toxicity against both lymphoma and carcinoma cell lines (LD50 = 0.3 μg/mL and 4.4 μg/mL, respectively).

ORGN 236

Substrate-controlled asymmetric total synthesis and structure revision of (+)- itomanallene A

Wonjang Jeong1, Mi Jung Kim2, [email protected], Hyoungsu Kim3, Sanghee Kim2, Deukjoon Kim2, Kye Jung Shin4. (1) Department of drug discovery, ILDONG pharmaceutical company, Gyeonggi-do, 23-9, Seogu-dong, Hwaseong-si 445-170, Democratic People's Republic of Korea (2) Department of Pharmaceutical Sciences, Seoul National University, Seoul, San 56-1, Shinrim-Dong, Kwanak-Ku, 151-742, Democratic People's Republic of Korea (3) Department of pharmacy, Ajou university, Suwon, San5, woncheon-dong, yeongtong-gu 443-741, Democratic People's Republic of Korea (4) Department of pharmacy, Catholic univesity, Gyeonggi-do, 43 Jibong-ro, Wonmi-gu, Bucheon-si 420-743, Democratic People's Republic of Korea

(+)-Itomanallene A was isolated by Suzuki et al. from the red alga Laurencia intricata collected at Itoman (Japan) in 2002. The first asymmetric total synthesis of (+)- itomanallene A (revised structure) has been accomplished starting from commercially available (S)-glycidol in a substrate-controlled fashion. The approach yields α,α'-cis- or α,α'-transtetrahydrofuran isomers by intramolecular alkylation with either an amide enolate or a nitrile anion, respectively.

ORGN 237

Enantioselective total synthesis of natural iridoid lactone

Sujin Lee1, Seung-Mann Paek2, Hwayoung Yun1, Nam-Jung Kim1, Jaebong Jang1, Jaehoon Sim1, [email protected], Young-Ger Suh1. (1) College of Pharmacy, Seoul National University, Seoul, Republic of Korea (2) College of Pharmacy, Gyeongsang National University, Jinju, Gyeongnam 660-751, Republic of Korea

Iridoids are a large family of natural monoterpenoid products, which are found in a number of folk medicinal plants used as bitter tonics, sedatives, hypotensives, remedies for wounds and skin disorders. Recently, this wide range of bioactivities encouraged us to investigate synthesis of a variety of iridoids, which are structurally characterized by a cis-fused cyclopenta[c]pyran ring system. We have accomplished the first and asymmetric total synthesis of a new iridoid lactone, 6-hydroxy-7-(hydroxymethyl)-4- methylenehexahydrocyclopenta[c]pyran-1-(3H)-one. The key features of our synthesis includes stereoselective Pd(0)-catalyzed allylic alkylation and silicon-tethered radical cyclization of the cyclopentenol intermediate via Stork-Nishyama procedure, which provided contiguous four stereogenic centers of the target iridoid lactone.

ORGN 238

WITHDRAWN

ORGN 239

Progress toward the total synthesis of communesin F utilizing the interrupted Fischer indolization reaction

Alex W Schammel, [email protected], Grace Chiou, [email protected], Neil K Garg. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, United States

Communesin F is a structurally complex indole alkaloid isolated in 2004. The unique structure of communesin F has prompted our laboratory to pursue its total synthesis. In this presentation, our progress toward the total synthesis of communesin F will be described. Our approach relies on an interrupted Fischer indolization reaction to construct the tetracyclic fused indoline scaffold.

ORGN 240

Studies toward the total synthesis of clavatadine A

Stephanie Conn, [email protected], Shannon M. Vreeland, Alexandra N. Wexler, Stephen Chamberland. Department of Chemistry, Central Washington University, Ellensburg, WA 98926, United States

Clavatadine A (1 ), recently isolated from the Australian marine sponge Suberea clavata, is a specific and potent inhibitor of coagulation factor XIa. Our efforts to complete the first total synthesis of clavatadine A feature the carbamoylation of phenol 3 , prepared by dibromination of homogentisic acid lactone (6 ), and azidoisocyanate 4 , derived from ethyl 5-bromopentanoate (5 ). From our advanced intermediate, carbamate 2 , we envision completing the synthesis of clavatadine A (1 ) by guanylation and lactone hydrolysis.

ORGN 241

Synthesis of Frondosin C analogs via rhodium catalyzed carbonyl ylide cycloaddition reactions

Mark C. McMills, John H Bougher, [email protected]. Department of Chemistry & Biochemistry, Ohio University, Athens, OH 45701, United States

The Frondosins are a family of sesquiterpene compounds collected from a marine sponge displaying promising bioactive profiles. They have been shown to inhibit the binding of interleukin-8 (IL-8) to either its receptor or protein kinase C. These natural products have also exhibited HIV-inhibitory activity in HIV assays. We report herein an approach to the synthesis of Frondosin C analogs via a rhodium catalyzed diazo- decomposition reaction, forming a carbonyl ylide intermediate, which proceeds along a cycloaddition pathway to form the desired cycloadduct.

ORGN 242

Total synthesis of syringolides

Sudhakar Kalagara, [email protected], Allyssa M Amaya, Shizue Mito. Department of Chemistry, University of Texas at El Paso, El paso, Texas 79968-0513, United States

Syringolides 1and2 are the bacterial signal molecules which were first isolated from pseudomonas syringae pv. tomato by sams et al. These elicit a hypersensitive response on soyabeen plants carrying the resistence gene. These molecules have significant biological interests as they comprise of molecular signal recognized by plants expressing a resistence gene.

Although there has been some reports for total synthesis of syringolides, none of them were successful in terms of yields. We propose a new synthetic pathway to achieve a high yield. Our restrosynthetic plan has two main fragments which finally lead to the syringolide 1and 2, one is α,β-unsaturated ketone which was prepared in six steps in good yield. The other is β-keto acid and we obtained it - more than 85% yield in two steps. Now we are currently investigating crucial steps - to construct stereiogenic centers including asymmetric dihydroxylation.

ORGN 243

Total synthesis of norcembrenolide B and scabrolide D

Alec M Saitman, [email protected]. Chemistry, University of California San Diego, La Jolla, California 92093, United States

An efficient stereoselective synthesis of norcembrenolides B (8) and C (9) will be discussed. The strategy is inspired by biogenetic relationships of related cembrenoids. Central to the approach is the construction of norbipinnatin J that, upon selective deoxygenation and nucleophilic epoxidation, produces norrubifolide and norcoralloidolide A respectively. A sequence of site-selective oxidations and skeletal reorganizations then yields in a divergent manner, norcembrenolide B and norcembrenolide C. The studies also allow for revision of the proposed structure of scabrolide D, which is identical to norcembrenolide C.

ORGN 244

Toward the total synthesis of the archazolid natural products

Leanne J Sebren, [email protected], Ann B Tran, Geoffrey C Melly, Matthew J Black, Gregory W O'Neil. Chemistry, Western Washington University, Bellingham, WA 98225, United States

The archazolids are a family of natural products that display potent growth inhibitory activity against a number of human cancer cell lines based on selective VATPase inhibition. A synthesis of the entirety of the archazolid carbon framework has been completed along with the development of convenient Arabidopsis-based VATPase assays.

ORGN 245

Concise, biomimetic syntheses of davanone, artemone, and related antifungal terpenoids

Kim Quach, [email protected], Corwyn D. Evans-Klock, Veerasak Srisuknimit, [email protected], Mary J. Van Vleet, [email protected], Katherine N. Maloney, David A. Vosburg. Department of Chemistry, Harvey Mudd College, Claremont, CA 91711, United States

Two enantioselective routes to the sesquiterpene natural products davanone and artemone will be presented. These strategies are inspired by biosynthetic proposals, use catalytic reactions, are devoid of protecting groups, and are atom- and redox- economical. The preparation of related natural and unnatural compounds for antifungal screens will also be described.

ORGN 246

Tandem cross-coupling/electrocyclization cascades toward endiandric and beilschmiedic acids

Katerina P. Hilleke, [email protected], Alix I. Chan, [email protected], Mary J. Van Vleet, [email protected], David A. Vosburg. Department of Chemistry, Harvey Mudd College, Claremont, CA 91711, United States

Progress has been made toward modular, biomimetic syntheses of endiandric acids (A, B, and H) and other structurally related, plant-derived natural products. Functionalized polyenes have been prepared using olefin metathesis, Wittig reactions, and Suzuki couplings (often with microwave activation). These polyenes are then coupled to trigger a biomimetic electrocyclization cascade.

ORGN 247

Synthesis of lagunamides: Antimalarial and cytotoxic natural products from the marine cyanobacterium lyngbya majuscula

Brent Banasik, [email protected], Lee Wang, [email protected], Mikael B Bergdahl. Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182-1030, United States

Lagunamides are complex novel cyclic depsipeptides obtained from a marine cyanobacterium Lyngbya majuscula. The lagunamides possess high antimalarial properties (IC50 0.19-0.91 mM) and significant cytotoxic properties against leukemia cell lines with (IC50 6.4-20.5 nM) respectively.

A highly convergent synthetic approach is utilized to solve the synthesis of these complex and interesting molecules. Asymmetric synthetic will be utilized in order to establish five of the 10 crucial stereo centers present in the molecular structure. NMR spectroscopy, crystallography, optical rotations and LCMS will specifically be used to characterize all the intermediates needed for connecting these fragments to yield the lagunamides.

Stereoselective synthesis of several advanced intermediates crucial for the preparation of the lagunamides will be presented. Specifically, one major fragment consisting of consecutive stereo centers has been prepared via a highly asymmetric route. The absolute stereochemistry (99% e.r.) of this intermediate obtained was confirmed using x-ray crystallography.

ORGN 248 Diversity oriented total synthesis of analogs derived from azaspirene: Powerful inhibitor of angiogenesis and inflammation

David Schmit, [email protected], Michael Barker, [email protected], Tim Montgomery, [email protected], Alex Rovira, Mikael B Bergdahl. Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182-1030, United States

Azaspirene is a recently discovered fungal metabolite with anti-angiogenic, and suspected anti-inflammatory properties. A milder type of chemotherapy shows promise: the utilization of angiogenesis inhibitors, particularly azaspirene.

The presented work is innovative in three major ways; 1) it creates an entirely new efficient synthesis of the core structure of the inhibitor azaspirene; 2) it utilizes this route to produce an exploratory library; 3) it seeks to determine whether these novel drugs can effectively inhibit tumor angiogenesis, inflammation, and progression.

Identification of chiral building blocks is the first step in the creation of a greatly simplified total synthesis that is economically more viable than other reported synthetic routes. The presented procedure allows us to initiate the synthesis with most of the oxygen atoms already contained with correct stereochemistry within the molecule which reduces the need for oxidation reactions to create the highly oxygenated molecule of the pseurotin analog library.

ORGN 249

Development of a short and concise synthesis of aminoglycoside mimics

Korry L Barnes, [email protected], Christopher D Becher, [email protected], Christopher S Jeffrey. Department of Chemistry, University of Nevada, Reno, Reno, NV 89557, United States

Polyhydroxylated piperidines, or aminoglycoside mimics, have recently attracted the attention of the synthetic community due to their glycosidase inhibitory properties. These properties make them powerful candidates in the treatment of various diseases including cancer and HIV. These nitrogen containing heterocycles that behave much like sugars can be grouped into five structural classes: polyhydroxylated piperidines, pyrrolidines, indolizidines, pyrrolizidines, and nortropanes. We have recently reported the generation of seven membered nitrogen heterocycles via a 4+3 cycloadditon that proceeds through an aza-oxyallycation intermediate. It was demonstrated that the heterocycle could be functionalized with a chlorine atom providing entry into the polyhdroxylated piperidine class of alkaloids. Recent progress towards the synthesis of these molecules as well as method development will be presented.

ORGN 250 Synthesis and functionalization of cavitands with a new arm for chiral recognition

Tayyebeh Panahi, [email protected]. Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84606, United States

A new cavitand structural motif has been developed by modifying tri-quinoxaline resorcinarenes. The unsymmetrical resorcinarene cavitands were synthesized by several steps. Diversity at one of the arm positions to make different cavitand walls is a highlight of the work. Our group has researched the area of functionalization of the upper part of resorcinarenes. We have synthesized chiral resorcinarene-based deep cavitands for the sequestration of guests of large sizes. In this report we give our success in synthesizing different quinoxalines to modify the upper rim of the resorcinarene host. H-NMR, IR and ESI-TOF mass spectrometry afforded the characterization of the unsymmetrical resorcinarene cavitands. Functionalization of the tri-arm resorcinarene with newly designed chiral and achiral arms is the main goal of our research. The following figures are represented the whole main of work.

ORGN 251 Progress towards the total synthesis of picrinine and progress towards other akuammiline alkaloids

Ben W Boal, [email protected], Joel M Smith, [email protected]. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, United States

Picrinine is a complex alkaloid that was isolated from Alstonia scholaris in 1965. Its unique structure has prompted our lab to pursue it as a synthetic target along with other related natural products. In this presentation, progress towards its total synthesis and other related natural products will be described. Our approach features a number of key steps including an intramolecular Heck reaction to assemble the [3.3.1]-bicycle and a late-stage interrupted Fischer indolization reaction to construct the caged indoline core.

ORGN 252

WITHDRAWN

ORGN 253

Navigating dispacamide dimer ensembles to access complex pyrrole/imidazole alkaloids

Andrew G Roberts, [email protected], Hui Ding, Patrick G Harran. Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, United States

We describe a concise synthesis of equilibrating dispacamide dimer ensembles and show how those materials can be channeled to complex pyrrole/imidazole alkaloids. A host of unusual reactions and unanticipated reactivity will be discussed. The first total syntheses of non-chlorinated axinellamines will also be presented.

ORGN 254

Total synthesis of Leucetta-alkaloids: Isonaamine C, isonaamidine E and related compounds

Beatriz J. Garcia-Barboza, [email protected], Heather M. Lima, Carl J. Lovely. Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, United States

The total synthesis of Leucetta-derived natural products has been an objective in our lab for several years. The total syntheses of two alkaloids, isonaamine C and isonaamidine E, were accomplished in 6 and 7 steps starting from 4,5-diiodoimidazole. The synthetic approach was based on successful work previously developed by our lab to access related natural products. Both compounds have been found to exhibit anti- cancer activity against stomach and liver cancer cell lines.

Furthermore, a synthetic approach toward the total synthesis of kealiiquinone, a cyclic member of the Leucetta alkaloid family, has been an ongoing endeavor. An intramolecular Diels-Alder approach has proven successful in constructing the benzimidazole framework of our target compound. An investigation of various Diels- Alder substrates will be presented as a way of completing the total synthesis of kealiiquinone.

ORGN 255

Efforts toward the total synthesis of the marine natural product murionolide

Krista Cunningham, [email protected], Isabelle Modolo, Michael Hoover, Craig J. Forsyth. Department of Chemistry, The Ohio State University, Columbus, OH 43210-1340, United States Murionolide is a complex natural product that was isolated from the marine sponge Phorbas sp. This sponge has yielded several potent anticancer drug leads, including the phorboxazoles. However, a very minute quantity of murionolide was isolated – only 90 micrograms of purified material. Remarkably, this was sufficient for Professor T. Molinski of UCSD to confidently determine the complete structure, which includes an unprecedented hexahydro-1H-isoindolone skeleton, a chlorocyclopropane, and a trichlorocarbinol ester. However, the limited amount of material available has prevented evaluation of the biological activities of murionolide. It is anticipated that the novel chemotype may have associated useful activities, given those of its natural product congeners. We are developing a convergent, biomimetic total synthesis of murionolide and its close structural analogs to allow full evaluation of their biomedical potential. This involves the preparation of several component fragments and their successive couplings. Progress towards the project goals will be provided.

ORGN 256

Kinetics of competing reactions of N-aryl-4-chloro-1,8-naphthalimides with primary amines

Ryan K McKenney, [email protected], Leah L Groess, David E Lewis, [email protected]. Department of Chemistry, University of Wisconsin-Eau Claire, Eau Claire, WI 54702-4004, United States

The unexpectedly facile displacement of the N-aryl substituent from the 4-chloro-1,8- naphthalimides by butylamine competes with displacement of the halogen by the same nucleophile. We have determined the rate constants for these reactions under pseudo- first order conditions, and we have found that the Hammett plot of the rate constants for N-(substituted)phenyl-4-chloro-1,8-naphthalimides with butylamine has a large positive value of ρ, consistent with heterocyclic ring opening being the rate-determining step. When the substituent on the phenyl ring is electron-donating, the displacement of the halide becomes competitive with attack of the nucleophile on the heterocyclic ring. The mechanistic implications of this study will be presented.

ORGN 257

α-Halopolyynes as synthons in organic and organometallic syntheses

Sławomir R. Szafert, Nurbey Gulia, [email protected], Bartłomiej Pigulski. Department of Chemistry, University of Wroclaw, Wroclaw, Poland

Compounds with rodlike, unsaturated elemental carbon chains (-CºC)n- constitute the most fundamental class of carbon-based molecular wires. Such one-dimensional assemblies are attracting a lot of attention from the standpoints of fundamental, physical, and chemical properties and are seeing extensive use in the development of molecular-scale devices. There is a number of synthetic pathways that lead to the above mentioned molecules. They usually involve few separate steps like (1) introduction of an alkyne moiety, (2) chain elongation, and (3) chain termination (also through dimerization).

Contribution will present an alternative pathway that utilizes α-haloalkynes and α- halopolyynes as substrate for one pot high-yield synthesis of polyynic compounds and complexes. Full characterization - including x-ray crystallography - for such obtained exemplary moieties will also be presented.

ORGN 258

Natural products, synthetic catalysts, unnatural products

Scott J. Miller, [email protected]. Department of Chemistry, Yale University, New Haven, CT 06520-8107, United States

Natural products have provided perennial inspiration for the development of synthetic methods, and enzymes have provided an analogous platform for the conception of new catalysts. This lecture will recount an interplay of experiments stimulated by these two major classes of naturally occurring substances. Specifically, the discovery and use of peptides as catalysts for a variety of asymmetric bond formations will be presented. Likewise, applications of these catalysts to the synthesis and selective modification of complex molecules, including biologically active natural products, will be described. A particular emphasis will be placed on reactions that present unusual stereochemical challenges.

ORGN 259

Synthetic and chemical biological studies of the diazofluorene antitumor antibiotics

Seth B Herzon, [email protected]. Department of Chemistry, Yale University, New Haven, CT 06511, United States

The kinamycins and lomaiviticins are cytotoxic natural products isolated from various strains of Streptomyces and Salinispora. These metabolites contain a diazo substituent embedded in a highly-oxidized carbocyclic skeleton ("diazofluorene"). Members of this family exhibit sub-nanomolar inhibitory potencies against several cultured cancer cell lines. This lecture will describe our syntheses of (–)-kinamycin F and (–)-lomaiviticin aglycon, as well as the preparation and evaluation of several unnatural diazofluorene- based anticancer agents. Insights into the chemical reactivity of these metabolites, which may have bearing on their mechanism of action, will be described.

ORGN 260

Recent advances in catalysis Erick Carreira, [email protected]. Department of Chemistry and Applied Biosciences, ETH-Zurich, Zurich, Switzerland

The talk will consist of a presentation of recent work from our group involving catalysis for the synthesis of small molecule building blocks. This includes our latest investigations with olefins as steering ligands for transition-metal complexes and our more recent exploration of catalysis under extreme conditions.

ORGN 261

Award Address (Herbert C. Brown Award for Creative Research in Synthetic Methods sponsored by the Purdue Borane Research Fund and the Herbert C. Brown Award Endowment). New methods for the synthesis and elaboration of amine containing compounds

Jonathan A Ellman, [email protected]. Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States

Practical new methods for carbon-carbon bond formation will be described that enable the efficient preparation of amine containing compounds. Additions to N-tert- butanesulfinyl imines, enantioselective reactions catalyzed by N-sulfinyl ureas, and Rh(I)- and Rh(III)-catalyzed C-H bond functionalization will be presented with an emphasis on regio- and stereoselective entry to pharmaceutically relevant classes of chiral amines and nitrogen heterocycles. The utility of these methods will be demonstrated with syntheses of bioactive natural products and drugs.

ORGN 262

Self-assembly of contorted aromatics and fullerenes into electronic materials

Colin P Nuckolls, [email protected]. Department of Chemistry, Columbia University, New York, NY 10027, United States

This lecture will detail our methods to make molecules that self-assemble with fullerenes to make efficient solar cells. The molecules are contorted aromatics that have shapes that are complementary to fullerenes. In addition to the shape complementarity, the molecules are good hole-transporting materials, forming an electronic complementarity to fullerenes. Assembly in the solid-state, at interfaces, and devices will be discussed.

ORGN 263

Systems chemistry: Building logic gates based on the gel-sol transition of a crown-ether-functionalized bis-urea gelator Christoph A. Schalley1, [email protected], Zhenhui Qi1, Wei Jiang1,2, Qi Wang1, Karol Novosinski1, Andrea Schulz1. (1) Institut für Chemie und Biochemie, Freie Universität Berlin, Berlin, Germany (2) The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, United States

A quite simple, achiral benzo-21-crown-7 bis-urea low-molecular weight gelator assembles into helical fibers, which further develop into a stable gel in acetonitrile. The gel-sol transition can be controlled by different molecular recognition events. With the gelator, potassium ions, a cryptand, secondary amines, an acid and a base, a number of different systems can be designed which behave as logic gates. They all contain the gelator and a subset of the other components. Two input signals determine the sol-gel transition as the output. Depending on the choice of components, NOT, OR, NOR, AND and NAND gates can be realized. Thus, the gel-sol transition as a property of the whole system can be influenced in a quite complex manner.

ORGN 264

Modular fluorescent receptors: Applications as molecular probes and functional materials

Calden N. Carroll, Jeffrey M. Engle, Matthew E. Carnes, Chrisgen L. Vonegut, Michael M. Haley, Darren W. Johnson, [email protected]. Department of Chemistry and Materials Science Institute, University of Oregon, Eugene, OR 97403-1253, United States

This talk will describe the development of modular, inherently fluorescent receptors as hosts for small molecules and ions. These new fluorescent anion receptors are based on a difunctionalized 2,6-alkynylpyridine scaffold. A sulfonamide-functionalized derivative forms a 2:2 dimer with both water or halides (Cl-, Br-) depending on the protonation state of the pyridine ring. This is a rare example of both halides and water molecules serving the same structural hydrogen bonding roles in a synthetic self- assembled system. This receptor class also exhibits tunable “off-on” or “on-off” fluorescence in the presence of anions, depending on the placement of electron- donating and -withdrawing groups on the periphery of the host. A new class of urea receptors that forms 1:1 complexes with halides will also be described. Protonation enhances binding over one order of magnitude, alters the binding selectivity, and provides a colorimetric indication of anion binding. Emerging applications in selective anion binding, sensing anions in wet and polar solvents, and fluorescent redox sensing will be discussed.

ORGN 265

Molecular capsules based on tetraurea-calix[4]pyrrole/tetraurea-calix[4]arene scaffolds Pablo Ballester, [email protected]. Institute of Chemical Research of Catalonia (ICIQ), Tarragona, Tarragona 43007, SpainCatalan Institution of Research and Advanced Studies (ICREA), Barcelona, Barcelona 08018, Spain

Tetra-urea calix[4]pyrrole 1 dimerizes into homocapsules 1 •1 either by including 4,4'- bipyridine N-N'-dioxide or through pair-wise encapsulation of trimethylamine-N-oxide. On the other hand, chloroform is a typical guest for tetra-urea calix[4]arene capsules like 2 •2 , complementing nicely its cavity size and lipophilicity. In this presentation, I will briefly introduce the assembly of dimeric capsules based on tetra-urea calix[4]pyrrole scaffolds. I will describe the results of self-sorting experiments directed towards the exclusive assembly of polar dimeric capsules between tetra-urea calix[4]pyrrole 1 and tetra-urea calix[4]arene 2 . Finally, the use of such hybrid assemblies in the construction of a dissymmetric and mechanically locked capsule with polar interior will also be presented. This latter capsular assembly features a bis-[2]catenated topology and shows reversible molecular co-encapsulation of two different neutral molecules or two oppositely charged ions.

ORGN 266

Calixpyrroles: Anion receptors, molecular building blocks, and "chemical switches"

Jonathan L. Sessler, [email protected]. Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, Texas 78712-1065, United States

Calix[n]pyrroles are synthetic compounds containing four or more pyrrole or pyrrole-like heterocyclic subunits within their non-conjugated frameworks. They act as simple-to- prepare anion binding agents. Lately, the chemistry of calixpyrrole-type compounds has grown to include systems built up from bipyrrole, bis(pyrrolyl)benzene, biimidazole, and a number of other heterocyclic subunits. While this latter synthetic chemistry will be reviewed briefly, in this lecture calix[n]pyrroles will be discussed in the context of recent collaborative efforts to develop “tunable” systems that are 1) capable of binding, extracting, and transporting selected substrates, including ion pairs, 2) acting as “molecular switches”, “capsules”, and “logic gates” for electron transfer reactions, as well as 3) serving as precursors for environmentally responsive, self-assembled materials. The potential utility of modified calixpyrroles in areas as diverse as energy storage, explosives detection, ion extraction, materials chemistry, drug development, and other areas of current technological interest will be highlighted.

ORGN 267

Site-specific incorporation of FnY (n = 2, 3) in place of Y122 to probe PCET in class Ia E. coli ribonucleotide reductases

JoAnne Stubbe, [email protected], Ellen Minnihan. Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, United States

Escherichia coli RNR is an a2b2 complex that catalyzes the conversion of nucleotides to deoxynucleotides and requires a diferric-tyrosyl radical (Y•) cofactor to initiate catalysis. The initiation requires long range PCET over a 35 Å between the two subunits by a specific pathway (Y122 D W48 D Y356 within b to Y731 D Y730 D C439 within a). The rate-limiting step in nucleotide reduction is conformational gating of the PCET process. Fluorinated tyrosines (FnY where n = 2 or 3) have been incorporated site-specifically in place of Y122. All proteins are able to catalyze multiple turnovers of CDP to dCDP. RFQ EPR and PELDOR experiments have been carried out with FnY122-b2 and FnY122Y356F- b2. The results will be discussed in terms of the relative redox potentials of Y356 and Y122 and the potential involvement of W48 in the PCET process.

ORGN 268

Methylated lysine residues and the histone code as targets for supramolecular tools

Fraser Hof, [email protected], Kevin D Daze, Samuel A Minaker, Manuel C.F. Ma, Florent Pineux. Department of Chemistry, University of Victoria, Victoria, BC, Canada

The post-translational methylation of lysine residues is a critical signaling mechanism for the control of gene expression that is part of the histone code. In all known cases, the methylation of a lysine residue on a peptide tail triggers a protein-protein interaction (PPI), and many of these interactions have been implicated as potent drivers of cancer aggression. We will report here on a class of calixarene-derived macrocycles that can recognize and bind to methylated lysine residues in the context of intact proteins and complex peptides. We have synthesized analogs that inform us on the varying roles of shape complementarity, weak interactions, and the hydrophobic effect in the successful recognition of these important motifs. Our studies have identified the first ever inhibitor of any methyllysine-triggered protein-protein interaction. We will report on our ongoing efforts to create new active compounds with improved drug-likeness, as well as the development of new biochemical assays in this area.

ORGN 269

Carbamoylmethyl phosphine oxides as chelating agents Shannon M. Biros1, [email protected], Eric J. Werner2. (1) Department of Chemistry, Grand Valley State University, Allendale, MI 49401, United States (2) Department of Chemistry and Physics, The University of Tampa, Tampa, FL 33606, United States

We have developed a series of tripodal ligands designed to bind lanthanide and actinide cations. These ligands contain carbamoylmethyl phosphine oxide (CMPO) groups, which are currently being used as part of the TRUEX process to remediate nuclear waste. A major focus of this study involves the exploration of novel ligand capping structures designed to link the CMPO units together to enhance metal binding. The synthetic approach to these ligands will be described as well as preliminary metal binding data.

ORGN 270

Nanoparticles and (Bio)molecular recognition: Engineering the interface for sensing and delivery

Vincent M. Rotello, [email protected]. Department of Chemistry, University of Massachusetts, Amherst, MA 01003, United States

Nanoparticles provide versatile scaffolds for multivalent recognition. Our research program focuses on the tailoring of nanoparticle surfaces for a variety of applications, coupling the atomic-level control provided by organic synthesis with the fundamental principles of supramolecular chemistry. We are using engineered nanoparticles for a range of biological applications, including drug/biomolecule delivery and sensing. This talk will focus on the interfacing of nanoparticles with biosystems, and will discuss our use of nanoparticles for delivery applications as well as their application as therapeutics in their own right.

ORGN 271

Molecular recognition at enzyme active sites

François N. Diederich, [email protected]. Department of Chemistry and Biosciences, ETH Zurich, Zurich, Switzerland

The objective of your program is the development of new general tools and strategies to enhance and facilitate small molecule drug discovery research, with a focus on structure-based design of ligands for selected enzymes. Specifically, we are interested in the quantification of intermolecular interactions which stabilize protein-ligand complexes. Active research is pursued on interactions between aromatic rings, sulfur-π and cation-π interactions, and interactions involving dipoles, in particular halogen bonding. Contributions of organofluorine to protein-ligand binding efficiency and selectivity are analyzed. We also investigate energetically beneficial displacements of crystallographically defined water molecules by ligand substituents. This lecture will address some of these issues, focusing on the development of potent ligands for the enzymes of the non-mevalonate pathway of isoprenoid biosynthesis, that is used exclusively by malarial parasites and mycobacterium tuberculosis, but not by humans. Inhibitors of the protozoan cysteine proteases falcipain-2 and rhodesain are other targets that will be discussed.

ORGN 272

Assembly of macrocyclic organo-peptide hybrids (MOrPHs) from genetically encoded precursors

Jessica M. Smith, [email protected], Rudi Fasan. Department of Chemistry, University of Rochester, Rochester, New York 14627, United States

Methods for generating diversified molecular libraries are central to the discovery of chemical probes and therapeutic agents to target protein-protein interactions and other relevant biomolecular complexes. We report a versatile methodology for embedding non-proteogenic, synthetic moieties into genetically encoded peptidic frameworks to generate macrocycles with a hybrid organo-peptide backbone. This approach exploits a dual chemoselective reaction between a bifunctional synthetic precursor and an alkyne- containing intein-fusion protein. The resulting macrocycles can be readily diversified by varying the nature of the synthetic precursor and that of the genetically encoded moiety. This method has been applied to produce cyclic and lariat compounds in isolated form or tethered to a protein of interest. Our further interest is in applying this technology toward high through-put screening in the on-going challenge to create and identify novel protein binders.

ORGN 273

Glycoengineering proteins and cell surfaces via synthetic aminooxy glycans

Jason Hudak1, [email protected], Helen Yu1, Carolyn Bertozzi1,2,3. (1) Chemistry, University of California, Berkeley, Berkeley, CA 94720, United States (2) Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, United States (3) Howard Hughes Medical Institute, United States

While glycosylation is known to govern a multitude of biological events, the tools available to study the activity relationship of specific glycan structures on glycoconjugate and cellular behavior remains limited. In response, we have developed methodology based on chemoselective oxime formation to introduce chemically-defined glycans onto proteins and cell surfaces. This technology centers on an improved synthesis of aminooxy glycans which can be reacted with aldehyde-tagged proteins to create homogeneous glycoproteins or poly-ketone polymers bearing phospholipids for cell membrane insertion.

ORGN 274

Multimodal protein cages for molecular imaging

Jealemy Galindo Millán1, [email protected], Melanie Brasch1, Andres de la Escosura2, Melissa S.T. Koay1, Jeroen J.L.M. Cornelissen1. (1) Biomolecular Nanotechnology Group, MESA+ Institute for Nanotechnology, University of Twente, Enschede, Overijssel 7500AE, The Netherlands (2) Department of Organic Chemistry, Universidad Autónoma de Madrid, Madrid, Spain

As contrast agents for Magnetic Resonance Imaging (MRI), viral protein cages have attracted a great deal of attention since the highest relaxivity measured until today is attributed to Gd3+ labeled virus nanoparticles.1 Nevertheless, Gd3+ release of such systems remains an issue and several (synthetically demanding) strategies have been followed in order to incorporate Gd3+ chelates into protein cages, including internal and external functionalization of the cage.2 In this work we encapsulate paramagnetic micelles consisting of Gd3+ complexes of 1,4,7,10-tetraazacyclododecane-1,4,7- tris(acetic acid) (DO3A)-based ligands in a protein cage of the cowpea chlorotic mottle virus (CCMV), forming in that way contrast agents by a process of hierarchical self- assembly. This concept is, furthermore, extended to multimodal agents by inserting therapeutic dyes in the “encapsulated” micelles [figure 1]. The results show the successful incorporation of the “encapsulated” dye in the CCMV as well as the paramagnetic micelles.

1. Allen, M.; Bulte, J. W. M.; Liepold, L.; Basu, G.; Zywicke, H. A.; Frank, J. A.; Young, M.; Douglas, T., Paramagnetic viral nanoparticles as potential high-relaxivity magnetic resonance contrast agents. Magnetic Resonance in Medicine 2005, 54 (4), 807-812.

2. Hooker, J. M.; Datta, A.; Botta, M.; Raymond, K. N.; Francis, M. B., Magnetic Resonance Contrast Agents from Viral Capsid Shells: A Comparison of Exterior and Interior Cargo Strategies. Nano Letters 2007, 7 (8), 2207-2210.

ORGN 275

Synthesis and evolution of genetically encoded cross-replicating ribozymes

Jonathan T. Sczepanski, [email protected], Gerald F. Joyce.Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, United States A ligase ribozyme was converted to a format whereby two enzymes catalyze each other's formation, enabling their self-sustained exponential amplification. The replicating ribozymes can mutate and evolve, providing an excellent model of a genetic system. Watson-Crick pairing between cross-catalytic partners transmits the “genotype”, which encodes a distinct sequence, or “phenotype”, that brings about the catalytic function of the enzyme. In order to prepare diverse populations of these cross-replicators, a novel split-and-pool technique has been developed using solid-phase DNA synthesis. The genotype and phenotype portions of the molecule are synthesized in tandem on two different arms of the same DNA molecule by employing three orthogonal phosphoramidite protecting groups. PCR amplification and transcription of these DNA templates produces the corresponding populations of RNA. Details of the synthetic method, as well as the evolution of a diverse cross-replicating population will be discussed.

ORGN 276

Preparation and analysis of peptide libraries with free C-termini for studying the prenylome

Mark D. Distefano, [email protected], Yen-Chih Wang. Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, United States

Protein prenylation is a post-translational modification of specific protein-derived cysteine residues critical for function in eukaryotic cells. Previous experiments with tetrapeptide sequences identified the motif known as the CaaX box as the key structural element recognized by protein farnesyltransferase (PFTase). Here we describe the synthesis of peptides containing free C-termini on solid supports. A photocleavable linker was designed to release the peptides from the support and to allow their analysis by MS. Four types of solid supports (TentaGel, PEGA, CPG and cellulose membranes) were evaluated. MS results show that the cysteine-containing peptide can be prenylated while containing a cysteine to serine “mutation” cannot. This approach should allow a large number of C-terminal peptides to be screened as substrates for PFTase and for other enzymes involved in protein prenylation as well. Such experiments should help to define what C-terminal sequences make up the prenylome.

ORGN 277

Design, synthesis and evalulation of small molecule H3K27me3-recognition protein inhibitors

Kevin D Daze, [email protected], Fraser Hof. Department of Chemistry, University of Victoria, Victoria, BC V8W 3V6, Canada

Recent research has shown numerous mechanisms of genetic regulation to exist through covalent changes of the Histone tail. Lysine can exist in three different methylation states and each triggers a unique protein-protein interaction. Increasingly these interactions are being implicated as factors in the increased proliferation and invasiveness of numerous cancers. My research focuses on chemical inhibitors of this interaction. By antagonizing both sides of this important protein-protein interaction we hope to better understand this important cancer pathway. To accomplish this goal I have begun the design, synthesis and in vitro testing of these novel inhibitors against their native binding partners. Through mimicry of the protein binding pocket I have studied the first known inhibitor of this trimethyllysine-dependant interaction. With this initial result I have begun the synthesis of a new class of macrocyclic compounds to enhance potency and selectivity. In a fragment-based screen, numerous small quaternary ammonium cations have been synthesized and tested against a native trimethyllysine binding partner in vitro. The next generation of these findings will be discussed.

ORGN 278

Chemical communication within and between species

Michael M. Meijler, [email protected], Josep Rayo, Neri Amara. Chemistry, Ben-Gurion University of the Negev, Be'er Sheva, N/A, Israel

Quorum sensing enables unicellular organisms to coordinate their behavior and function in such a way that they can adapt to changing environments and compete, as well as coexist, with multicellular organisms. Pseudomonas aeruginosa is an opportunistic pathogen that causes disease in immunocompromised patients. Quorum sensing in this pathogen is mediated by binding of the transcriptional activator, LasR, to its ligand 3- oxo-C12-HSL, leading to biofilm formation and secretion of virulence factors. We are targeting QS in P. aeruginosa with various chemical tools, such as a set of electrophilic probes that are designed to bind LasR covalently, leading to inhibition of QS regulated gene expression. These probes can be used as molecular tools to obtain new insights into the mechanisms of activation and deactivation of bacterial quorum sensing. Furthermore, recent reports have shown that several QS molecules can also directly affect the behavior of other bacterial species as well as that of eukaryotes. Diverse eukaryotes have been found to react strongly to the presence of these compounds (often initiating counter-warfare to jam bacterial communication), however, to date no eukaryotic protein has been identified that binds bacterial QS molecules. We have synthesized and evaluated 'tag-free' probes to isolate and identify such receptors, in order to unravel mechanisms that govern these important interkingdom signaling events.

ORGN 279

Fluorescent labeling of lantibiotics

Noah Bindman, [email protected], Wilfred van der Donk. Department of Chemistry, University of Illinois, Urbana, IL 61801, United States

Lantibiotics are a group of ribosomally-synthesized, post-translationally modified cyclic natural products that are active against a variety of bacterial pathogens with clinical relevance. However, the modes of action by which many lantibiotics exert their bioactivities are not known. Therefore, it would be beneficial to develop a general way to visualize lantibiotics in their natural environment. We report the enzyme-mediated installation of a ketone onto the N-terminus of numerous lantibiotics. This labeling was achieved by dehydration of a threonine residue, inserted at the N-terminus of the core peptide, during enzymatic modification of the core peptide. Proteolysis of the leader peptide then afforded an N-terminal α-ketoamide, which was reacted with a hydroxylamine linked to an alkyne or fluorophore during a bioorthogonal, aniline- catalyzed oxime ligation. Once purified, the labeled lantibiotics were incubated with bacteria to allow visualization of their spatial distributions in their native environment.

ORGN 280

Expansion of the genetic alphabet: Optimization and applications of an unnatural base pair

Thomas Lavergne1, [email protected], Denis Malyshev1, Young Jun Seo1, Phillip Ordoukhanian2, Floyd Romesberg1. (1) Departement of Chemistry, The Scripps Research Institute, San Diego, CA 92037, United States (2) Center for Protein and Nucleic Acid Research, The Scripps Research Institute, San Diego, CA 92037, United States

Expansion of the genetic alphabet with an unnatural base pair is a long-standing goal of synthetic biology. We have developed a class of unnatural base pairs, formed between d5SICS and analogues of dMMO2 , that are efficiently and selectively replicated and transcribed. In an effort to further characterize and optimize replication, we report the synthesis and evaluation of more than twenty new dMMO2 analogues bearing different substituents designed to be oriented into the developing major groove. In addition, we describe the synthesis and analysis of the ribo- and deoxyribo-variants, (d)5SICS and (d)MMO2 , modified with propargylamine linkers that allow for the site-specific modification of DNA or RNA during or after enzymatic synthesis. Finally, we reveal the structural basis for the polymerase recognition of a predominantly hydrophobic unnatural base pair.

ORGN 281

Combinatorial model for the prebiogenesis of tetrapyrrole macrocycles

Masahiko Taniguchi, Vanampally Chandrashaker, Ana R. M. Soares, Jonathan S. Lindsey, [email protected]. Department of Chemistry, North Carolina State University, Raleigh, NC 27695, United States

The extant biosynthesis of tetrapyrrole macrocycles has been considered a paradigm ('window on evolution') for their prebiotic formation, yet only a few individual (analogous non-enzymic) reactions along the overall process have been demonstrated. We recently showed that the aqueous reaction of a dione and an aminoketone (aminolevulinic acid) affords in 10% yield uroporphyrinogen, Nature's last universal precursor to all extant tetrapyrroles. Now, we report that combinatorial reaction of two diones and two aminoketones affords (via 4 pyrroles) a distribution of porphyrinogens (538 predicted by virtual library generation owing to combinations and permutations). The collection spans the entire range of polarity enabled by the biosynthesis including uro- (# carboxylic acids = 8), copro- (4), meso- (2), and etio-porphyrinogen (0). The latter two resemble in polarity the advanced biosynthetic products protoporphyrin and chlorophyll. Thus, a facile combinatorial process recapitulates - and may have preceded - the biosynthesis to afford diverse tetrapyrrole macrocycles.

ORGN 282

Conformational control of tetrapyrrole cofactors in nature

Mathias O. Senge, [email protected], Stuart A. MacGowan. School of Chemistry, Trinity College Dublin, Dublin, Ireland

Porphyrins are a unique class of ubiquitous natural compounds that function in a wide variety of roles ranging from oxygen transport, electron transfer and oxidation reactions to photosynthesis. They are important natural cofactors and are crucial regulatory effectors in many biochemical processes and diseases. Their natural function is controlled by a subtle interplay between the cofactor conformation and the apoprotein. Using conformational control as a common design principle tetrapyrroles with optimal photophysical and materials properties are now within reach in biomimetic chemistry. The underlying chemistry allowed us to elucidate how cofactor properties are controlled in nature and has significant application potential. Using the tetrapyrrole pigments of the photosynthetic reaction center as an example, statistically reliable evidence has been obtained for the existence of functional classes of specific conserved porphyrin conformations. Thus, the conformation of the macrocycle is a key factor in determining its functional behavior and biological function.

ORGN 283

Hyperpolarized MRI contrast agents for sub-second molecular imaging

Roman V Shchepin1, [email protected], Aaron M Coffey1,2, Kevin W Waddell1, Eduard Y Chekmenev1,2,3. (1) Department of Radiology, Vanderbilt University Institute of Imaging Science (VUIIS), Nashville, TN 37232-2310, United States (2) Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, United States (3) Department of Biochemistry, Vanderbilt University, Nashville, TN 37205, United States

MRI is one of the most useful imaging modality for characterization of malignant tumors and evaluation of their state before and after treatment. While conventional MRI avoids harmful ionizing radiation and allows measuring biophysical and physiological characteristics of tumors such as angiogenesis, it fails to provide information on tumor metabolism due to its low signal-to-noise ratio. Hyperpolarization technique PASADENA (Parahydrogen and Synthesis Allow Dramatically Enhanced Nuclear Alignment) can routinely increase MRI sensitivity of injectable contrast agent compounds by 10,000- 5,000,000 fold . These hyperpolarized agents report on metabolic rate and can delineate between benign and malignant tumors. The bottleneck of this technology is the availability of unsaturated precursors necessary to react with parahydrogen that provides the source of hyperpolarization. In this work we describe the synthesis of isotopically enriched 13C, 15N, D unsaturated choline and lactate precursors, they ultra- fast parahydrogen reduction in the automated polarizer as well as the preliminary imaging results.

ORGN 284

Novel approach to useful thiopyran synthons using a sulfur enabled cascade

Fang Li1, [email protected], David Calabrese2, Matthew Brichacek2, Ivy Lin1, Jon T Njardarson1,2. (1) Chemistry and Biochemistry, Univesity of Arizona, TUCSON, ARIZONA 85719, United States (2) Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, United States

As a part of program focused on the development of sulfur chemistry, a novel cascade reaction for building up tetrhydrothiopyran synthon from readily available building blocks was proposed. The one pot anionic cascade contain addition of a vinyl nucleophile to the carbonyl group, a sulfur substituent migrate to the newly produced alkoxide thus forming a leaving group, and heterocyclization. A Diels-Alder reaction and sulfur specific transformation on diene containing thiopyran products provided access on highly complex structures and new strategy for natural product synthesis.

ORGN 285

Copper catalyzed selective oxidative dehydrocouplings of P-H bonds generating C-P, P-P and P-O-P bonds

Li-Biao Han, [email protected] Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8565, Japan

Cu efficiently catalyzed an aerobic oxidative coupling of terminal alkynes with H- phosphonates to generate alkynylphosphonates in high yields (oxidative dehydrocoupling) (eq 1). This oxidative dehydrocoupling reaction can also be applied to the selective generation of other P-heteroatom bonds. Thus, by slightly changing the reaction conditions, copper can catalyze an aerobic oxidative dehydrogenative coupling of H-phosphonate to selectively produce hypophosphate (P-P compound) and pyrophosphate (P-O-P compound) in high yields (eq 2).

ORGN 286

Development of synthetic methodologies and their application in drug discovery

Bhahwal Ali Shah1,2, [email protected], Geert Jan Boons1. (1) Complex Carbohydrate Research Center,, University of Georgia,, Athens, Georgia 30602, United States (2) Indian Institute of Integrative Medcine,, Jammu, Jammu and Kashmir 180001, India

The advent of economical, facile and reliable synthetic methodologies has always been central to synthesis of intricate architecture of natural products, pharmaceutical candidates or polymers as well as libraries of structural analogs of biologically active scaffolds with improved activity profile and drug-ability. Our research interests include development of new synthetic methodologies like1 1) orthogonal protection and glycosylation strategies for sugars, 2) synthesis and biocatalytic kinetic resolution of important drugs/intermediates such as beta-lactams and vic-amino alcohols, 3) enzymatic separation of geometrical isomers, 4) asymmetric organocatalytic strategies. Moreover our emphasis is also on generation of natural product based libraries by isolation and structural modifications.2 Certain leads with improved/potent activity than natural counterparts have been identified and taken forward as potential therapeutics for treatment of cancer and infection.

ORGN 287

Transition-metal catalyzed C-alkylation of nitroalkanes

Donald A Watson, [email protected], Peter G Gildner, Di Cui, Amber A. S. Gietter. Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19711, United States

Nitroalkanes are commonly used building blocks in organic synthesis. Although these molecules are competent nucleophiles in a wide range of reactions, the C-alkylation of nitroalkanes with simple alkyl electrophiles remains a significant challenge. The difficulty stems from the inherent preference for nitronate anions to undergo O-alkylation under simple base-promoted reaction conditions. Recent efforts in our lab have led to the discovery of reaction conditions to overcome this long-standing problem. We have found that the use of transition-metal based catalysts results in the C-alkylation of nitroalkanes using simple alkyl halide electrophiles. This method allows for the rapid synthesis of complex nitroalkanes by the direct alkylation of simple nitroalkane starting materials. The development, scope and limitations of the method, as well as its application to the synthesis of complex amines, will be discussed.

ORGN 288

Synthesis and chemistry of bifunctional organoboron species

Erich Altenhofer, [email protected], Michael Harmata. Department of Chemistry, University of Missouri-Columbia, Columbia, Missouri 65211, United States

As part of a program directed toward the study of new electrocyclization reactions, we became interested in the chemistry of functionalized vinyl boronates, which might be used to create polyenes via cross-coupling reactions with the appropriate electrophilic partners. In this context, we began studying the chemistry of the known boronate 1 and various congeners. We will report on the synthesis of various congeners of 1 as well as current progress associated with their cross-coupling reactions. Further, we will report our synthetic and mechanistic studies regarding the deprotonation and alkylation of 1 .

ORGN 289 Combining a single catalyst and three starting materials for the selective formation of propargylamines, allenes, α,β-unsaturated ketones, or heteroarenes

Courtney E. Meyet, Conor J. Pierce, Yoo-Jin Ghang, Catharine H. Larsen, [email protected]. Department of Chemistry, University of California, Riverside, Riverside, CA 92521, United States

Generally when a reaction is capable of providing more than one structure, it is as an intractable mixture of products. We have developed efficient syntheses of propargylamines, allenes, α,β-unsaturated ketones, and heteroarenes in one-pot from commercially available starting materials. Surprisingly, the same catalyst selectively provides each of these products from the same three functional group starting materials. Herein is discussed how the mechanistic requirements for the selection of one product over another are determined in some cases solely by temperature or solvent and in others by the electronic nature of the amine component.

ORGN 290

Silanediols: Novel hydrogen bond donor catalysts

Andrew G Schafer, [email protected], Joshua M Wieting, Anita E Mattson. Departments of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, United States

Noncovalent organic catalysis is emerging as a powerful tool in organic synthesis. Hydrogen bond donors (HBDs) are a useful family of noncovalent catalysts able to activate a variety of functional groups for further reaction. Attractive features of HBD catalysts include their accessibility, low cost, and low toxicity. Recent successes in this area often exploit the anion recognition abilities offered by urea, thiourea, and guanidinium functionalities. Expansion of HBD catalyst scaffolds to include novel functional groups capable of recognizing anions will afford additional catalyst classes to explore in overcoming the barriers with current HBD catalysts such as low turnover and limited reaction scopes. To this end, we have discovered that silanediols operate as a novel family of HBD catalysts for the activation of nitroalkenes towards nucleophilic attack. Details surrounding the development of silanediol catalysis including a study of the catalyst structure, proposed catalytic cycles, and potential enantioselective variants will be discussed.

ORGN 291

Epoxidation studies as the key step toward the total synthesis of (-)-pironetin

Gerardo Torres, [email protected], José A. Prieto, Elizabeth Valentín. Department of Chemistry, University of Puerto Rico-Río Piedras, San Juan, PR 00931, Puerto Rico Pironetin is a natural polypropionate compound that shows plant growth regulatory activity, as well as immunosuppressive activity. It also shows remarkable antitumor activity. The structure of pironetin, which contains an unusual ethyl-substituted unsaturated δ-lactone ring joined to a syn,anti,syn stereotetrad, has attracted much research interest since its isolation, and several total syntheses have been published. We have undertaken an approach to pironetin employing a reiterative epoxide-based methodology for the synthesis of polypropionate fragments developed in our laboratory during the past years. Our approach consists of three reactions: stereoselective epoxidation of homoallylic or allylic alcohols, regioselective organometallic cleavage of epoxy alcohols and cis/trans reduction of the incorporated alkyne to produce each propionate unit. Employing this methodology, we were able to synthesize the C2-C4 and C6-C10 fragments of pironetin with the correct absolute configuration. The details of these studies will be presented. Work supported by NIH SCORE 2S06GM-08102-29.

ORGN 292

Regioselective semihydrogenation of dienes: Development and synthesis applications

Brian C Goess, [email protected]. Department of Chemistry, Furman University, Greenville, SC 29613, United States

Whereas general strategies exist for the direct regioselective semihydrogenation of the less substituted alkene of a differentiallysubstituted diene, there have been no corresponding reports of the opposite selectivity. A one-pot, three-step strategy for such a regioselective semihydrogenation of dienes will be described. Yields range from 55% to 95%, and the reaction is tolerant of a variety of common functional groups. Two specific applications of this methodology in natural product synthesis will be highlighted.

ORGN 293

New synthetic route towards ∆1-tetrahydrocannabinol analogs

Angie Garcia, [email protected], Michael J Marsella. Department of Chemistry, University of California, Riverside, Riverside, California 92521, United States

Cannabinoids are a promising class of therapeutic compounds, and there is increasing interest in modular synthetic approaches to both endogenous cannabinoids and their analogues. In particular, ∆1-Tetrahydrocannabinol (∆1-THC) and its analogues have been synthetic targets for decades, an indication of complexities that exist, despite apparent simplicity of structure. Most current syntheses do not support facile substitution of the bioactive R-group, a pentyl sidechain attached to the aromatic moiety. Discussion will focus on our synthetic strategies aimed at facilitating diversity in cannabinoid structure.

ORGN 294

Efficient and rapid divergent synthesis of PEO-based dendrimers through catalyst-free click chemistry

Mathieu Arseneault, [email protected], Isabelle Levesque, Jean- Francois Morin. Department of Chemistry, Universite Laval, Quebec, Quebec G1V 0A6, Canada

In this talk, we present our recent work on the synthesis of a third generation PEO- based dendrimer containing triazole units prepared divergently on grams scale through metal-free Huisgen 1,3-dipolar cycloaddition ("click") reaction between activated disubstituted alkyne and terminal azide groups. Synthetic efforts leading to the optimized and efficient route are presented. The growth of the dendrimers was achieved in high yield without purification. The presence of PEO and triazole units makes this dendrimer a very promising material for bio-related applications. Structural variations at the core and periphery of the dendrimer are underway in our laboratory and the results will be presented. Finally, toxicity studies as a function of generation, core and nature of termini will be discussed as well.

ORGN 295

Selective synthesis of tetraalkynylarenes via consecutive dual Sonogashira couplings of benzene-1,2-diiodo-4,5-ditriflate

Thomas J. Fisher, [email protected], Patrick H. Dussault. Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0304, United States

The palladium-catalyzed cross-coupling of aryl halides or triflates with terminal alkynes is a popular method for the synthesis of aryl alkynes. One class of possible reaction products, tetraalkynylarenes, is of particular interest in the field of molecular organic materials. Synthesis of unsymmetrical tetraalkynylarenes has been accomplished by sequential couplings of tetrahaloarenes which exploit the difference in reactivity between aryl iodides and bromides. However, while the Pd-mediated displacements of the iodides a occur readily, we and others have experienced challenges with subsequent displacements of the aryl bromides. To overcome this challenge, we envisaged conducting consecutive two-fold Sonogashira couplings on the bistriflate diester of 4,5-diiodo-1,2-dihydroxybenzene. We now report the application of this electrophilic platform for the synthesis of symmetric and nonsymmetric tetraalkynylarenes. ORGN 296

Enantioselective cycloaddition of N-metalated azomethine ylides onto fullerenes

Salvatore Filippone, [email protected], Izquierdo Marta, Maroto Ernesto Enrique, Ángel Martín-Domenech, Martín Nazario.Química Orgánica, Universidad Complutense de madrid, Madrid, Madrid 28040, Spain

In this communication, we report on the first catalytic enantioselective synthesis in fullerene science affording enantiomerically pure fullerenes with a total control of the stereochemical result. The suitable choice of the chiral metal catalyst ([Cu(II) or Ag(I)] in combination with a variety of different chiral ligands) directs the 1,3-dipolar cycloaddition of N-metalated azomethyne ylides on C60 (Nature Chem., 2009 ),on C70 (Angew. Chem. Int. Ed.,2011 ) and on endohedral metallofullerenes.(J. Am. Chem. Soc. ,2011 ) with high levels of site-,regio-, diastereo- and enantio-selectivity.

ORGN 297

Highly enantioselective synthesis of 3-substituted-γ-butenolide via palladium- catalyzed kinetic resolution of unsymmetrical allyl acetates

Bin Mao, [email protected], Yining Ji, Martín Fañanás-Mastral, Giuseppe Caroli, Ben L. Feringa.Stratingh Institute for Chemistry, University of Groningen, Groningen, The Netherlands

Palladium-catalyzed asymmetric allylic alkylation (AAA) has turned out to be an extremely useful and versatile method for carbon-carbon bond formation.[1] Here we present the palladium-catalyzed kinetic resolution of 1,3-disubstituted unsymmetrical allylic acetates, using silyl enol ether TMSOF as nucleophile to access 3-substituted-γ- butenolide for the first time (Figure 1). Preliminary studies showed that the hydrogen bonding interactions play a key role in controling the enantio- and regio- selectivity. An unusual reactivity profile of TMSOF was also observed during this investigation.

ORGN 298

Approach to metal-free asymmetric allylation

Caroline P Stovold, [email protected], Martin D Smith. Department of Chemistry, University of Oxford, Oxford, United Kingdom

An ion-binding approach to catalytic asymmetric allylation has been developed that facilitates the addition of allylsilanes to imines under mild and metal-free conditions. A mechanistic interpretation and its implications for the development of this transformation will be presented.

ORGN 299

Development of bisdiimidophosphite ligands and their application to the asymmetric trimethylenemethane [3+2] cycloaddition

Tom M Lam, [email protected], Barry M Trost. Department of Chemistry, Stanford University, Stanford, CA 94305, United States

Recent advances in the palladium-catalyzed [3+2] trimethylenemethane cycloaddition (Pd-TMM) have demonstrated the synthesis of tetrahydrofurans, pyrrolidines, and cyclopentanes in great enantioselectivities and yields. The success of this transformation has been due, in large part, to the development of chiral phosphoramidite ligands. We have expanded the scope of these chiral ligands to diimidophosphite ligands such as L1 . Utility of such C2-symmetric bisdiimidophosphite ligands have been differential to the application of substituted-TMM donors to this transformation, forming tetra-substituted cyclopentanes bearing three contiguous stereocenters in high yields, with good diastereo- and enantioselectivities. Herein, we discuss the development of such ligands and their application to the asymmetric TMM cycloaddition.

ORGN 300

Combining organocatalysis and Lewis acid catalysis for the synthesis of enantioenriched cyclic and heterocyclic structures

Kim Lebek Jensen, [email protected], Karl Anker Jørgensen. Department of Chemistry, Aarhus University, Aarhus C, Denmark

In recent years, the idea of combining organocatalysis with Lewis acid catalysis has emerged as a promising strategy for developing and enabling unprecedented transformations, which are not possible by employing either of the two catalytic systems alone. By application of this strategy two protocols merging aminocatalysis and hydrogen-bonding catalysis with Lewis acids have been developed, allowing for the syntheses of optically active cyclopentene carbaldehydes and 2,3-dihydropyrroles.

ORGN 301

Total synthesis of (+)-reserpine: Application of an aminothiourea-catalyzed cycloaddition of enones and cyclic imines

Naomi S. Rajapaksa, [email protected], Meredeth A. McGowan, Matthew Rienzo, Eric N. Jacobsen. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, United States

The catalytic, asymmetric synthesis of (+)-reserpine is reported. A catalyst-controlled diastereoselective cycloaddition reaction generated the tetrahydro-β-carboline core and installed the C20 and C3 stereogenic centers. The reaction is proposed to proceed by enamine formation between the primary aminothiourea catalyst and enone, followed by cyclization onto the β-carboline imine. An intramolecular aldol reaction formed the E- ring, and a highly-selective hydrogenation provided access to reserpine. This route differs from previous syntheses, which rely on substrate control to install the C3 center.

ORGN 302

Enantioselective synthesis of α-hydroxy amides via umpolung amide synthesis

Matthew W Leighty, [email protected], Bo Shen, Jeffrey N Johnston. Department of Chemistry, Vanderbilt University, Nashville, TN 37235, United States

The α-hydroxy amide is present within many natural products and medicinal agents. These motifs are commonly prepared asymmetrically through the corresponding carboxylic acids which can be accessed through enantioselective cyanohydrin or enzymatic methods. However, the following couplings to arrive at the corresponding amide products are susceptible to racemization. Alternatively, the Passerini reaction allows direct access the desired amides. However, enantioselective variants of this reaction are scarce in the literature. We sought a complementary route to these motifs based on our recently reported Umpolung Amide Synthesis (UmAS). In this approach, an asymmetric Henry reaction with bromonitromethane is added to aldehydes employing a readily available catalyst system to afford the desired α-hydroxy bromonitroalkanes with high levels of enantioselection. After MOM protection of these adducts, UmAS affords the desired α-hydroxy amides in good yields and without racemization. The reaction optimization and substrate scope for both the Henry reaction and UmAS will be discussed.

ORGN 303

Z-Selective copper-catalyzed asymmetric allylic alkylation with Grignard reagents

Massimo Giannerini, [email protected], Martín Fañanás-Mastral, Ben L Feringa. Department of synthetic organic chemistry, University of Groningen, Groningen, Groningen 9747 AG, The Netherlands

Cu-catalyzed asymmetric allylic alkylation (AAA) is a powerful synthetic tool as an enantioselective C-C bond forming reaction. This methodology has been applied extensively to the synthesis of terminal olefins. However the synthetic utility of this process for the synthesis of 1,2-disubstituted olefin is affected by the difficulty in controlling the geometry of the resulting double bond. In particular the less stable Z- isomer is difficult to obtain with this protocol with high selectivity. We reported an efficient AAA method on gem-dichlorides capable of generating chiral Z-vinyl-chlorides with high enantioselectivity and control on the configuration of the double bond. These compounds can undergo Suzuki cross-coupling with various boronic acids giving access to structurally diverse chiral Z-disubstituted olefins.

ORGN 304

β-keto heteroarylsulfones: Versatile nucleophiles in asymmetric organocatalysis

Christian Borch Jacobsen, [email protected], Karl Anker Jørgensen. Department of Chemistry, Aarhus University, Aarhus C, Denmark

The utilization of β-keto heteroarylsulfones as nucleophiles in asymmetric organocatalytic reactions, has allowed us to construct a range of one-pot protocols, leading to the formation of elusive enantioenriched products. Among other notable results, this has made it possible to develop the first asymmetric catalytic β-alkynylation of enals and the first asymmetric monofluorovinylations.

This presentation will focus on the development of these novel nucleophiles, and on their ability to function as versatile reaction partners in the construction of new enantioenriched molecules.

ORGN 305

Anomalies in the Noyori asymmetric transfer hydrogenation of several polycyclic meso compounds David R Clay, [email protected], Matthias C McIntosh. Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, United States

The Noyori asymmetric transfer hydrogenation (ATH) of ketones and alcohols is widely used in both industrial and academic labs. Over the course of developing a multi-gram scale preparation of an epoxy quinol via ATH, we observed several unexpected phenomena during desymmetrizations of meso diketones and a meso diol with the Noyori Ru(arene)(S,S-TsDPEN) catalysts. These include: (1) preferential alkene vs ketone reduction; (2) a significant arene ligand effect on the reaction products; (3) and a solvent-based reversal of the sense of enantioinduction. Details of the investigations and possible mechanistic rationales will be described.

ORGN 306

[C+NC+CC] coupling-enabled synthesis of influenza neuramidase inhibitor A- 315675

Laksiri P. Weerasinghe1, [email protected], Philip P. Garner1, Wiley J Youngs2, Brian Wright2. (1) Department of Chemistry, Washington State University, Pullman, WA 99163, United States (2) Department of Chemistry, University of Akron, Akron, OH 44325, United States

Neuramidase inhibitor A-315675 is a pyrrolidine-based compound developed at Abbott Laboratories. This compound exhibits superior activity against certain influenza virus strains when compared to oseltamivir. In this presentation, an efficient asymmetric synthesis of A-315675 is reported. The fully-functionalized pyrrolidine ring is assembled via an exo-selective asymmetric [C+NC+CC] coupling reaction. Subsequent steps involve a Fukuyama thioester reduction and (Z)-selective Wittig olefination.

ORGN 307

Toward the total synthesis of Antascomicin B: Building the C10-C21 fragment

Juliette Rivero-Castro, [email protected], Matthias C McIntosh. Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, Arkansas 72701, United StatesDepartment of Chemistry and Biochemistry, University of Arkansas, Fayetteville, Arkansas 72701, United States

Antascomicin B is a macrolide isolated from a strain of Micromonospora, It possesses structural similarities to FK506 and rapamycin and exhibits potent binding ability to FKBP12. Recent reports suggest that small molecule ligands of FKBP12 possess potent neuroprotective and neurodegenerative properties in mouse models of Parkinson's disease. Our approach to the C10-21 fragment of antascomicin B involves an asymmetric amino-Claisen rearrangement originally developed by Tsunoda et al.1 We are exploring the scalability of the preparation and rearrangement of an allylic amide possessing a silyloxy group at the terminal position of the alkene. The Tsunoda-Claisen rearrangement uses inexpensive (S)-α-methylbenzylamine as the chiral auxiliary. The allylic amide underwent rearrangement to establish the C14 and C15 stereocenters in high yield and good diastereoselectivity. This approach will potentially provide a low cost alternative to the Evans aldol for the preparation of b-siloxy amides formally derived from the aldol reaction of α,β-unsaturated aldehydes. A surprisingly high yielding acid mediated lactonization was employed to cleave the α-methylbenzyl amide. Details of these studies and further elaboration of the lactone will be discussed.

1. A Total Synthesis of (-)-Antimycin A3b Nishii, T., Yoshizuka, M., Yamasaki, C., Suzuki, T., Ito, S., Tsunoda, T. Tetrahedron Letters, 2000 , 41, 7667-7671.

ORGN 308

Towards well-defined polymer/electrode interfaces Raymond A Weitekamp, [email protected], Robert H Grubbs. Department of Chemsitry, Califronia Institute of Technology, Pasadena, CA 91125, United States

One of the fundamental challenges to improving efficiency in organic electronic devices is charge carrier recombination at both polymer/polymer and polymer/electrode interfaces. The achievement of both spatial and energy level alignment is crucial to suppressing recombination and optimizing device efficiencies. The longstanding goal of bringing the atomic-level control of organic synthesis to bear on device design is now within reach as a result of recent advances. Our current process for synthesizing organic/inorganic junctions was designed with these challenges specifically in mind. Through this technique, we hope to achieve novel device architectures in which the interfaces between the electrodes and active materials are chemically well defined.

ORGN 309

Synthesis of polydiacetylenes and polytriacetylenes precursors for carbon-rich materials.

Jules Romeo Neabo, [email protected], Jean-François Morin. Université Laval, Department of Chemistry, Quebec, Quebec G1V0A6, CanadaUniversité Laval, Department of Chemistry, Québec, Quebec G1V0A6, Canada

Several methods have been developed to synthesize carbon-rich materials. One of the most efficient method is oxidative cyclodehydrogenation of planary three-dimensionnal dendritic oligophenylene derivatives. Materials obtained by this method usually have good electronics properties which allow their use in electronic and optoelectronic transistors.

Our method uses cycloaromatization of polydiacetylenes (PDAs) and polytriacetylenes (PTAs) derivatives activated by temperature, light or catalysts. PDAs are synthesised by topochemical polymerization of 1,4-diphenylbutadiynes derivatives in the solid and gel states using 254 nm UV light. PTAs are obtained via Glaser coupling of triacetylene derivatives bearing terminal alkynes.

The materials obtained were characterized using different techniques including UV- Visible, fluorescence, NMR and raman spectroscopies as well as SEM et TEM imaging. These studies provide good understandings of such materials for potential use in electronic and optoelectronic devices.

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ORGN 310

Tantalum-boronate metallocavitand for selective encapsulation of fullerenes

Hassan Iden, [email protected], Jean-François Morin, Frédéric-Georges Fontaine. Department of Chemistry, Universite Laval, Quebec, Quebec G1V0A6, Canada

Tantalum-boronate trimetallic cavitands bearing electron rich π-conjugated systems have been synthesized. The interaction between the tantalum cavitands (host) and the fullerene C60 (guest) have been studied by UV-Visible spectrophotometry. Noncovalent immobilization of C60 on gold surfaces will be performed on self-assembled monolayers (SAMs) of thiol-functionalized tantalum metallocavitands. These studies will provide a good understanding of the host-guest relationship between cavitands and fullerene C60, and may help in designing new generations of n-type materials for electronic applications.

ORGN 311

Synthesis and characterization of open fullerenes with variable functionalities for use in bulk heterojunction organic solar cells as n-type materials

Shih-Ching Chuang1, [email protected], Yu-Wei Lin1, Fu-Wei Chan1, Chien-Yu Huang1, Chih-Ping Chen2. (1) Department of Applied Chemistry, National Chiao Tung University, Hsinchu, Taiwan Republic of China (2) Materials and Chemical Research Laboratories, Industrial Technology Research Institute, Chutong Township, Taiwan Republic of China

Generating power with green and renewable technology is the present focus in developing solar technology. The features of organic photovoltaics–light weight, flexibility, economical and large-area fabrication procedure–that are displayed by thin- film techniques make themselves rising targets for applications in future life. Thin-film organic photovoltaics (OPVs), embedding poly(3-hexylthiophene) (P3HT) and fullerene derivative, [6,6]-phenyl-C61 butyric acid methyl ester (PC61BM) in the active layer have been known for generating power efficiently upon illumination. Power conversion efficiency (PCE) of OPVs has been improved over 6% using the blends of new conjugated polymers and PCBM. In this paper, we report synthesis of new open-cage fullerenes with variable solubilizing functionalities featuring a variety of frontier molecular orbital energy levels. We further evaluate their performances with P3HT as active layers in the device. The mystery of photovoltaic application using open-cage fullerenes is disclosed in this study.

ORGN 312

Cucurbit[7]uril stabilization of water-sensitive alkylfluorodimethylsilanes and the design of a fluoride-controlled molecular switch

Xiaoyong Lu, [email protected], Eric Masson. Department of Chemistry & Biochemistry, Ohio University, Athens, Ohio 45701, United States

Water-sensitive gas fluorotrimethylsilane could be trapped and stabilized by Cucurbit[7]uril (CB[7]) to the expense of the hydrolyzed trimethylsilanol in aqueous medium and in the solid state. To the best of our knowledge, this represents the first case of reactive gas encapsulation into CB[n]s. This mechanism is applied to the design of a simple fluoride-controlled molecular switch. We then show that CB[n]s can also stabilize silver nanoparticles in aqueous medium, and we discuss the impact of the CB[n] ring size.

ORGN 313

Effect of chiral branching on the polar orthogonal smectic liquid crystalline phase formed by bent-core molecules

Ha Thi Thu Nguyen, [email protected]. Department of Organic and Polymeric Materials, Tokyo Institute of Technology, Tokyo, Japan An antiferreoelectric bent-core liquid crystal compound which exhibits a uniaxial SmA- biaxial SmAPA transition has been mixed with a non-liquid crystalline compound containing optically active element. The formed mixture has been used to study the effect of branched terminal group in chiral form on mesomorphic properties. These were investigated by means of differential scanning calorimetry (DSC), polarizing optical microscopy (POM), circular dichroism (CD), X-ray diffraction and electro-optical techniques (EO). All the mixtures with low concentration of the chiral compound kept showing the two original orthogonal smectic phases. However, the results of optically uniaxial texture in vertical aligned samples, the induced birefringence upon applying electric field and the arising of CD peaks in the temperature range of antiferreoelectric biaxial SmAPA suggested the emergence of a helical structure in which the helical axis is perpendicular to the layer. This is very unique in the sense that so far the helical structure has never been reported to appear in orthogonal smectic phases.

Fig 1. Electrooptical switching of the mixture in an in-plane switching cell

ORGN 314

New strapped porphyrins as hosts for fullerenes for the immobilization of pristine C60 on surfaces

Jean-Benoît Giguère, [email protected], Jean-François Morin. Department of Chemistry, Université Laval, Quebec, Quebec G1V 0A6, Canada

Supramolecular complexation and immobilization of pristine C60 on surfaces is an attractive method to keep the electronic properties of fullerenes intact and allow the control of the organization at the nanoscopic level for its use in electronic devices. New strapped porphyrin-based hosts with different π-conjugated moieties and linkers have been prepared and their ability to bind with fullerenes was studied in diluted solution. We found that the ability of these hosts to bind with fullerenes strongly depends on their chemical nature and more precisely on the substitution pattern of the porphyrin deck. The surface immobilization of C60 in self-assembled monolayer was studied through axial coordination of metallated porphyrins with ligand-functionalized surfaces followed by supramolecular complexation of the fullerenes. We will present the synthesis and characterization of supramolecular hosts and their binding properties with fullerenes in solution and on surfaces.

ORGN 315

Stille-coupling polymerization toward rod-rod conjugated block copolymer

Sung-Yu Ku1,4, [email protected], Neil D Treat1,2, Michael A Brady1,2, Justin E Cochran1,3, Michael L Chabinyc1,2,4, Craig J Hawker1,2,3,4. (1) Materials Research Laboratory, University of California, Santa Barbara, Santa Barbara, CA 93106, United States (2) Materials Department, University of California, Santa Barbara, Santa Barbara, CA 93106, United States (3) Department of Chemistry and Biochemistry, University of California, Santa Barbara, Santa Barbara, CA 93106, United States (4) Mitsubishi Chemical Center for Advanced Materials, University of California, Santa Barbara, santa Barbara, CA 93106, United States

The ability of all conjugated-block copolymers (BCPs) to self-assemble into thermodynamically ordered nanostructures provides an appealing strategy for controlling the active layer morphology in organic photovoltaic devices. All-conjugated BCPs have significant potential to reduce the phase separation spacing between donor and acceptor components to a length scale on the order of exciton diffusion (10-20nm).

To date, very few approaches for the synthesis of all-conjugated BCPs have been successfully realized. The ideal BCP has high molecular weight, low polydispersity, and high purity. Previously, meeting these strict requirements in the laboratory has proved to be incredible challenging. However, recent developments have made these interesting materials more accessible. We present the synthesis of all-conjugated BCPs using a Stille-coupling polymerization strategy. This method provides access to novel, well- defined BCPs that demonstrate phase-separated nanostructures in thin films for enhanced electronic properties.

ORGN 316

Microwave initiated ultrafast carbon nanotube growth

Xinyu Zhang, [email protected], Zhen Liu, Selcuk Poyraz, Yang Liu. Department of Polymer and Fiber Engineering, Auburn University, Auburn, AL 36849, United States

Carbon nanotubes (CNT) possess superior mechanical, thermal and electrical properties, lead to broad applications in composite materials, smart structures, chemical sensors, energy storage and nano-electronic devices. However, the high cost and difficulty in getting homogeneous dispersion remain challenges in CNT processing and applications. We demonstrate for the first time an affordable and scalable microwave approach for the direct growth of CNT on a wide range of substrates, including carbon fibers, glass fibers, Kevlar, fly ash, Kaolin, and Basalt fibers. The microwave initiated CNT growth will take only 30 seconds under the microwave irradiation at room temperature in the air, no need of any inert gas protection, and additional feed stock gases, usually required in CVD approach.

ORGN 317

Structure-property relationships of molecular organic semiconductors for organic photovoltaic materials

Thomas S van der Poll, [email protected], Gregory C Welch. Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, California 93106, United States

Organic π-conjugated materials have shown great promise as active components in optoelectronic devices including light-emitting diodes, field effect transistors, optical sensors, and solar cells. Some appealing features of organic systems is the amenability of processing via thermal evaporation at moderate temperatures or solution deposition methods, affording thin, lightweight and flexible device architectures. The performance of such devices relies on optical, electronic, thermal and physical properties of active materials, as they will translate into the ability to behave as a semiconductor, and to absorb and emit light. Molecular and bulk properties can be systematically tuned via synthetic manipulation, which is crucial to guiding future molecular design of π- conjugated materials.

ORGN 318

C-H Activation as a method toward accessing biologically active heterocycles

Jerry A Murry, [email protected] Molecule Process and Product Development, Amgen, Thousand Oaks, CA 91320, United States

Heterocycles are important sub-units of Biologically active molecules. The efficient synthesis of poly-substituted heterocycles can be challenging and iterative. One approach that provides direct access to functionalized heterocyclic rings involves CH activation and functiuonalization. This talk will focus on the application of CH activation of heterocycles as an efficient means for the production of biologically active molecules.

ORGN 319

New synthetic transformations using alkenes: From transition metal catalysis to metal-free radical reactions

Erik J Alexanian, [email protected]. Department of Chemistry, University of North Carolina Chapel Hill, Chapel Hill, NC 27599, United States Our work involving the development of new synthetic reactions using alkenes will be presented. Topics will include transition-metal-catalyzed cycloadditions, alkyl-Heck-type reactions, and metal-free alkene difunctionalizations.

ORGN 320

New approaches to C–F and C–C bond formation by transition metal catalysis

Abigail G. Doyle, [email protected]. Chemistry, Princeton University, Princeton, NJ 08544, United States

This lecture will cover recent developments in my laboratory aimed at the design of chemical strategies for complex molecule synthesis. The use of transition metal catalysts to enable valuable C-F and C-C bond-forming reactions will be discussed, as will our efforts to elucidate the scope and mechanistic underpinnings of these reactions.

ORGN 321

Award Address (Elias J. Corey Award for Outstanding Original Contribution in Organic Synthesis by a Young Investigator sponsored by the Pfizer Endowment Fund). Complexity and simplicity in organic synthesis: Some recent case studies

Jeffrey Johnson, [email protected]. Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599-3290, United States

This lecture will detail some of our laboratory's recent endeavors in the development of new reagents and reactions for organic synthesis. Attention will be paid to unconventional complexity-building transformations that deliver useful functional group arrays. Some efforts to simplify traditionally challenging bond constructions will also be discussed.

ORGN 322

Multicomponent reactions as useful tools for efficient diversity oriented synthesis

Romano Orru, [email protected] & Bioorganic Chemistry, VU Amsterdam, Amsterdam, Netherlands 1081 HV, The Netherlands

In this era of "-omics" and structural biology there is an ever-increasing need for novel small molecules that can modulate biological processes. For this, combinatorial synthesis is undisputed as an enabling tool to access the required small-molecule based compound collections. Although, the benefit for efficient biological evaluation and ultimately successful drug discovery seems obvious, the actual hit rates for new drug candidates have decreased steadily over the past decade. Structural diversity and complexity are essential to address "drug likeliness" in the design and synthesis of compound libraries. So far only a very limited number of molecules that cover the enormous potential of the chemical space have been actually made by Man and explored for potential useful properties, like their biological relevance. This continues to drive synthetic chemists to develop novel reactions that can efficiently access unexplored regions of chemical space.

Rapid generation of diverse sets of complex molecules can be achieved by employing diversity-oriented synthetic strategies in combination with so-called complexity- generating reactions. Multicomponent reactions (MCRs), which combine in one-pot at least three simple building blocks, provide a most powerful platform to access diversity as well as complexity in a limited number of reaction steps. Here we describe novel modular reaction sequences based on our previously reported MCR chemistry in combination with other common organic reactions or even with a second MCR. Combination of our MCRs with, e.g., cycloadditions, transition-metal mediated cross- coupling reactions or with more traditional MCRs like Biginelli-3CR, Ugi-4CR and the Passerini-3CR will be shown. Examples in which the synthetic methodology was applied for the easy generation of focused libraries for the synthesis of medicinally relevant ligands will be discussed.

ORGN 323

Optimization of a stereoselective Ugi reaction in the discovery of the oxytocin antagonist retosiban

John Liddle, [email protected] Research Centre, GlaxoSmithKline R&D, Stevenage, Hertfordshire SG1 2NY, United Kingdom

The optimisation and stereoselective synthesis of a series of diketopiperazine oxytocin antagonists, leading to the discovery of Retosiban, will be described. The chemistry proceeds via an initial Ugi reaction using a versatile convertible isonitrile. Activation of the intermediate amido phenol followed by amine addition promotes epimerisation at the exocyclic position and yields the required diastereoisomer as the major product.

ORGN 324 Development of new IMCR (isocyanide multi-component reactions) and MCR derived methodologies

Chris Hulme, [email protected], UA, Tucson, AZ, United States

This presentation covers significant recent advances in this laboratory aimed at the development of new IMCR (isocyanide multi-component reactions) and MCR derived methodologies. Specifically, the talk will cover recently discovered isocyanide based MCRs and utilization of novel post-condensation modifications for rapid generation of molecular diversity. Non-obvious synthetic routes (< 3 steps) to a range of pharmacologically relevant templates will be revealed. Efforts and statistics concerning the successful preparation and purification of > 2000 compounds for the MLPCN repository will also be discussed, along with drug discovery paradigms established at the BIO5OV facility at the University of Arizona.

ORGN 325

Catalytic enantioselective multciomponent reactions

Jieping Zhu, [email protected]. Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne,, Switzerland

Multicomponent reaction (MCR) is a process in which three or more reactants are combined in a single reaction vessel to produce a product that incorporates substantial portions of all the components.1 While many uni- or bi-molecular reactions can currently be performed under catalytic conditions to provide products in high yields with excellent ees, the development of enantioselective MCRs remained to be an under-exploited field. In this presentation, we will present our work on the development of catalytic enantioselective isocyanide-based MCRs,2 and the Povarov reaction3.

References and notes

1) Reviews on enantioselective MCRs: (a) Seayad, J.; List, B. Catalytic Asymmetric Multicomponent Reactions; in “Multicomponent reaction” Zhu, J.; Bienaymé, H., Eds.; Wiley-VCH, Weinheim, 2005, pp 277-299. (b) Guillena, G.; Ramón, D. J.; Yus, M. Tetrahedron: Asymmetry 2007 , 18, 693-700. (c) Gong, L-Z.; Chen, X.-H.; Xu, X.-Y. Chem. Eur. J. 2007 , 13, 8920-8926. Enantioselective domino process: (d) D. Enders, D.; Grondal, C.; Hüttl, M. R. M. Angew. Chem. Int. Ed. 2007 , 46, 1570-1581.

2) a). Wang, S.-X; Wang, M.-X.; Wang, D.-X.; Zhu, J. Angew. Chem. Int. Ed. 2008 , 47, 388-391; b) Yue, T.; Wang, M.-X.; Wang, D.-X.; Zhu, J., Angew. Chem. Int. Ed. 2008 , 47, 9454-9457; c) Yue, T.; Wang, M.-X.; Wang, D.-X.; Masson, J.; Zhu, J. Org. Chem. 2009 , 74, 8396-8399; d) Yue, T.; Wang, M.-X.; Wang, D.-X.; Masson, J.; Zhu, Angew. Chem. Int. Ed. 2009 , 48, 6717-6721.

3) Liu, H.; Dagousset, G.; Masson, G.; Retailleau, P.; Zhu, J. J. Am. Chem. Soc. 2009 , 131, 4598-4599. Dagousset, G.; Drouet, F.; Masson, G.; Zhu, J. Org. Lett. 2009 , 11, 5546-5549. Dagousset, G.; Zhu, J.; Masson, G. J. Am. Chem. Soc. 2011 , 133, 14804- 14813.

ORGN 326

MCRS: A rapid and efficient way of exploring chemical space around kinase hinge binders to identify potent kinase inhibitors

Irini Akritopoulou-Zanze, [email protected]. R4CP, Abbott Laboratories, Abbott Park, IL 60048, United States

Multicomponent reactions have been employed for the rapid preparation of potent kinase inhibitors against multiple kinase targets. We capitalized on the ability of MCRs to generate unique and underexplored chemical space around kinase hinges for the dual purpose of obtaining novel new inhibitors and thoroughly explore the ATP- competitive binding site of kinases. The compounds prepared were evaluated against a panel of kinase assays and potent inhibitors were identified for Gsk3b, Rock2 and Egfr

[Figure 1]

Figure 1. Design of novel molecules based on known kinase hinges

ORGN 327

ANCHOR approach to leverage the very large chemical space of multicomponent reactions

Carlos Camacho1, [email protected], Alexander Dömling2. (1) Department of Computational and systems biology, University of Pittsburgh, Pittsburgh, PA 15260, United States (2) Drug Design, University of Groningen, Groningen, The Netherlands

Abstract Body: The synthetic advantages of multicomponent reactions (MCRs) are highly appreciated in pharmaceutical, agrochemical and other industries. An increasing number of products based on MCRs are marketed or in development. Recent examples include boceprivir, retosiban or mandipropamide, just to name a few.1

A key feature of MCR chemistry is the very large chemical space which is amenable to discover useful compounds to advance human mankind. In fact it can be estimated that the breath of the MCR chemical space is easily approaching 1020. Synthetic technologies, however cannot efficiently leverage this huge chemical space and only a very minor fraction of the MCR space can be realistically synthesized. Thus the question arises “How to leverage the very large chemical space of multicomponent reactions”.

Here we will discuss pros and cons of different approaches to discover useful compounds from the MCR universe, including combinatorial chemistry, targeted (library) approaches, computational similarity searches, computational docking and the recently introduced ANCHOR approach (Fig.1).2

References and notes

1 A. Dömling, W. Wang, K. Wang Chemistry & Biology of Multicomponent Recations Chem. Rev. 2011 in press.

2 A. Czarna et al. Robust Generation of Lead Compounds for Protein–Protein Interactions by Computational and MCR Chemistry: p53/Hdm2 Antagonists Angew. Chem. 2010 , 49, 5352.

3 D. Koes et al. Enabling large-scale design, synthesis and validation of small molecule protein-protein Antagonists PLoS One 2011 , in press.

ORGN 328

Nucleobase-functionalized Locked Nucleic Acids (LNAs): Optimized probes for nucleic acid targeting

Patrick J Hrdlicka, [email protected]. Department of Chemsitry, University of Idaho, Moscow, Idaho 83843, United States

Locked Nucleic Acids (LNAs) are extensively explored as fundamental research tools and therapeutic agents against diseases of genetic origin due to their interesting nucleic acid targeting characteristics. Major efforts have been undertaken by academic and industrial laboratories to develop LNA analogs with more desirable hybridization properties and pharmacokinetic profiles.

We have recently developed synthetic routes toward nucleobase-functionalized LNA, which has facilitated attachment of structurally diverse moieties with differential charge, size, and hydrophobicity. Our studies have revealed that nucleobase-functionalized LNA display: a) extensively increased binding affinity toward single stranded DNA/RNA and double stranded DNA targets, b) increased target specificity, c) enhanced protection toward enzymatic degradation, and d) efficient fluorescent discrimination of single nucleotide polymorphisms (SNPs). These aspects will be discussed along with data from gene knockdown experiments.

ORGN 329

New cyclooctynes and their application in tumor labeling

Marjoke F Debets1, [email protected], Kiek Verrijp2, Floris P.J.T. Rutjes1, Floris L van Delft1, William P.J. Leenders2, Jan C.M. van Hest1. (1) Department of Organic Chemistry, Radboud University Nijmegen, Nijmegen, Gelderland 6525 AJ, The Netherlands (2) Radboud University Centre for Oncology, Radboud University Nijmegen Medical Center, Nijmegen, Gelderland 6500 HB, The Netherlands

In the last decade, interest in bio-orthogonal ligation strategies has grown impressively. Cyclooctynes, trans-cyclooctenes, tetrazoles and tetrazines have been developed and found wide application in biological research, together with already more established techniques like thiol-maleimide ligation and native chemical ligation (NCL). We used NCL to equip a tumor-vessel targeting nanobody with an azide and a thiol, and subsequently prepared a dual-labeled nanobody using thiol-maleimide ligation and strain-promoted azide-alkyne cycloaddition. This dual-labeled nanobody was then successfully used for tumor tissue labeling.

ORGN 330

β-Linked mono- and oligovalent mannosides by Click-approach: Synthesis and immunological screening Chinmoy Mukherjee1, Kaarina Ranta2, Johannes Savolainen2, Reko Leino1, [email protected]. (1) Laboratory of Organic Chemistry, Åbo Akademi University, Åbo, Finland (2) Pulmonary Diseases and Clinical Allergology, University of Turku, Turku, Finland

Considerable efforts have been directed towards search of small molecules which could be used in development of more effective and safer vaccines for immunisation against infections and therapeutic approaches to treat autoimmune, atopic and malignant diseases. Oligomannosides from C. albicans have in earlier studies been shown to be potentially immunogenic eliciting protective antibody responses against infections. Here, we describe the preparation of several mono- and oligovalent β-(1,2)-linked mannosides by utilization of a Click-based approach and results from their immunological screening. Some of the compounds prepared show considerable promise as modulators of Th and Treg cell-mediated immune responses.

ORGN 331

Small ring heterocyclic carbamates and carboxamides: The search for species- selective acetylcholinesterase inhibitors against the malaria mosquito

Fnu Astha1, [email protected], Qiao-Hong Chen1, Dawn M Wong1, James M Mutunga2, Jianyong Li3, Polo C.-H. Lam4, Maxim M. Totrov M. Totrov4, Jeffrey R. Bloomquist2, Paul R. Carlier1. (1) Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, United States (2) Department of Entomology and Nematology, Emerging Pathogens Institute, University of Florida, Gainesville, FL 32610, United States (3) Department of Biochemistry, Virginia Tech, Blacksburg, VA 24061, United States (4) Molsoft LLC, 11199 Sorento Valley Road, San Diego, CA 92129, United States

Reduction of malaria transmission in sub-Saharan Africa depends heavily on the use of insecticide-treated nets. At present only pyrethroid insecticides are used on these nets, but the emergence of pyrethroid-resistant mosquitoes has seriously jeopardized this disease control method. To identify a potential new class of insecticides that are safe for use on nets, we have been exploring the titled structures, to identify compounds that are highly selective for inhibition of An. gambiae acetylcholinesterase over the human enzyme. An additional design goal is to potently inhibit the G119S resistant mutant of the mosquito enzyme. Modulation of the heterocycle and substituents can confer both high enzymatic selectivity, and good toxicity to the wild-type and G119S mutant malaria mosquito

ORGN 332

Forward chemical genetics in Arabidopsis: Synthesis and characterization of bioactive fluorescent small molecules containing photoaffinity labels

Andrew J Defries1, [email protected], Suvadeep Nath2, Rizaldy Garcia1, Sean Cutler1, Michael C. Pirrung3. (1) Department of Botany and Plant Sciences, University of California Riverside, Riverside, CA 92521, United States (2) TCG Life Sciences, Kolkata, West Bengal, India (3) Department of Chemistry, University of California Riverside, Riverside, CA 92521, United States

A formidable challenge in the genomic era is the assignment of structure and function to unknown genes in model organisms. Forward chemical genetics seeks to discover and characterize pathways through the identification of novel phenotypes induced by organic small molecules and subsequent isolation of their target gene(s). Downstream genetic and biochemical strategies to dissect the action of bioactive molecules can be hampered by weak target-ligand interactions, low target abundance, genetic factors, and synthetic inaccessibility of analogs. We designed a synthetic scaffold that simultaneously permits fluorescence detection (dansyl) and photoaffinity labeling (diazirine) in a combinatorial library of thousands of drug-like small molecules synthesized through click chemistry. Using this library, we identified several bioactives in Arabidopsis thaliana and generated EMS-induced resistant mutants for SSLP marker- assisted mapping and downstream SNP identification by Illumina sequencing. Our proof-of-principle study will facilitate target identification of novel bioactives and accelerate future chemical genetics based discoveries.

ORGN 333

Enhancing catalytic activity of nucleic acids by making them more protein like

David M. Perrin, [email protected], Marcel Hollenstein, Curtis H. Lam, Christopher J. Hipolito. Department of Chemistry, University of British Columbia, Vancouver, BC V6T-1Z1, Canada Most DNAzymes are Mg2+-dependent and concentrations of 10 mM Mg2+ enable both folding and catalysis. Nevertheless, DNAzyme action is dramatically reduced at intracellular levels of Mg2+ e.g. 0.5 mM. Thus targeting viral RNA requires more robust catalysis than standard catalytic nucleic acids provide. Pioneering work by Ronald Breslow on ribonuclease-A mimics highlighted the importance of generating catalysts to cleave RNA without Mg2+.

To target viral mRNAs, we generated modified DNAzymes with imidazoles, amines, and now guanidiniums. These Mg2+-free DNAzymes are the most active M2+-free catalysts ever reported and now rival some of the best Mg2+-dependent ones. These catalysts represent a new class of synthetic biopolymers that capture the efficiency and complexity of biology and extend the possibilities of nucleic acid catalysis and synthetic biology beyond their natural limits.

ORGN 334

Chemoenzymatic site-specific modification, reversible immobilization and labeling of proteins without prior purification

Mohammad Rashidian, [email protected], Mark D. Distefano. Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, United States

In proteomic analysis, the desired target protein for capture or for labeling is not always pure or in high abundance; therefore, specific modification strategies that functionalize polypeptides in crude mixtures are necessary. Here, we describe the preparation of aldehyde-containing substrates that can be enzymatically incorporated into proteins in crude cell extract using farnesyltransferase; the resulting aldehyde-functionalized polypeptides can be employed for a variety of applications including site-specific fluorescent labeling and immobilization. A key feature of this modification strategy is its reversible nature, which makes it useful for applications where purification or enrichment of the target protein is required. Result indicates that the protein can be site- specifically modified in the crude mixture, immobilized into the hydrazide-surfaces, and labeled and released back into the solution by an aminooxy-fluorophore. Overall, the method shows great potential in selectively immobilizing and labeling any desired proteins from the crude cell extract without any further purification. ORGN 335

Multidisciplinary approach to probing enthalpy-entropy compensation and the interfacial mobility model

Erin Marie Wilfong1,4, [email protected], Yuri Kogiso2, Sivaramakrishnan Muthukrishnan2, Thomas Kowatz3, Yu Du1, Amber Bowie1, James H. Naismith3, Christopher M Hadad2, Eric J Toone1, Terry L Gustafson2. (1) Department of Chemistry, Duke University, Durham, NC 27708, United States (2) Department of Chemistry, The Ohio State University, Columbus, OH 43210, United States (3) Biomedical Sciences Research Complex, The University of St. Andrews, Fife, Scotland KY169ST, United Kingdom (4) Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, United States

Interfacial mobility has recently gained popularity as a model with which to rationalize both affinity in ligand binding and the often observed phenomenon of enthalpy-entropy compensation. While protein contraction and reduced mobility, demonstrated both computationally and by NMR techniques respectively, have been correlated to entropies of binding, to our knowledge, Raman difference spectroscopy has never been included in these analyses. Here, nonresonance Raman difference spectroscopy, isothermal titration calorimetry, and X-ray crystallography were utilized to correlate protein contraction, as demonstrated by an increase in protein interior packing and decreased residual protein movement, with trends of enthalpy-entropy compensation. These data are in accord with the interfacial mobility model and lend additional credence to this view of protein activity.

ORGN 336

WITHDRAWN

ORGN 337

Total synthesis of enantiomeric pure β-D-mannosyl phosphomycoketide (C32- MPM): A natural product from mycobacterium tuberculosis

Nan-Sheng Li1, [email protected], Louise Scharf1, Erin J. Adams1, Joseph A. Piccirilli2. (1) Department of Biochemistry & Molecular Biology, University of Chicago, Chicago, IL 60044, United States (2) Department of Biochemistry & Molecular Biology and Chemistry, University of Chicago, Chicago, IL 60637, United States

Three synthetic routes from the commercially available methyl (2S)-3-hydroxy-2- methylpropionate (>99% purity) to β-D-mannosyl phosphomycoketide (C32-MPM) were developed. Method A using Julia-Kocienski couplings and platinum-catalyzed hydrogenations afforded the C32 mycoketide with ~80% optical purity. Methods B and C using Julia-Kocienski couplings and diimide reduction gave enantiopure C32 mycoketide in high yield. The enantiopure C32 mycoketide from methods B and C was further converted to the C32-MPM and the C32-MPM could be as an auxillary for the CD1c cystallization.

ORGN 338

Metabolic labeling of trehalose glycolipids in mycobacteria

Benjamin M. Swarts, [email protected], Carolyn R. Bertozzi. Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, United States

Mycobacterium spp., including the pathogen Mycobacterium tuberculosis, synthesize the nonmammalian disaccharide trehalose, which is used as a store of carbon, a stress protectant, and a scaffold for glycolipids that are involved in cell wall biosynthesis and pathogenesis. Here we describe a strategy for exploiting trehalose metabolic pathways to label glycolipids using azide-modified trehalose (TreAz) analogs, followed by attachment of fluorescent and affinity probes using copper-free click chemistry. Exhaustive characterization of the metabolic fates of four TreAz compounds in mycobacteria revealed intriguing differences in labeling mechanism and efficiency.

ORGN 339

Investigating the synthesis of aromatic esters and amines of medicinal values under micro waves

Nagarajan Vasumathi, [email protected]. Department of Physical and Earth Sciences, Jacksonville State University, Jacksonville, AL 36265, United States p-Aminobenzoic acid esters and polyamines are known to be involved in cell damage and yet are also useful in the treatment of seizures and epilepsy. They play the neuroprotective role when administered in specific concentrations. This contradicting but important nature of these compounds interested us in exploring the synthesis of such compounds. Attempted synthesis of cyclohexyl ester of p-aminobenzoic acid by Fischer Esterification under thermal heating led to a mixture of products and the product isolation was troublesome. However, under micro waves, a pure single product was achieved. Synthesis of aromatic monoamines and polyamines via the nucleophylic aromatic substitution reactions are quite cumbersome and involve longer reaction times under thermal heating. Micro wave irradiation of 2,4-dinitrobromobenzene by ammonia, aniline and hexane diamine respectively gave the corresponding aromatic amines in good yields with maximum purity. The compounds are characterized by IR and NMR. The method of synthesis and characterizations are discussed. ORGN 340

Metal catalysis for the application of the hydration of alkynes and the Diels-Alder addition to nitriles

Dominic van der Waals, [email protected], Jonathon M.J. Williams. Department of Chemistry, University of Bath, Bath, United Kingdom

The use of metal catalysts, in order to hydrolyse terminal alkynes, to yield methyl- ketones presents an interesting challenge; current methods include the use of mercury compounds with intrinsic unfavourable health effects and so other routes would be desirable. Some Group (III) triflates show activity for the hydration of benzylic alkynes and concurrent work is investigating analogous modes of nitrile activation for the production of pyridines via a Diels-Alder type reaction.

ORGN 341

New high turn-over manganese catalyst systems for selective oxidation of alcohols, aldehydes, alkanes and alkenes with hydrogen peroxide

Pattama Saisaha1, [email protected], Dirk Pijper1, Jia Jia Dong1, Margarethe van der Meer1, Tim Meinds1, Edwin G Ijpeij2, Ruben P van Summeren2, Paul L Alsters2, Johannes W de Boer3, Ronald Hage3, Ben L Feringa1, Wesley R Browne1. (1) Department of synthetic organic chemistry, University of Groningen, Groningen, The Netherlands (2) DSM Pharmaceutical Products, Innovative Synthesis and Catalysis, Geleen, The Netherlands (3) Rahu Catalytics, BioPartner Center Leiden, Leiden, The Netherlands

Recently we reported that pyridyl based ligands decompose in situ to pyridine-2- carboxylic acid and its derivatives, in the presence of Mn(II), H2O2 and a base in acetone. The pyridine-2-carboxylic acid/ Mn(II) and base provide for the observed catalytic activity. In this presentation the application of this system for selective oxidation of organic substrates with multiple oxidation sensitive functional groups including alcohols, aldehydes, alkanes and alkenes and the use of Raman spectroscopy for lead identification and reaction optimization will be discussed.

ORGN 342

Boronate urea activation of strained systems

Tyler J. Auvil, [email protected], Sonia S. So, Anita E. Mattson. Department of Chemistry, The Ohio State University, Columbus, OH 43210, United States

Hydrogen bond donor (HBD) catalysis has emerged as a powerful tool in organic synthesis. Attractive attributes of HBD catalysts include their accessibility, low cost and toxicity, and ability to provide complementary reactivity patterns to conventional metallic catalysts. While HBD catalysis has shown great potential, certain challenges such as high catalyst loadings and limited reactivity patterns prevent its widespread use in both academia and industry. In an effort to address these limitations boronate ureas have been developed as new HBD catalysts with enhanced activity relative to traditional ureas, due to internal coordination to a strategically placed Lewis acid. The improved activity of boronate ureas was taken advantage of for the activation of nitrocyclopropanes toward nucleophilic attack, a new reactive mode for HBD catalysts. Details behind the development of boronate urea catalysis for the activation of strained rings, including mechanistic studies and applications toward the syntheses of bioactive targets, will be discussed.

ORGN 343

Fluorobenzene derivatives as multifunctional tools

Frederik Diness1,2, [email protected], Mikael Begtrup Begtrup1, David P. Fairlie2. (1) Department of Medicinal Chemistry, University of Copenhagen, Copenhagen, Denmark (2) Institute of Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia Arylation of heteroatoms are extremely important reactions in organic synthesis. Traditional these are carried out through transition-metal-catalyzed cross coupling reactions. Catalyst-free arylation has been reported effected by direct SnAN substitution on electron deficient fluorobenzene derivatives with nitro, carbonyl, sulfone or nitrile substituents, but reported methods gives low yields for less activated fluorobenzene derivatives and are not feasible for unactivated fluorobenzenes.[1] Here we present our resent advances in high yielding catalyst-free arylation of heteroatoms in which fluorine is displaced with the nucleophile through a SnAE reaction. These reactions are complimentary to cross coupling reactions and give facile access to a range of products which are difficult to obtain through other methods. The versatility of the chemistry provides the base for using fluorobenzene derivatives as multifunctional tools in a broad span of natural science disciplines.

[1] H. Amii, K. Uneyama Chem. Rev. 2009 , 106, 2119-2183.

ORGN 344

Multistep continuous flow system for on-demand synthesis of chemokine receptor ligands

Trine P. Petersen1,2, [email protected], Andreas Ritzén1, Trond Ulven2. (1) Discovery Chemistry & DMPK, H. Lundbeck A/S, Valby, Denmark (2) Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense, Denmark

Synthesis in continuous flow reactors offers a number of potential advantages over traditional batch synthesis, including precise regulation of temperature and pressure over wide ranges, improved safety with exothermic and potentially explosive reaction mixtures, possibilities of automation and of coupling to continuous multi-step sequences. As optimization in drug discovery often involve synthesis of similar compounds by a short reaction sequence consisting of relatively simple steps, we anticipated that multistep continuous flow synthesizers might be especially useful in medicinal chemistry. To explore this, we constructed a 3-step continuous flow system for synthesis of ligands for chemokine receptors.1 The design and optimization of the flow synthesizer and use of the system for the synthesis of new potential chemokine receptor ligands will be described.

1) T. P. Petersen, A. Ritzén, and T. Ulven, Org. Lett. 2009, 11 , 5134.

ORGN 345

Intramolecular Friedel-Crafts reactions with indole and allylic alcohols

Bryan Wakefield1, [email protected], Allen Benson1, Michael Brown2, Nicole Williams1. (1) Chemistry, Delaware State University, Dover, DE 19901, United States (2) Biology, Delaware State University, Dover, DE 19901, United States The intramolecular Friedel-Crafts reaction of allylic alcohols tethered to the nitrogen of indole has been investigated. Using Bronsted or Lewis acid conditions, a variety of substrates have been found to produce the cyclization product in good yield. This method has been used to construct the core of flinderole C.

ORGN 346

Novel method for reduction of amides

J. Thomas Ippoliti, [email protected], Gabriella T. Perell. Department of Chemistry, University of St. Thomas, St. Paul, MN 55105, United States

The typical method of reducing amides with lithium aluminum hydride has many drawbacks that all stem from the high reactivity of the reducing agent. A new method whose inspiration comes from the Appel reaction has been developed. Reaction of triphenylphospine, a secondary amide and carbon tetrachloride was carried out in a microwave reactor in a variety of solvents to give an imine phosphorane intermediate. The intermediate has been isolated and well characterized. The intermediate is then reduced with sodium triacetoxyborohydride to give the amine in good yield.

ORGN 347

New methods for the addition of small, gaseous molecules to unsaturated hydrocarbons

Jennifer M. Schomaker, [email protected], R. David Grigg, Jared W. Rigoli, Sara A. Moyer, Sam Neale. Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, United States

Although CO2 is a readily available and inexpensive C1 source, it is quite challenging to access alkyl carboxylic acids without employing organometallic reagents that limit the substrate scope of the reaction. Very few examples of the direct hydrocarboxylation of olefins are known and these approaches often utilize either precious metal catalysts or pyrophoric organometallic reagents. This presentation will discuss our synthetic and mechanistic efforts in the development of Cu-catalyzed tandem reactions for the conversion of olefins and related substrates into alkyl carboxylic acids using CO2 as the C1 source. The extension of these mild, inexpensive and functional-group tolerant methods to other C-C bond-forming reactions will also be described.

ORGN 348

One-pot synthesis of pyrroloquinoxaline-embedded complex heterocyclic molecules Metin Zora1, [email protected], Arif Kivrak1,2, Nuray Esra Yazıcı1. (1) Department of Chemistry, Middle East Technical University, Ankara, Turkey (2) Department of Chemistry, Yüzüncü Yıl University, Van, Turkey

Pyrroloquinoxalines have been recently studied as a prominent class of heterocycles and still receive considerable attention for both material and pharmaceutical benefits. Although many methods have been developed for their syntheses and new variants continue to appear, the synthesis of pyrroloquinoxaline-embedded complex heterocyclic systems remains a significant challenge for organic chemists. We have uncovered that InCl3-catalyzed reactions of 1-(2-aminophenyl)pyrroles 1 with functionally substituted aldehydes 2 and 4 provide a rapid entry to isoquinolino-pyrroloquinoxalines 3 and benzooxazepino-pyrroloquinoxalines 5 in good to high yields. The scope, limitations and mechanism of these reactions will be discussed.

ORGN 349

Highly chemoselective and controlled conversion of secondary amides to ketones

William S. Bechara, [email protected], Guillaume Pelletier, André B. Charette. Department of Chemistry, Université de Montréal, Montreal, Quebec H3C 3J7, Canada

A general and chemoselective method is described based on an activation/addition sequence on secondary amides allowing the controlled isolation of structurally diverse ketones and ketimines. The generation of a highly electrophilic imidoyl triflate intermediate is found to be pivotal in the observed exceptional functional group tolerance, allowing the facile addition of readily available Grignard and diorganozinc reagents to amides, and avoids commonly observed over-addition or reduction side- reactions.

ORGN 350

Calcium catalyzed reactions of alcohols and olefins

Meike Niggemann, [email protected], Matthias J Meel, Stefan Haubenreisser, Vera Meyer. Department of Organic Chemistry, RWTH Aachen University, Aachen, NRW 52074, Germany

In the past decades, catalysts have been developed almost exclusively on the basis of transition metals. Nowadays, it is increasingly significant to create more sustainable alternatives, wherever it is possible. Calcium, among other alkaline earth metals, seems to be an ideal metal catalyst. It is essentially free of toxicity and the fifth most frequent element in the earth crust. Surprisingly, its catalytic potential remains hitherto almost unexplored. Our research focuses on the development of calcium catalyzed reactions.

We were the first to successfully apply calcium salts as highly efficient Lewis acidic catalysts in organic synthesis. In direct transformations of environmentally benign p- activated alcohols and olefins with different nucleophiles we demonstrated that our new calcium catalyst is more active than most of the known Lewis acidic catalysts, reflected by a broad substrate scope under very mild reaction conditions.

M.Niggemann, M.Meel, Angew. Chem.Int.-Ed. 2010 , 49, 3684; M.Niggemann, N.Bisek, Chem.-Eur.J. 2010 , 11246.

ORGN 351

Strategic use of palladium-catalyzed carboelimination from tertiary alcohols: Application to carbocycle and heterocycle synthesis

Arturo Orellana, [email protected]. Department of Chemistry, York University, Toronto, Ontario M3J1P3, Canada

The palladium-catalyzed β-carboelimination of tertiary alcohols has been observed from cyclopropanols, cyclobutanols and a number of other systems. We have disclosed a number of strategic applications of this fundamental process in cross-coupling reactions. In this talk I will describe our recent advances in the application of alkyl- and arylpalladium intermediates derived from tertiary alcohols towards the synthesis of carbocyclic and heterocyclic systems.

ORGN 352

Exploiting latent symmetry in a synthesis of spongistatins

Paul S. Tanis, [email protected], James L. Leighton. Department of Chemistry, Columbia University, New York, New York 10027, United States

The recognition of latent symmetry in the backbone of the F ring of the highly cytotoxic macrolide spongistatin 1 has allowed the development of a facile synthesis of the 6 contiguous stereocenters of the F ring fragment in 7 steps. The analysis and route will be described, and when concatenated to the new chemistry being developed for the ABCD ring fragment, this chemistry will facilitate the construction of analogues and the development of an SAR around these fascinating anticancer agents.

ORGN 353

Progress towards total synthesis of 3-allyl-3-hydroxy oxindole natural products

Narayanaganesh Balasubramanian, [email protected], Anthony J Ostlund, Gregory R Cook. Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 5802, United States

Oxindole and its derivatives are abundant in many natural substances and endogeneous to mammals and plants. Oxindole core is found in numerous biologically relevant compounds exhibiting broad spectrum of activity. 3-substituted-3-hydroxy oxindoles are found in numerous targets. The presence of the quaternary stereo-center at the 3-position has generated significant attention of the synthetic chemist for the past decade. A direct approach for the motif is nucleophilic addition to isatin. Recently we have developed enantioselective methodologies based on indium and bismuth metal for the construction of the quaternary center.

ORGN 354

Applications of a new phosphorus-based 1,3-dipole: Towards highly regio- and enantiocontrolled cycloadditions Marie S. T. Morin, [email protected], Daniel St-Cyr, Bruce A. Arndtsen. Department of Chemistry, McGill University, Montréal, Canada

1,3-dipolar cycloaddition reactions have emerged as an important tool to construct 5- membered ring heterocycles. In order to develop more general and practical methods to generate dipolar cycloaddition reagents, we have recently designed a new type of 1,3- dipole, a phospha-Münchnone, synthesized in a modular fashion from imines, acid chlorides and phosphonites (PR3). This phosphorus-containing analogue to Münchnones can undergo cycloaddition reaction with alkynes leading to a wide scope of pyrroles with high regioselectivity. This contrasts with Münchnones, which often show poor cycloaddition regioselectivity unless there is a large bias in the dipole-substituents. This phospha-Münchnone is also able to generate pyrroline molecules by intramolecular cycloaddition of alkenes. In addition to its high efficiency, this approach affords a new way to control the enantioselectivity of the cycloaddition by incorporating easy accessible chiral phosphite unit. This 1,3-dipole therefore provides a unique approach to control chirality in pyrroline synthesis, where enantioenriched products are generated in one pot from imines, alkenes and acid chlorides.

ORGN 355

Efficient and scalable enantioselective synthesis of a CGRP antagonist

David K. Leahy1, [email protected], Yu Fan1, Lopa V Desai1, Collin Chan1, Jason Zhu1, Guanglin Luo3, Ling Chen3, Ronald L Hanson1, Masano Sugiyama1, Thorsten Rosner1, Nicolas Cuniere1, Zhiwei Guo1, Yi Hsiao1, Qi Gao2. (1) Chemical Development, Bristol-Myers Squibb, New Brunswick, NJ 08903, United States (2) Analytical and Bioanalytical Development, Bristol-Myers Squibb, New Brunswick, NJ 08903, United States (3) Neuroscience Discovery Chemistry, Bristol-Myers Squibb, Wallingford, CT 06492, United States

A scalable enantioselective synthesis of the CGRP antagonist BMS-846372 is presented. This new synthesis showcases a chemo- and enantioselective reduction of a cyclohepta[b]pyridine-5,9-dione as well as a Pd-catalyzed alpha-arylation reaction to form the key carbon-carbon bond and set the molecule's absolute and relative stereochemistry. The initial method for the enantioselective reduction was accomplished via the use of a reductase enzyme. However, superior results were obtained using an asymmetric rhodium-catalyzed hydrogenation. An aryl moiety was then installed with a 1,4-trans relative orientation via a diastereoselective Pd-catalyzed arylation where a subsequent crystallization induced dynamic resolution increased the diastereomeric ratio to 38:1

ORGN 356

Asymmetric synthesis of the (5R,6R,9S)-6-hydroxy-9-methyl-1,8- diazaspiro[4.5]dec-3-en-2-one scaffold and synthesis of novel BACE inhibitors for the treatment of Alzheimer's disease

Erik A. LaChapelle, [email protected], Christopher J. Helal, Luis Martinez- Alsina, John C. Murray, Joseph M. Young, Brian T. O'Neil. Department of Neuroscience Medicinal Chemistry, Pfizer, Groton, Connecticut 06340, United States

As part of the ongoing effort to identify novel BACE inhibitors that show proper alignment of potency and ADME properties, we envisioned targets incorporating a 5- hydroxyl group on a 4,4-spirolactam scaffold. The challenge in constructing this scaffold was with the regio- and stereocontrol of integrating the hydroxyl and spirolactam stereocenter relative to the (S)-methyl substituent. Starting with benzyl-2-(S)-methyl-4- oxopiperidine-1-carboxylate, a novel application of a rhodium catalyzed hydrosilyation- oxidation process proceeded in high stereoselectivity to provide (2S,5R)-benzyl 5- hydroxy-2-methyl-4-oxopiperidine-1-carboxylate. Introduction of the quaternary stereocenter proceeded in high yield and complete stereoselectivity through a metal- free hydroxyl-accelerated Overman rearrangement. Subsequent functionalization provided the chiral 6-hydroxy spirocyclic scaffold which was further elaborated to give the desired BACE inhibitors.

ORGN 357

Guilding asymmetric catalysis design through substituent effects and multidimensional modeling

Kaid C. Harper, [email protected], Matthew S. Sigman. Chemistry, University of Utah, Salt Lake City, Utah 84112, United States

Applying steric and electronic parameters to describe substituent effects led to the development of three-dimensional free energy relationships and revealed several possible synergistic effects between isolated substituents on the same catalyst. Using simple ligand libraries which systematically vary different substituents, these three- dimensional models were created and used to efficiently determine optimal catalyst properties. Application of these models led to redesign and eventual discovery of an enantioselective catalyst for the Nozaki-Hiyama-Kishi propargylation of ketones.

ORGN 358

Diastereoselective synthesis of advanced fragments of zincophorin and related isomers via a combined approach of Mukaiyama aldol reaction and radical reduction

Francois Godin1,2, [email protected], Philippe Mochirian1,2, Ioannis Katsoulis1, Isabelle Fontaine1, Jean-Francois Brazeau1,2, Yvan Guindon1,2,3. (1) Bio- Organic Chemistry Laboratory, Institut de recherches cliniques de Montréal, Montreal, Quebec H2W 1R7, Canada (2) Department of Chemistry, Université de Montréal, Montreal, Quebec H3C 3J7, Canada (3) Department of Chemistry, McGill University, Montreal, Quebec H3A 2K6, Canada

We are reporting the diastereoselective synthesis of advanced fragments of zincophorin, namely its C1–C13 subunit, as well as isomers thereof. This is achieved using a two-reaction sequence: a Mukaiyama aldolization using a tetrasubstituted enoxysilane and a hydrogen-transfer reaction, both under Lewis acid control. Selection of the optimal synthetic route to construct the polypropionate sequence was found to be influenced by the number of complexation sites that can interfere in the aldol step under bidentate Lewis acid control.

ORGN 359 Enantioselective synthesis of (+)-hypercalin C

Morgan E. Shirley, [email protected], Daniel Romo. Department of Chemistry, Texas A&M University, College Station, Texas 77840, United States

Hypercalin C is a dearomatized isoprenylated phloroglucinol (DIP) isolated from the aerial parts of Hypericum calycinum L. It has been shown to be more potent than current colon cancer therapies, displaying an ED50 value of 0.78 μM against Co-115 HeLa cell line. The synthesis involves a practical, multi-gram sequence to access a versatile bicyclic β-lactone from (R)-carvone. The key transformation employs a diastereoselective nucleophile catalyzed aldol-lactonization (NCAL) process (dr >19:1) for the generation of the desired bicyclic β-lactone. Subsequent steps involve coupling of the β-lactone with an aromatic moiety and a late stage ortho-Claisen rearrangement to establish the dearomatized natural product. Studies toward the enantioselective synthesis of (+)-hypercalin C will be presented.

ORGN 360

Progress towards the total synthesis of (-)-zampanolide

Matthew R Wilson, [email protected], Eric Stefan, Richard E. Taylor. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, United States

(-)-Zampanolide, isolated from Fasciospongia rimosa in 1996 by Tanaka and co- workers, is a 20-membered macrolactone containing a cis-2,6-disubstituted tetrahydropyran, ample unsaturation, and an unusual N-acyl hemiaminal side chain. This structurally unique polyketide exhibits significant cytotoxicity in the low nanomolar range against various tumor cell lines and induces microtubule bundles in cells. As of recently, only small amounts of (-)-zampanolide have been provided by total synthesis or extraction from its marine host. As a result, we have undertaken the large-scale preparation of this potent polyketide using electrophile-induced ether transfer methodology developed within our lab to supply material for biological studies. Advances towards this goal will be presented.

ORGN 361

Sulfenate substitution as an alternative synthetic access to β–amino sulfoxides

Adrian L. Schwan, [email protected], Stefan C. Soderman. Department of Chemistry, University of Guelph, Guelph, Ontario N1G 2W1, Canada

Access to diastereomerically enriched β–amino sulfoxides is often achieved through oxidation of the corresponding β–amino sulfides. An unexplored synthetic option is to incorporate the sulfur containing unit through substitution chemistry, while the sulfur is already possessing an oxygen. This process can be achieved using sulfenic acid anion substitution chemistry and we have explored this option for a variety of sulfenate anions. Thus the reaction of aromatic sulfenates with N-protected β–amino sulfoxides proceed in good yields with dr's reaching 94:6.1 In addition to aromatic sulfenates,1 we have also explored vinylic and alkyl sulfenates. Yields are more variable, but dr's of the vinylic and aromatic systems are comparable. Some surprising features about sulfenate reactivity were also uncovered in this study.

1. S.C. Soderman and A.L. Schwan Org. Lett. 2011 , 13, 4192-4195

ORGN 362

Highly enantioselective synthesis of α-amino acid derivatives by an NHC- catalyzed intermolecular Stetter reaction

Nathalie E Wurz, [email protected], Thierry Jousseaume, Michael Schedler, Frank Glorius. Organisch-Chemisches Institut, WWU Münster, Münster, Germany

Whilst many successful protocols for the intramolecular asymmetric Stetter reaction have been reported,[1] its more versatile intermolecular counterpart has proven much more challenging.[2] Here we present a highly enantioselective intermolecular Stetter reaction:[3] Starting from simple starting materials, highly enantioenriched α-amino acid derivatives are obtained in an atom-economic, and mild process. As the key step a highly stereoselective intramolecular proton transfer is proposed.

In addition, a generalization of this reaction was achieved by the development of novel chiral NHCs.

[1] For reviews on NHC organocatalysis, see: a) D. Enders, O. Niemeier, A. Henseler, Chem. Rev. 2007 , 107, 5606; b) J. L. Moore, T. Rovis, Top. Curr. Chem. 2010 , 291, 77; c) A. T. Biju, N. Kuhl, F. Glorius, Acc. Chem. Res. 2011 , DOI: 10.1021/ar2000716; d) K. Hirano, I. Piel, F. Glorius, Chem. Lett. 2011 , 40, 786-791.

[2] Selected examples: a) D. Enders, J. Han, A. Henseler, Chem. Commun. 2008 , 3989; b) Q. Liu, S. Perreault, T. Rovis, J. Am. Chem. Soc. 2008 , 130, 14066; c) D. A. DiRocco, K. M. Oberg, D. M. Dalton, T. Rovis, J. Am. Chem. Soc. 2009 , 131, 10872; d) D. A. DiRocco, T. Rovis, J. Am. Chem. Soc. 2011 , 133, 10402.

[3] T. Jousseaume, N. E. Wurz, F. Glorius, Angew. Chem Int. Ed. 2011 , 50, 1410.

ORGN 363

Steric effects to enhance Diels-Alder and ene cycloaddition reactions

Nandeo Choony, [email protected]. Chemistry, University Of South Carolina Aiken, Aiken, SC 29801, United States

Different bulky groups have been used as a steric buttress to enhance Diels-Alder and ene reactions. The most effective bulky group has been found to be the trityl group. Some similar reactions were also carried out on solid phase using the trityl polymer bound resin as the steric buttress.

ORGN 364

New organic and Ru-complex dyes synthesis for dye-sensitized solar cells (DSSC) application

Der-Gun Chou, [email protected], Kuan-Wei Lee.Development of R&D Center, Everlight Chemical Industrial Corporation, Taiwan Republic of China

Series of dyes containing a fluorene moiety in the spacer have been designed, synthesized, and characterized. These dipolar compounds contain an arylamine or cycloalkylamine as the electron donor, a 2-acrylic acid as the electron acceptor, and a conjugated spacer between the donor and the acceptor. We designed variety of the conjugation length with one fluorine moiety as well as the innovated synthesis process for industrial mass production. The device performance data were obtained under AM 1.5 illumination. and the efficiency of DSSCs exhibited good performance (η), ranging from 2.22 %-4.76 %, which reached 40%-87 % with respect to that of the standard cell from N719-based device fabricated under the same condition.

Beside the organic DSSC dyes development, Everlight R&D center also concentrate on the improvement of novel Ruthenium dyes. The performance results indicated that higher efficiencies compared to the standard reference dye, N719 and Z907.

ORGN 365

Fabrication of a true conjugated polymer p-n junction using a polyelectrolyte mediated electrochemical technique

Stephen G. Robinson, [email protected], Christopher D. Weber, Mark C. Lonergan. Department of Chemistry, University of Oregon, Eugene, OR 97403, United States The formation of a true conjugated polymer p-n junction has been a challenging problem due to the diffusion of dopant counter-ions. To resolve this problem we synthesized ionically functionalized conjugated polymers with a variety of ionic densities, fabricated bilayer devices, and separately introduced p and n type regions using a three electrode polyelectrolyte mediated electrochemical (PMEC) technique. Because the ionic functional groups/dopants are covalently bound to the backbone of the polymer, ion diffusion after doping is prevented. The conjugated polymer p-n junctions were observed to exhibit diode behavior with a rectification ratio greater than 500 at 1V. The junctions also exhibited a small photovoltaic effect. The synthesis of these ion functionalized polymers and their optoelectronic properties will be presented.

ORGN 366

Advanaces in the chemical synthesis of polyaniline at high ionic strength

Srikanthrao Agnihotra1, [email protected], Neha Manohar1, Mark Lalli1, Purnathosh Saha2, Sanjeev K. Manohar3. (1) Department of Chemistry, University of Massachusetts Lowell, Lowell, MA 01854, United States (2) Department of Plastics Engineering, University of Massachusetts Lowell, Lowell, MA 01854, United States (3) Department of Chemical Engineering, University of Massachusetts Lowell, Lowell, MA 01854, United States

A significant improvement in reaction yield and bulk conductivity of polyaniline is achieved by carrying out chemical oxidative polymerization of aniline at high ionic strength using hydrogen peroxide as an environmentally benign oxidant. We have previously described the synthesis of moderately conducting polyaniline (1-5 S/cm) at ~10% yield when NaCl is used to control the ionic strength. In this study, we have used other dissolved salts to synthesize highly conducting polyaniline having pressed pellet room temperature conductivity of 60 S/cm in near-quantitative yield. Unlike the semiconducting behavior observed in polyaniline synthesized using NaCl, films of the new polyaniline cast from m-cresol show metallic behavior.

ORGN 367

Recognition of carbon-based materials and devices with phage displayed peptides

Yue Cui, [email protected]. Department of Biological Engineering, Utah State University, Logan, UT 84322, United States

The development of a general approach for the functionalization of a variety of carbon- based materials could expand opportunities in both fundamental studies and a variety of materials and device platforms. Phage display is a powerful method for identifying peptides that possess enhanced selectivity and binding affinity toward a variety of targets. Here, I will describe the identification of phage displayed peptides for the recognition of a variety of carbon-based materials for the development new materials and devices. These results could open up opportunities for various applications in healthcare, defense, environment and energy storage.

ORGN 368

Novel aza-acenes towards new n-type materials

Jonathan R Sommer, [email protected], Andrew N Bartynski, Peter I Djurovich, Mark E Thompson. Department of Chemistry, University of Southern California, Los Angeles, California 90089, United States

Theoretical calculations have shown acenes and more specifically aza-acenes as attractive materials for organic semiconductors (Houk et al JACS, 2007 , 129, 1805). Interest in aza-acenes for n-type materials has increased substantially over the past few years. However realization of new derivatives has been severely hindered by current synthetic approaches. New synthetic strategies will be presented which have allowed for the first time new diaza-tetracene and diaza-pentacene derivatives. The HOMO and LUMO energy levels of these materials are tunable through appropriate substitution and as predicted deepened (DFT Calculations). For example, determination of the LUMO energy levels by cyclic voltammetry for a dichlorodiazatetracene (-1.5 V vs ferrocene) shows that these materials are in the range of common fullerene acceptors (e.g. C60). The photophysical and electrochemical characterization of these materials will be presented along with the photovoltaic performance.

ORGN 369

Metal–organic frameworks as hydrogen–bond catalyst: A strategy to avoid catalyst self–quenching

John M Roberts, [email protected], Branden M Fini, Omar K Fahra, Amy A Sarjeant, Joe T Hupp, Karl A Scheidt. Department of Chemistry, Northwestern University, Evanston, IL 60208, United States

Activating Lewis basic groups with hydrogen-bond donors (usually ureas/thioureas) has emerged over the past 15 years as a mild, biomimetic alternative to Lewis acid catalysis. This organocatalytic approach is not without its drawbacks, as catalysts can 'self-quench' by hydrogen-bonding each other instead of substrates. We sought to eliminate the possibility of catalyst self-quenching by incorporating a hydrogen bond catalyst (such as a urea) into a metal-organic framework (MOF). By precluding any catalyst self-quenching, reaction rates could potentially increase and these catalysts would also be rendered reusable. Additionally, because MOFs materials contain ordered, defined pores, we could observe size selectivity in potential catalysis reactions. To date we have synthesized a novel MOF containing a urea hydrogen-bond catalyst, employed this material as a catalyst for Friedel-Crafts reactions, and observed size selectivity from our material in catalysis reactions.

ORGN 370

Brominated analogs of rhodamine as pH responsive photosensitizers for singlet state oxygen

Quinn A Best, [email protected], Colleen Scott, Matthew E McCarroll. Department of Chemistry and Biochemistry, Southern Illinois University Carbondale, Carbondale, Illinois 62901, United States

We report on the synthesis and characterization of a series of fluorophores, which potentially could be used as photodynamic therapy agents. These fluorophores were designed to have a pH responsive action that may better target cancer cells that are known to be more acidic. The fluorophores consist of brominated analogs of rhodamine regulated by a spiro-cyclic structure that is responsive to environmental pH. It is our long term goal that this PDT agent could simultaneously be used for medical imaging and cancer treatment.

ORGN 371

Crystallography and magnetic studies of polymorphs and co-crystals of nitroxide-type radicals with disk shaped pendants

Handan Akpinar1, [email protected], Joel T. Mague2, Miguel A. Novak3, Jonathan R. Friedman4, Paul M. Lahti1. (1) Department of Chemistry, University of Massachusetts, Amherst, MA 01003, United States (2) Department of Chemistry, Tulane University, New Orleans, LA 70118, United States (3) Department of Physics, Universidade Federal do Rio de Janeiro, Rio de Janeiro-RJ, Brazil (4) Department of Physics, Amherst College, Amherst, MA 01002, United States

Organic based magnetism is emerging in material science for generating new-featured electronic properties, but small changes in crystal packing affect exchange interactions between spin units. We aimed to investigate how polymorphism and co-crystallization can be used to modulate magnetic behavior of radicals organized by disk shaped aromatics. Magnetostructural studies of pyrene-1-yl (Pyr) bearing nitronylnitroxide (NN) and iminoylnitroxide (IN) radicals found that PyrNN gives two allotropes: one has spin- paired dyads with ΔE = J/k ∼ (–)178 K, and one is only half spin-paired with ΔE = J/k ∼ (–)102 K, and the other half paramagnetic. PyrIN also gives two allotropes, an anti conformation that is spin paired with ΔE = J/k = (–) 410 K, and a syn conformation that is disordered and paramagnetic. PyrNN co-crystallizes with C6F6 in 2:1 ratio to give chains linked into networks exhibiting low dimensional 1-D or 2-D antiferromagnetic exchange behavior.

ORGN 372

Synthesis of a conjugated [2]rotaxane: The first step for a stable organic nanotube

Katy Cantin, [email protected], Antoine Lafleur-Lambert, Jean-François Morin.Departement of chemistry, Laval University, Quebec, Quebec G1V 0A6, Canada

With the success of carbon nanotubes, researchers have been encouraged to develop methodologies to prepare synthetic, all-organic nanotubes. However, the strategies developed to date lead to kinetically unstable architectures of limited utility. To improve nanotubes stability, we developed a new strategy to prepare stable, covalently-linked nanotubes. Specifically, we synthesized phenylacetylene macrocycles (PAM) with proper functional groups. Polymerization reaction carried out on the core of those PAMs provides a long molecular cylinder. Cross-linkable dendrons were then attached to the outer shell of the cylinder in order to link them together, thus forming a stable nanotube wall. Finally, we removed the core to obtain our organic nanotubes. However, we need to assess whether or not the center of the nanotube passes through the macrocycles. We thus synthesized a [2]rotaxane by adding stoppers on the center of the same macrocycle and cleaving the center and the results we obtained will be presented.

ORGN 373

Expanding the phosphorus-carbon analogy: Acetylenic phosphaalkenes, phospholes, and unprecedented cascade reactions

Sascha Ott, [email protected]. Department of Photochemistry and Molecular Science, Uppsala University, Uppsala, Sweden

Low-valent phosphorus compounds such as phosphaalkenes and –alkynes are often termed “carbon-copies” as their chemistry parallels that of alkenes and alkynes in many respects. The fusion of these two fields, low-valent phosphorus chemistry and carbon- based p-conjugates such as oligoacetylenes, brings about novel materials with unprecedented electronic and coordination properties.

A novel building block for the construction of oligomeric mono-disperse p-conjugates has been realized in C,C-diacetylenic phosphaalkene 1 (ACIE 2008, 8228, Chem. Eur. J. 2011, 12153). The P-heteroatom has a pronounced effect on the compounds FMOs. Recently obtained results of unprecedented and unpublished cascade reactions that lead to phospholes and other phosphorous heteroaromatics will be disclosed.

ORGN 374

Photoredox catalysis and accelerated serendipity

David W. C. MacMillan, [email protected]. Chemistry, Merck Center for Catalysis, Princeton University, Princeton, NJ 08544, United States

This lecture will discuss the advent and development of new concepts in chemical synthesis, specifically the combination of photoredox catalysis with organic catalysis. This new approach to “concerted catalysis” will demonstrate that multiple yet separate catalytic cycles can be aligned to generate activated intermediates that rapidly combine with each other, thereby allowing new approaches to enantioselective C–C and C- heteroatom bond formation.

We will also introduce an approach to the discovery of new chemical reactions that we term accelerated serendipity. Accidental or 'serendipitous' discoveries have led to some of the most important breakthroughs in scientific history, many of which have directly affected human life. Given our overarching goal of developing fundamentally new and useful chemical transformations using catalysis and by acknowledging the tremendous impact of serendipity in scientific discovery, we instead wondered whether this phenomenon could be forced or simulated to occur and therefore be used as a tool for reaction discovery. In this way, the starting point becomes the decision to accelerate serendipity, meaning there is no preconceived bias as to which chemical reaction is discovered or the mechanism by which it may happen.

In this presentation, we will describe several new transformations that have been discovered via “accelerated serendipity” that we expect will find widespread adoption throughout the field of chemical synthesis. Moreover, we will further describe how mechanistic understanding of these processes has led to the design of valuable new chemical reactions.

Acknowledgements Financial support was provided by NIHGMS (R01 01 GM093213-01) and kind gifts from Merck, Amgen, and Abbott.

ORGN 375

Dual catalysis in enantioselective oxidopyrylium-based [5+2] cycloadditions

Eric N Jacobsen, [email protected]. Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA 02138, United States

A new method has been identified for effecting catalytic enantioselective intramolecular [5+2] cycloadditions based on oxidopyrylium intermediates.

The dual catalyst system consists of a chiral primary aminothiourea and a second achiral thiourea. Experimental evidence points to a new type of cooperative catalysis with each species being necessary to generate a reactive pyrylium ion pair which undergoes subsequent cycloaddition with high enantioselectivity.

ORGN 376

Construction of stereogenic quaternary carbons in polycyclic natural products

Larry E. Overman, [email protected]. Department of Chemistry, University of California, Irvine, Irvine, CA 92697-2025, United States

When the target of a chemical synthesis endeavor contains one or more stereogenic quaternary carbons, how to assemble these quaternary stereocenters becomes a central component of synthesis planning and execution. Many factors contribute to this challenge: steric hindrance, the need generally to forge such carbon centers by C–C bond formation, and the inability in most situations to invert quaternary stereocenters. That the chemical synthesis of such carbons is particularly challenging can be seen in the structures of existing pharmaceutical agents. Of the 150 top-selling brand-name drugs in 2008, the only ones that contain stereogenic quaternary carbons are steroid or opioid derivatives, which undoubtedly are prepared by semisynthesis. This lecture will consider how the challenge of constructing stereogenic quaternary carbons was tackled in several recent and ongoing total synthesis endeavors in our laboratories.

ORGN 377

Award Address (Ernest Guenther Award in the Chemistry of Natural Products sponsored by Givaudan). The enterprise of synthesis: From concept to practice

Stephen Hanessian, [email protected]. Department of Chemistry, Université de Montréal, Montréal, Québec H3C 3J7, Canada

The present-day level of achievements in organic synthesis methodology in general, and natural products in particular, is the highest ever compared to as recently as a generation ago. Natural products varying in their structures and biological activities continue to provide synthetic chemists the incentives to initiate and pursue challenging research programs. This has also led to innovative methods toward efficient bond- forming reactions and greater rewards in co-worker training. When presented with the structure of a target molecule to synthesize, our first contact is visual. What follows is a subliminal interplay between the eye and the mind's eye, triggering a complex, yet quasi-instantaneous series of visual relational and visual reflexive chemical thought processing events that are a part of the psychobiological basis of generating a synthesis plan. The heuristic aspects of visual and mental thinking paradigms, coupled with computer-generated information will be discussed in the context of viable synthetic strategies toward biologically relevant molecules.

ORGN 378

Recent progress in understanding allosteric modulators of GPCRs

Arthur Christopoulos, [email protected] Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria 3052, Australia

It is now well accepted that G protein-coupled receptors (GPCRs) possess allosteric sites. We have identified examples of allosteric ligands that differentially affect orthosteric ligand affinity and/or efficacy, concomitantly recognize orthosteric and allosteric sites (i.e., 'bitopic' ligands), promote allosteric modulation across a GPCR dimer, and bias orthosteric signaling in a pathway-selective manner. However, to facilitate allosteric modulator classification and structure-activity studies, it is necessary to experimentally differentiate the contributions of the cellular host system from the desired molecular (ligand-receptor) properties that contribute to the observed behaviors. For translational studies, the choice of orthosteric ligand used as a probe of the desired GPCR target is also paramount, as this will have a direct bearing on compound classification and determination of its degree of on-target selectivity. Most recently, we have discovered that various GPCR allosteric ligands can differentially modulate endogenous metabolites, which has implications for target validation and allosteric modulator drug development

ORGN 379

Discovery and optimization of novel, small molecule probes for central nervous system disorders

Corey R. Hopkins, [email protected]. Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, TN 37232, United StatesVanderbilt University Medical Center, Nashville, TN 37232, United States

Disorders of the central nervous system remain some of the most elusive targets for the pharmaceutical industry and academic researchers to tackle. Conditions such as Alzheimer's Disease (AD) and Parkinson's Disease (PD) are the two most common neurodegenerative diseases, yet no effective long term treatment or cure has been developed. As part of the NIH's Molecular Libraries Production Center Network (MLPCN), Vanderbilt and collaborators have discovered and optimized novel molecular probes for a variety of CNS disorders. This presentation will highlight some of the highly selective molecular probes that we have developed aimed at gaining a better understanding of how these targets affect these diseases.

ORGN 380

Designing molecules that survive in neuroscience medicinal chemistry: CNS MPO desirability

Travis T Wager, [email protected], Anabella Villalobos, Patrick R Verhoest, Xinjun Hou.Neuroscience Medicinal Chemistry, Pfizer, Groton, CT 06320, United States

A key strategic imperative of research and medicinal chemistry is designing molecules that survive to achieve positive proof of mechanisms and test new hypotheses in the clinic. Advances in prospective design include the development of a novel approaches to assess drug-likeness. A new multi-parameter design tool (CNS MPO Desirability) based on six fundamental physicochemical properties (ClogP, ClogD, MW, TPSA, HBD, and pKa) focuses on a holistic approach to drug discovery and aims to align drug-like attributes such as low P-gp liability, low metabolic clearance, high passive permeability and safety in one molecule.

Examination of the desirability approach to drug discovery will be presented, including: case studies of past drug candidates, current clinical candidates and current application within Pfizer's neuroscience portfolio.

ORGN 381

Molecular switches on mGluR allosteric ligands that modulate modes of pharmacology and/or subtype selectivity

Craig W Lindsley, [email protected], Vanderbilt University, Nashville, TN 37232-6600, United States

G-Protein-coupled receptors (GPCRs) represent the largest class of drug targets, accounting for over 40% of marketed drugs; however, discovery efforts for many GPCRs have failed to provide viable drug candidates. Historically, drug discovery efforts have focused on developing ligands that act at the orthosteric site of the endogenous agonist. Recently, efforts have focused on functional assay paradigms and the discovery of ligands that act at allosteric sites to modulate receptor function in either a positive, negative or neutral manner. Allosteric modulators have numerous advantages over orthosteric ligands including high subtype selectivity, the ability to mimic physiological conditions, lack of densensitization/down regulation/internalization and reduced side effects. Despite these virtues, challenging issues have now arisen for allosteric modulators of metabotropic glutamate receptors (mGluRs): shallow SAR, ligand-directed trafficking and the identification of subtle 'molecular switches' that modulate the modes of pharmacology (from PAM to NAM or SAM), as well as mGluR subtype selectivity. Here, we will discuss the impact of modest structural changes to multiple mGluR allosteric ligands scaffolds that unexpectedly modulate pharmacology and/or subtype selectivity, as well as a concept of 'molecular locks', to describe series free from 'molecular switches'.

Finally, this talk will convey lessons learned, and raise concerns over metabolism and the pharmacology of metabolites.

ORGN 382 Peptide disruption of the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) interaction with protein phosphatase and tensin (PTEN) maintains 5-HT2CR activation

Kathryn A. Cunningham, [email protected]. Center for Addiction Research, University of Texas Medical Branch, Galveston, Tx 77555-0615, United States

Compromised function of the 5-HT2CR system contributes to the symptomatology of many psychiatric disorders (e.g., addiction, eating disorders), and strategies to augment 5-HT2CR signaling may prove therapeutically useful in such disorders. The goal here was to detail the structural and functional significance of the protein:protein interaction between 5-HT2CR and PTEN, and to test the hypothesis that a peptide fragment of the 5-HT2CR (3L4F) will compete with PTEN and enhance 5-HT2CR signaling. Co- immunoprecipitations demonstrated formation of the complex in native brain tissue as well as in CHO cells stably transfected with the 5-HT2CR while a proximity ligation assay validated the direct association between the 5-HT2CR and PTEN. The 3L4F and one peptide fragment enhanced 5-HT-stimulated mobilization of intracellular calcium in 5- HT2CR-CHO cells. These data suggest that the 5-HT2CR:PTEN complex is essential to the efficiency of 5-HT2CR signaling and ongoing behavioral evaluations suggest that peptide disrupters exhibit a profile consistent with enhanced 5-HT2CR function in vivo. Based upon 3L4F as the lead candidate and knowledge of the smallest active portion of 3L4F, a combination of molecular modeling and parallel and target-oriented library synthesis are being employed to design peptidomimetics that possess optimal activity and are not subject to enzymatic degradation, and convert these peptidomimetics into small molecules with high activity and drug-like properties. Thus, peptide disrupters of the 5-HT2CR:PTEN association may prove to be novel compounds with promise in psychiatric disorders in which disrupted 5-HT2CR signaling is implicated.

ORGN 383

Chemical evolution of quinolizidinone M1 positive allosteric modulators

Scott D Kuduk1, [email protected], Ronald K Chang1, Thomas J Greshock1, William J Ray2, Lei Ma2, Marion Wittmann2, Matthew A Seager2, Kenneth A Koeplinger3, Charles D Thompson3, George D Hartman1, Mark T Bilodeau1. (1) Department of Medicinal Chemistry, Merck & Co., West Point, PA 19486, United States (2) Department of Neuroscience, Merck & Co., West Point, PA 19486, United States (3) Department of Drug Metabolism, Merck & Co., West Point, PA 19486, United States

Identification of new mechanisms to treat the neurodegenerative effects of Alzheimer's disesase (AD) represents a major unmet medical need. One approach to ameliorate the cognitive decline in AD has been to target the neurons of the basal forebrain cholinergic system via activiation of the M1 muscarinic receptor. Non-selective M1 muscarinic agonists have previously shown positive cognitive effects in AD patients, but were limited due to cholinergic events due to lack of selectivity. One strategy to confer selectivity is to target an alloseric site on the receptor, rather than the highly conserved orthosteric site. This presentation describes the chemical evolution of HTS lead quinolone carboxylic acid BQCA into a highly selective quinolizidinone class of M1 PAMs with pharmacokinetic and in vivo properties.

ORGN 384

Exploring chemical neuroscience with T-type calcium channel antagonists

James C. Barrow, [email protected]. Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205-1503, United States

Voltage-gated ion channels play important roles in a variety of biological processes, and the availability of potent and selective modulators of these channels has facilitated understanding of their roles in health and disease. T-type calcium channel antagonists are low-voltage activated ion channels implicated in a number of conditions such as epilepsy, pain, sleep disorders, tremor, and schizophrenia. While a number of compounds have been reported to inhibit T-type calcium channels such as ethosuximide, mibefradil, and pimozide, their activity at a number of different receptors and ion channels precludes conclusive determination of the consequences of T-type calcium channel inhibition. This presentation will describe the identification and optimization of several different structural classes of T-type calcium channel antagonists for increased potency, selectivity and brain penetration. Evaluation of optimized compounds in epilepsy, pain, sleep, and schizophrenia models will be described. The consistent biological results from each of the different classes of compound tested in the same animal models give confidence that the observed effects are due to T-type calcium channels inhibition, and suggest that these compounds could be useful in a variety of neurological disorders.

ORGN 385

Submonomer synthesis and study of arylopeptoids [oligomeric N-substituted aminomethyl benzamides]

Thomas Hjelmgaard1, [email protected], Sophie Faure2,3, Dan Staerk1, Claude Taillefumier2,3, John Nielsen1. (1) Department of Basic Sciences and Environment, University of Copenhagen, Frederiksberg, Denmark (2) Laboratoire SEESIB, CNRS, Aubière, France (3) Clermont Université, Université Blaise Pascal, Clermont-Ferrand, France

Aromatic oligoamides is a group of foldamers which has received an ever increasing interest during the last two decades. Herein, the development of efficient and versatile protocols for iterative submonomer synthesis of arylopeptoids (oligomeric N-substituted aminomethyl benzamides) both in solution and on solid-phase is presented.

The arylopeptoids were studied by NMR and while most side chains gave rise to cis/trans isomerism, the tert-butyl and phenyl side chains allowed for complete control over the amide conformation (100% cis and 100% trans, respectively).

ORGN 386

Structure-based design and synthesis of bimodal proteasome inhibitors as therapeutic agents

Marion Gotz, [email protected], Stephanie Steiner, Matthew Goldfogel, Haya Jamali, Frederick Tomlin. Department of Chemistry, Whitman College, Walla Walla, Washington 99362, United States

The proteasome is a multicatalytic proteolytic enzyme that is essential for the degradation of intracellular proteins thereby regulating processes such as signal- transduction, cell-cycle control, antigen processing and apoptosis. Inhibition of the proteasome offers a promising approach in the treatment of cancer. The majority of the inhibitors that have been developed react with the catalytic threonine residue within the active site. The natural product TMC-95, however, is a macrocyclic peptide that reversibly inhibits the proteasome through a hydrogen-bonding network between the enzyme subsites and the extended peptide backbone of the macrocycle. This research investigates the design and synthetic strategy of novel macrocyclic peptidyl inhibitors that simultaneously contain a reactive functional group. The design not only addresses inhibition through a hydrogen bonding array, as observed with TMC-95, but also aims to covalently modify the active site nucleophilic threonine residue.

ORGN 387

Novel reversible cyclic peptides for the identification of affinity ligands

Stefano Menegatti2, [email protected], Amith D. Naik2, Kevin L. Ward2, Ruben G. Carbonell1,2. (1) Biomanufacturing Training and Education Center (BTEC), North Carolina State University, Raleigh, North Carolina 27695, United States (2) Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina 27695, United States

Cyclic peptides, due to their conformational rigidity, possess high target affinity and biochemical stability. Combinatorial libraries of cyclic peptides are powerful tools in discovering novel ligands and drugs. The process of lead discovery, however, is bottlenecked at the sequence identification step, mainly performed via multiple stages of MS/MS. While the determination of linear sequences is straightforward, the sequencing of cyclic peptides is much more challenging. We therefore propose a method for the synthesis of a combinatorial library of reversible cyclic peptides. Our strategy includes the insertion of a cleavable linker within the peptide sequence before cyclization. The cleavable linker allows to open the cyclic peptide in a predetermined position upon treatment with a cleaving agent. The linearized peptide is released from the solid support to the liquid phase and finally sequenced by single stage MS/MS. This library is a very promising tool for the discovery of affinity ligands and drugs.

ORGN 388

Advances in a sub-monomer approach to synthesize azapeptide modulators of the activity of the CD36 receptor as drugs to treat age-related macular degeneration

William D. Lubell, [email protected], Caroline Proulx, Stéphane Turcotte, Yesica García Ramos, Robert Hopewell, David Sabatino.Département de Chimie, Université de Montréal, Montréal, Québec H3C 3J7, Canada

In a peptide, substitution of nitrogen for the alpha-carbon of an amino acid residue may create conformational restrictions, which bend the resulting azapeptide away from linear geometry.[1] Employing sub-monomer synthesis of azapeptides on solid phase, the inherent difficulties for making differentiated hydrazines were overcome.[2] Novel methodology for the synthesis of azapeptide mimics will be presented in the context of a project to explore the relationships between peptide biological activity and structure to develop modulators of the activity of the CD36 receptor as potential treatments of age- related macular degeneration.[3]

[1] Proulx, C.; Sabatino, D.; Hopewell, R.; Spiegel, J.; García-Ramos, Y.; Lubell, W.D. Future Med. Chem. 2011, 1139– 1164.

[2] Sabatino, D.; Proulx, C.; Klocek, S.; Bourguet, C.B.; Boeglin, D. Ong, H.; Lubell, W.D. Org. Lett. 2009 11 (16), pp 3650-3653.

[3] Sabatino, D., Proulx, C., Pohankova, P., Ong, H., Lubell, W.D. J. Am. Chem. Soc. 2011, 133, 12493–12506.

ORGN 389 New chemical biology tools for detecting/controlling protein-protein interactions in extracellular communication networks

Andrew T Krueger1, [email protected], Barbara Imperiali1, Linda Griffith2. (1) Department of Chemistry, Massachussetts Institute of Technology, Cambridge, MA 02139, United States (2) Department of Biological Engineering, Massachussetts Institute of Technology, Cambridge, MA 02139, United States

Protein-protein interactions are the core of many intracellular and extracellular biological functions. Monitoring and potentially biasing these activities in real time is of great importance. Robust, versatile, environmentally-sensitive fluorophores such as 4-N,N- dimethylamino-1,8-naphthalimide (4-DMN) can be invaluable tools for reporting on protein-protein interactions. Presented is a strategy for site-specific labeling of efficiently expressed mutant cytokines which will allow for the ultimate goal of further deconvoluting the complexities of cellular signal transduction. Also presented in a complimentary context, is a new robust and efficient strategy for development of divalent receptor cytokines. Divalent cytokine ligands have been previously shown to bias protein-protein interactions among cell-surface receptors by sequestering HER3 receptors and preventing them from forming potentially cancerous heterodimers with HER2 receptors. The data presented here will be highly beneficial for understanding extracellular communication and its role in observed phenotypes within a cell, which is of great interest to scientists, and the medical community.

ORGN 390

Comprehensive analysis of explored and available physicochemical space for alpha-amino acids

A. Patrícia Bento, [email protected], John P. Overington. Department of Computational Chemical Biology, EMBL-European Bioinformatics Institute, Cambridge, Cambridgeshire CB10 1SD, United Kingdom

Oligopeptides are the single largest class of bioactive molecules – with roles in signal transduction, structural, enzymatic and regulatory processes. There has been intense historical research in the development of peptide-derived drugs, and following this research into the depeptidisation of peptide leads. Nature has used an infinitesimally small subset of available chemical space, with ca. 20 amino acids being available to an organism. Synthetic chemists and drug discoverers have a far larger set of possible amino acids, and the exploration of the available chemical space has led us to perform a series of analyses.

Firstly, we have built a comprehensive set of approved and late-stage clinical candidate peptide drugs. Within this set, we have identified both natural and unnatural amino acids, and performed an analysis of the site-specific modification (relative to N- and C- termini), and also of the physicochemical properties of theses. Then we have also analysed the peptide content of the ChEMBL database (which contains 21,844 peptides and 91,032 associated bioactivity data points). Similar decomposition of the amino acid content was performed on this set, and showed clear differences to launched and late- stage clinical peptides. We have also investigated the ligand efficiency properties of this set of bioactive peptides and found striking differences to synthetic small molecules. Finally, we have analysed a nominally comprehensive set of all possible amino acids (containing up to 13 heavy atoms from GDB-13 database). Various clusterings of the possible vs. known amino acids (in drugs, clinical candidates and the medicinal chemistry literature) were performed.

ORGN 391

β-Sheet macrocycles containing a nonapeptide β-strand

Johnny D Pham, [email protected], James S. Nowick. Department of Chemistry, University of California, Irvine, Irvine, CA 92697-2025, United States

The amyloids from Aβ, islet amyloid polypeptide, and the human prion protein contain long β-strands, comprising nine or more amino acids, that self-assemble through intermolecular hydrogen bonding to form extended networks of β-sheets. Here, we describe a new class of β-sheet macrocycles that present a nonapeptide β-strand and self-assemble to form stable, well-defined water-soluble oligomers. These macrocycles hold the promise of inhibiting amyloid aggregation and providing insight into amyloid structure and formation.

ORGN 392

Amyloid β-sheet mimics that antagonize amyloid aggregation and reduce amyloid toxicity

Pin-Nan Cheng1, Cong Liu2, Minglei Zhao2, David Eisenberg2, James S. Nowick1, [email protected]. (1) Department of Chemistry, University of California, Irvine, Irvine, CA 92697-2025, United States (2) UCLA-DOE Institute for Genomics and Proteomics, Howard Hughes Medical Institute, Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095-1570, United States

We describe here a class of macrocyclic peptides that adopt a β-sheet structure and can present a variety of heptapeptides from amyloids in a pre-organized β-strand conformation. These amyloid β-sheet mimics (ABSMs) contain the turn and template units δOrn and Hao, which help enforce a β-strand conformation in the heptapeptide strand and block aggregation. ABSMs containing suitable heptapeptide sequences inhibit amyloid aggregation and protect cells from the toxic effects of amyloids.

ORGN 393

Abiotic fluorescent probe for cardiac troponin I

Michael Heagy, [email protected], Premchendar Nandhikonda. Chemistry, New Mexico Institute of Mining & Technology, Socorro, NM 87801, United States

The first ratiometric fluorescent reporter was designed for the detection of cardiac troponin I (cTnI), a key protein elicited during cardiac muscle cell death. In designing this abiotic fluorescent probe, docking simulation studies were performed to predict the probe/protein interactions along the solvent exposed regions of cTnI. Simple cuvette titration experiments in aqueous buffered solution indicate remarkable selectivity for cardiac troponin in the clinically relevant nM region versus skeletal troponin.

ORGN 394

Design and synthesis of FtsZ-T7-loop mimics

Nohemy A Sorto, [email protected], Phil Painter, Jared T Shaw, Dean J Tantillo. Department of Chemistry and Biochemistry, University of California, Davis, Davis, California 95616, United States

FtsZ is a bacterial cell division protein that polymerizes in a GTP dependent fashion to form what is known as the Z-ring. The formation and constriction of the Z-ring is crucial for cytokinesis. In the event of DNA damage, an endogenous inhibitor, SulA, halts cell division by binding to FtsZ. This mechanism of bacterial survival ensures that daughter cells do not inherit damaged DNA. FtsZ has become a novel target in the effort to find new ways to fight bacterial infections. As revealed by the FtsZ-SulA x-ray co-crystal structure, the closest point of protein-protein interaction occurs at the T7- loop of FtsZ. Aided by docking methodologies, we have design and synthesized a series of small molecules that mimic the T7-loop of FtsZ. These small molecules share a common rigid scaffold that is easily diversified to yield a library of compounds that will potentially disrupt the interactions between FtsZ and SulA.

ORGN 395

Progress towards the total synthesis of the lantibiotic Mersacidin

Angela K Carrillo, [email protected], Michael S VanNieuwenhze. Department of Chemistry, Indiana University, Bloomington, Indiana 47405, United States

Mersacidin is a type B lantibiotic active against gram-positive bacteria, including vancomycin-methicillin resistant S. aureus. Its structure consists of four cyclic peptides composed of bridging lanthionine units and a (Z)-aminovinyl cysteine functionality. Mersacidin is believed to inhibit the transglycosylation pathway to cell wall biosynthesis by forming a stoichiometric complex with Lipid II, targeting a different site than vancomycin. Thus, it may represent a new avenue for antibacterial therapeutics.

The CD bicyclic fragment seems to be involved in the binding mode with Lipid II. However, the nature of this interaction is unknown. Structure-activity relationship studies on the mode of action of Mersacidin and its derivatives not only would reveal its mechanism of action, but also would contribute to the rational design of new lead compounds. We are currently investigating the orthogonal construction of each ring as well as the sensitive (Z)-aminovinyl cysteine linkage. Our efforts towards these aims will be presented.

ORGN 396

WITHDRAWN

ORGN 397

WITHDRAWN

ORGN 398

Synthesis of 1,4-diazaspiro[2.2]pentanes as reactive intermediates for the rapid preparation of novel stereotriads Jared W Rigoli, [email protected], Luke A Boralsky, Cale D Weatherly, John C Herschberger, Jennifer M Schomaker. Department of Chemistry, University of Wisconsin, Madison, WI 53706, United States

The snytheses and reactivity of an unusual class of heterocycles, the 1,4- diazaspiro[2.2]pentanes (DASPs), will be discussed. Several approaches were explored to effectively prepare these molecules with high levels of chemo-, regio-, and diastereocontrol, thus enabling their use as reactive intermediates for the flexible preparation of nitrogen-containing stereotriads. Inter/inter-, intra/intra-, and intra/intermolecular bis-aziridinations were investigated and the intra/intermolecular approach was the most useful for differentiating the electronics of the two aziridines based on the identity of the nitrogen “protecting groups”. The reactivity of the DASPs were explored in terms of selective ring opening at both C1 and C3 positions of the original allene. Assessible motifs include N,N-aminals, vicinal diamines, triamines, and azetidines depending on the structure of the allene and the reaction conditions employed. Also, rearrangement and ring contraction of N,N-aminals to 1,3- diaminoketones will be discussed.

ORGN 399

Introduction of a new single electron transfer sensitive protecting group

Goran Hilmersson, [email protected], Tobias Ankner. Department of Chemistry, University of Gothenburg, Gothenburg, Sweden

Protecting groups constitute one of the most powerful tools in the synthesis of multifunctional compounds such as oligosaccharides and peptides to temporarily mask sites of similar reactivity. Due to the inherent low atom economy it is desirable to minimize the use of protecting groups although the efficiency of proper protecting group strategy is still unprecedented. Protecting groups should ideally meet several criteria; (i) easy and high yielding to introduce, (ii) be stable under a wide range of reaction conditions and (iii) to be removed under mild conditions. We have previously developed highly efficient protocols for removing both allylethers and tosylamides using SmI2/Et3N/H2O [1].

We have now developed 3,5-bis-(trifluoromethyl) benzylcarbamate as a protecting group that can be selectively cleaved under mild SET conditions while it is unusually stable under hydrogenation conditions. (Figure 1) In this respect, this group has a unique property that is not shared with any of the existing carbamate protecting groups (cbz, Troc, Aloc, Boc etc).

Figure 1 . Orthogonal deprotection of the cbz-group using Pd/C or the 3,5-bis- (trifluoromethyl) benzylcarbamate using SmI2/Et3N/H2O.

1(a) Dahlén, A.; Sundgren, A.; Lahmann, M.; Oscarson, S. and Hilmersson, G., Org. Lett. 2003 , 4085. (b) Ankner, T; Hilmersson, G., Org. Lett., 2009 , 11, 503.

ORGN 400

Highly selective methods for synthesis of internal (α-) vinylboronates through efficient NHC−Cu-catalyzed hydroboration of terminal alkynes

Hwanjong Jang, [email protected], Adil R Zhugralin, Yunmi Lee, Amir H Hoveyda. Department of Chemistry, Boston College, Chestnut Hill, MA 02467, United States

An efficient set of NHC (N-heterocyclic carbine)−Cu-catalyzed protocols for site- selective boron−copper addition to terminal alkynes to efficiently afford α-vinylboronates is presented. Propargyl alcohol and amine, and their derivatives are effective substrates for this transformation, and a variety of aryl-substituted terminal alkynes are also suitable class of substrates. Mechanistic studies are presented, which indicate that both the structural and electronic features of the NHCs and alkyne substrates affect the α selectivity.

ORGN 401

Combined allylic azide rearrangement and intramolecular Schmidt reaction Ruzhang Liu1, [email protected], Osvaldo Gutierrez2, Dean J. Tantillo2, Jeffrey Aubé1. (1) Department of Medicinal Chemistry, University of Kansas, lawrence, kansas 66047, United States (2) Department of Chemistry, University of California at Davis, Davis, California 95616, United States

A stereoselective route towards vinyl-substituted lactams will be presented. This reaction uses an inter-converting mixture of allylic azides, which are subjected to intramolecular Schmidt reaction to afford the desired products. The scope of the reaction and source of its stereoselectivity has been studied from experimental and computational perspectives. Its application towards the synthesis of pinnaic acid will be discussed.

ORGN 402

Metal-free, aerobic ketooxygenations of alkenes using hydroxamic acids

Valerie A Schmidt, [email protected], Erik J Alexanian. Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States

We have previously reported on the unique reactivity of N-phenyl hydroxamic acids in general approaches to two-electron, metal-free alkene dioxygenations. Methods that achieve the four-electron oxidation of alkenes are less developed, despite the potential of such a process for use in alpha-ketol synthesis. This presentation will discuss the implementation of our radical-mediated approach in order to achieve four-electron alkene oxidations using molecular oxygen as the sole oxidant.

ORGN 403

Visible light–promoted [2+2] radical anion cycloadditions with cleavable redox auxiliaries

Elizabeth L Tyson, [email protected], Elliot P Farney, Tehshik P Yoon. Department of Chemistry, University of Wisconsin – Madison, Madison, WI 53706, United States 2-Acyl imidazolyl groups can be used as "redox auxiliaries" that can tune the reduction potential of α,β–unsaturated carbonyl substrates such that they can participate in photocatalytic [2+2] cycloadditions with a variety of Michael acceptors. Methylation of the imidazolyl group of the cycloadduct enables the auxiliary to be readily cleaved by a variety of nucleophiles, generating functionalized cyclobutanes that are otherwise inaccessible via other methods.

ORGN 404

Stereospecific cross-couplings of diarylmethyl ethers to form tertiary stereocenters

Margaret Greene, [email protected], Elizabeth Jarvo. Department of Chemistry, University of California, Irvine, Irvine, California 92697-2025, United States

A stereospecific nickel-catalyzed cross-coupling of diarylmethyl ethers has been developed. Alkyl Grignard reagents are competent nucleophiles in the desired reaction. The scope of the reaction includes both electron-rich and electron-poor arenes. Achiral nickel catalysts and optically enriched diaryl alcohol derivatives provide products with inversion of configuration with high stereochemical integrity. This methodology has been used to prepare biologically active diarylethanes that, to the best of our knowledge, have not previously been synthesized as single enantiomers.

ORGN 405

Radical resculpturing of an enzyme active site: Tailoring the substrate pocket Ylva Wikmark, [email protected], Anders G. Sandström, Maria Svedendahl Humble, Karin Engström, Jonas Nyhlén, Jan-E. Bäckvall. Department of Organic Chemistry, Stockholm University, Stockholm, Sweden

By introducing nine mutations simultaneously, the active site of the enzyme Candida antartica Lipase A (CalA) was enlarged. The resculptured biocatalyst is environmentally friendly, fast, highly enantioselective and tailor-made for our needs.

The applied combinatorial mutagenesis approach allows for fine tuning of the active site for a specific organic transformation. In this way, the enzyme substrate binding pocket is designed to convert only one enantiomer of a racemic substrate into product.

ORGN 406

Visible light photocatalysis of radical anion hetero-Diels-Alder cycloadditions

Anna E. Hurtley, [email protected], Megan A. Cismesia, Michael A. Ischay, Tehshik P. Yoon. Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53715, United States

We have developed a visible light-promoted formal hetero-Diels-Alder cycloaddition of tethered bis(enones). The intermediacy of radical anions allows the coupling of an electron-deficient heterodiene with an electronically mismatched enone dienophile to generate a bicyclic structure that is challenging to achieve by conventional cycloaddition chemistry. Synthetic manipulation of the dihydropyran cycloadducts provides access to number of diverse structures.

ORGN 407

Reaction of pinacolborane with iodine and magnesium under ambient Grignard and Barbier conditions utilizing THF as a leaving group

Chris L Murphy, [email protected], Jacob W Clary, Aaron M Hall, Melissa Jupp, Bakthan Singaram. Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95060, United States

Grignard reagents react with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, pinacolborane, under ambient reaction conditions to afford the corresponding pinacolboronate esters. This reaction is very general, one equivalent of halide (aliphatic, aromatic, heteroaromatic, vinyl or allylic) is transformed into the corresponding Grignard reagent followed by the addition of a single equivalent of pinacolborane in THF. Iodine also reacts with pinacolborane at ambient reaction conditions in THF to form the iodo-alkoxy borate species (4-iodobutoxy)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. One equivalent of iodine and PinBH react to form iodo-PinB, which then interacts with THF by cleavage of one carbon-oxygen bonds to form the corresponding iodo-alkoxy pinacolborate. Treatment with aryl Grignard reagent reacts with iodo-alkoxy pinacolborate in THF to then form the corresponding aryl pinacolboronate ester while reforming and liberating THF as a leaving group.

ORGN 408

Substituent effects on the stabilities of triazolyl carbenes: Carbon acid pKa values for twenty triazolium ions in aqueous solution

Richard S. Massey1, [email protected], Christopher J. Collett2, Andrew D. Smith2, AnnMarie C. O'Donoghue1. (1) Department of Chemistry, University of Durham, Durham, United Kingdom (2) School of Chemistry, University of St Andrews, St Andrews, United Kingdom

Kinetic acidities towards hydroxide ion have been determined and pKa values estimated for a series of triazolium ions in aqueous solution by application of a kinetic method. The wide range of triazolium ions studied enables steric and electronic substituent effects to be assessed.

ORGN 409

From organic mixed valence to molecular wires

Oliver S Wenger, [email protected]. Institute for Inorganic Chemistry, Georg-August-Universitaet Goettingen, Goettingen, Germany

Recent results on photoswitchable mixed valence systems will be discussed. A specific example, illustrated below, is a dithienylcyclopentene system with tertiary amines as redox-active units.1 Charge delocalization phenomena in mixed valence systems with oligo-thiophene bridges will be compared to photoinduced charge transfer across oligo- p-phenylene and oligo-p-dimethoxybenzene wires.2-4 Lastly, nitrogen-to-boron charge transfers in dimesitylboryl-substituted tertiary amines will be considered.5

(1) He, B.; Wenger, O. S. J. Am. Chem. Soc. 2011 , doi: 10.1021/ja207025x

(2) Wenger, O. S. Acc. Chem. Res. 2011 , 44, 25-35

(3) Walther, M. E.; Wenger, O. S. ChemPhysChem 2009 , 10, 1203-1206

(4) Walther, M. E.; Wenger, O. S. Inorg. Chem. 2011 , doi: 10.1021/ic201446x

(5) Schmidt, H. C.; Reuter, L. G.; Hamacek, J.; Wenger, O. S. J. Org. Chem. 2011 , doi: 10.1021/jo2019152

ORGN 410 Distal effect of electron-withdrawing groups on the stability of peptide enolates and its exploitation in the stereocontrolled synthesis of amino acid derivatives

Junming Ho, [email protected], Christopher J Easton, Michelle L Coote. Department of Chemistry, Australian National University, Canberra, ACT 0200, Australia

Normally amides and esters exhibit much weaker carbon acidities than ketones mainly as a result of the effects of the various carbonyl carbon substituents to attenuate resonance stabilisation of the corresponding enolates. In a recent computational study,1 we predicted that N-electron-withdrawing substituents, hydrogen bonding and protonation at amide nitrogen selectively increase the acidity of a distal proton adjacent to the amide carbonyl, to the extent that the α-carbonyl acidity of some N-substituted amides exceeds that of typical ketones. In this contribution, the origin of the distal effect is examined using high-level ab initio methods and its relevance to certain enzymatic reactions is highlighted. Using a combination of theory and experiment, the synthetic utility of the effect is also demonstrated through the controlled stereochemical inversion of amino acid derivatives.2

1. Ho, J.; Easton, C. J.; Coote, M. L. J. Am. Chem. Soc. 2010 , 132,5515. 2. Ho, J.; Coote, M. L.; Easton, C. J. J. Org. Chem. 2011 , 76, 5907.

ORGN 411

Can graphene promote the self-assembly of hybrid nucleobases?

Harold D Banks, [email protected]. Research and Technology, U.S. Army Edgewood Chemical Biological Center, APG, MD, United States

The five nucleobases foster nucleic acid self-assembly. Since this process occurs on a molecular scale, it suggests potential applications in nanotechnology. The question of self-assembly of hybrid nucleobases was explored computationally with compounds that had complementary head-tail interactions. Hydrogen and halogen bonding were explored for their potential contributions to association. Because graphene is the ultimate polynuclear aromatic hydrocarbon, and provides the possibility for ∏-∏ interactions similar to those found in DNA, it was chosen as a matrix for self-assembly. Bonding a hydrid nucleobase to the graphene surface by means of reaction with an azomethine ylide (1) to initiate assembly was also considered (2). Calculations were performed with DMol3 using model supercells to represent graphene. Rather large supercells are required (7x7x1 in the figure.) The planarity of this graphene model is distorted by the presence of the hydrogen bonded hybrid nucelobases. Corrections for BSSE and dispersion interactions were incorporated.

(1) See (a) Banks, H.D. Org. Biomol. Chem. 2011 , 6335. (b) Banks, H.D. J. Org. Chem. 2010 , 75, 2510 and references cited therein.

(2) Cao, Y.; Houk, K.N. J. Mater. Chem. 2011 , 21, 1503. ORGN 412

Cage opening/rearrangement of iodinate cubane derivatives

Ronny Priefer, [email protected]. Department of Chemistry and Biochemistry, Niagara University, Niagara University, New York 14109, United States

Recently we observed that iodinated vinylcubane had a tendency to undergo cage opening/rearrangement to yield a styrene compound. It was in this finding that a cubyl styrene derivative was proposed in order to deter the cage opening of the cubane and thus perform polymerization from a vinylcubane-based monomer. Ultimately this cubyl styrene derivative underwent a more rapid cage opening/rearrangement than its none phenyl counterpart. The path to its opening was observed to initially form a tricyclooctadiene, followed by cyclooctatetraene, and finally the rearrangement to a β- iodo-styrene compound. In addition, an iodinated cubyl aldehyde was also examined and remarkably, benzyl benzoate was ultimately formed, suggesting an alternate fragmentation pathway.

ORGN 413

15N NMR spectral parameters for structure elucidation and conformational analysis: Indole, quinoline and azobenzene derivatives

Albina A. Pushkareva1, [email protected], Alla K. Shestakova2, Vyacheslav A. Chertkov1. (1) Chemistry Department, Moscow State University, Moscow, Russian Federation (2) State Research Institute of Chemistry and Technology of Organoelement Compounds, Moscow, Russian Federation

Current strategy of structure elucidation for nitrogen containing aromatics imply routine use of 15N HMBS experiments optimized on certain values of spin-spin couplings 15N-H and 15N-C. There is a little or no experimental data available up to date even for such important model systems like indole, quinolone, azobenzene. We elaborated convenient synthetic ways to 15N-enriched compounds and performed detailed analysis of their high resolution 1H, 13C and 15N NMR spectra. NMR spectra were used for determination of long range spin-spin coupling constants for all pairs of 1H-1H, 1H-15N and 13C-15N nuclei. All these coupling constants were calculated by FP DFT technique. For quantum- mechanical description of conformational dynamics in azobenzenes, we first used dynamics approach in terms of vibration with large amplitude. Our data reveals characteristic stereochemical dependencies of long range spin-spin coupling constants, which can be useful for structure elucidation and conformational analysis of small and medium sized nitrogen-containing compounds

ORGN 414

Mechanistic investigations of aryl‒aryl bond fragmentation reactions Hee Yeon Cho, [email protected], Lawrence T Scott. Department of Chemistry, Boston College, Chestnut Hill, MA 02467-3860, United States

High-temperature gas-phase chemistry of polycyclic aromatic hydrocarbons reveals many reactions that are not observed under ordinary laboratory conditions. As one such example, phenyl substituted polyaromatic hydrocarbons undergo aryl‒aryl bond fragmentations under pyrolysis conditions. We envision three plausible mechanistic pathways for the C‒C bond cleavages: direct homolysis (eq 1), hydrogen atom attachment (eq 2), and a benzyne extrusion process (eq 3). Both experimental and theoretical mechanistic investigations on the fragmentations will be presented.

ORGN 415

Radically green approaches to C-H activation and ether functionalization via allyl transfer reaction

Shradha Patil, [email protected], James M Tanko. Department of Chemistry, Virginia Tech, Blacksburg, VA 24060, United States

Functionalization of hydrocarbons and C-H bond activation via an allyl transfer reaction using various allyl-PINO substrates (X = PINO) (Figure 1), has been previously studied. We recently discovered that the allyl-phthalimido-N-oxyl (PINO•) substrates are successful for the ether functionalization as well, and provides a suitable method to activate C-H bonds of ethers. The chemistry is also successful using low conc. of ether in solution. Synthesis of photolabile precursors for Laser flash photolysis studies to determine the rate constant of the allyl transfer reaction is in progress. Use of allyl- phthalimido-N-oxyl (PINO) compounds for the functionalization of various amines and optimization of the reaction for milder reaction condition will be discussed.

ORGN 416 Decomposition of malonic anhydrides

Charles L Perrin, [email protected], Agnes Flach. Department of Chemistry, Univ Calif San Diego, La Jolla, CA 92093-0358, United States

Decomposition kinetics of malonic anhydrides (1a , R,R' = H,H; 1b , R,R' = H,CH3; 1c , 1 R,R' = CH3,CH3) are measured by H NMR. Products are CO2 + a ketene (2 ). The order of reactivity is 1b > 1a > 1c , with the lowest ΔH‡ for 1b , and the least negative ΔS‡ for 1c . The ΔH‡ is too low to correspond to breaking any bond in a stepwise process. The nonlinear dependence of rate on number of methyls is consistent with concerted [2+2] cycloreversion, via a twisted transition state.

ORGN 417

Photochemical generation of trans-dioxoruthenium(VI) porphyrin complexes

Eric Vanover, [email protected], Yan Huang, Chris Abebrese, Helen Thompson, Cathleen Webb, Rui Zhang. Department of Chemistry, Western Kentucky University, Bowling Green, Ky 42101, United States

High-valent transition metal-oxo species have proven to be the heart both synthetic and natural oxidative catalysis. This research aims to explore the photo-induced generation of a trans-dioxoruthenium(VI) porphyrin species. These complexes exhibit prolific importance in their ability to perform selective oxidations, and to serve as a model for the production of a synthetic catalyst effectively mimicking cytochrome P-450 enzymes. The methods presented here provide a new photochemical entry to the well-know trans- dioxoruthenium(VI) porphyrins through the photo-induced ligand cleavage reactions. The visible light photolysis of the ruthenium(IV) dichlorates or dibromates produced trans-dioxo species as a result of the simultaneous cleavages of two X-O bonds. The formation of the trans-dioxoruthenium(VI) porphyrins was observed in sterically encumbered, unencumbered and chiral porphyrin systems.

ORGN 418

Cyclic homologues of diammoniate of diborane (DADB): Dehydrogenation and dissociation in the gas phase

Jay-Ar Bendo, [email protected], Thomas Morton, Jos Oomens. Department of Chemistry, University of California Riverside, Riverside, CA 92521, United States Boron-nitrogen compounds can serve as hydrogen storage molecules. One of the + - simplest boron-nitrogen compounds, H3N-BH2-NH3 BH4 (DADB), is known to lose H2 thermally. If the two flanking amino groups of DADB are connected by a methylene chain, the positively charged rings are isoelectronic to the corresponding cycloalkanes.

Like DADB, the release of H2 originates from the boron and nitrogen atoms. Investigations of hydrogen release from these cations by Infrared Mutiple Photon Dissociation (IRMPD) spectroscopy suggest that the dehydrogenated ions prefer dissociation rather than a second dehydrogenation. The fragmentation has been further investigated by site specific deuteration. Hydrogen scrambling occurs between the nitrogen and boron. Comparisons between calculated normal modes and IRMPD spectra allow determination of the structures of the cyclic ions and their fragments.

ORGN 419

Biphasic platinum catalyzed hydrosilylation of 1-alkenes

Tobias Schulz, [email protected], Thomas Strassner.Physical Organic Chemistry, Technical University of Dresden, Dresden, Saxony 01062, Germany

Recently, we developed a new class of ionic liquids, the so called Tuneable Aryl Alkyl Ionic Liquids (TAAILs). The use of ionic liquids in biphasic catalysis allows the recovery of the precious catalyst and prevents a contamination of the product. Ideally simple metal salts are sufficient, instead of expensive and complicated ligand systems. We present a new catalytic system based on TAAILs in combination with different platinum species for the hydrosilylation of various 1-alkenes. In our study we focused on the recyclability of the catalytic system, the reduction of by- products and the influence of the ionic liquid´s structure. As a benchmark we used the Karstedt catalyst, the common industrial standard. We also compared our results to 1- Butyl-3-methyl-1H-imidazolium bis(trifluoromethylsulfonyl)imide as a representative for a commercially available ionic liquid.

ORGN 420

Ligand and complex engineering toward ligand accelerated catalysis of the Pauson-Khand reaction Agusti Lledo, [email protected]. Department of Chemistry and Molecular Pharmacology, Institute for Research in Biomedicine, Barcelona, Barcelona, Barcelona 08028, Spain

The intramolecular Pauson-Khand reaction has found widespread use as a late stage cyclization transformation to construct complex polycyclic scaffolds. Conversely, several limitations in substrate scope have hampered the popularization of the intermolecular version, despite its great potential for the preparation of high value added compounds from readily available starting materials. We will describe here our efforts towards the development of an elusive ligand accelerated catalysis which we identify as a solution to the major bottleneck of this technology.

ORGN 421

Highly efficient and aldehyde-selective Wacker oxidation: Achieving novel selectivities for old reactions by catalyst development

Peili Teo1,2, [email protected], Zach W Wickens1, Robert H Grubbs1. (1) Department of Chemistry, California Institute of Technology, Pasadena, California 91125, United States (2) Institute of Chemical and Engineering Sciences, Singapore, Singapore

The PdII-catalysed oxidation of olefins to carbonyl compounds, commonly known as the Wacker oxidation, is one of the most well-known reactions mediated by palladium and has extensive synthetic applications. The formation of carbonyl compounds through Wacker oxidation however, obeys the Markonikov's rule to yield methyl ketones in the majority of terminal olefins. Herein, we present a new catalytic system for forming aldehydes using the Wacker oxidation process on non-activated olefins that not only yields aldehydes in high yields (>90%) but also with high selectivity (∿ 98%). The new catalytic system is not only highly efficient where TOF of greater than 70 h-1 can be achieve, it is also very robust where the entire reaction can be carried out under aerobic conditions. A variety of olefins ranging from aromatic to aliphatic ones can be tolerated by the catalyst to yields aldehydes selectively.

ORGN 422 Ruthenium catalyzed sp3 C−H bond arylation with arylboronates directed by 3- substituted pyridines

Michael Schnürch, [email protected], Navid Dastbaravardeh, Marko D. Mihovilovic.Intitute of Applied Synthetic Chemistry, Vienna University of Technology, Vienna, Vienna A-1060, Austria

Herein, we report a Ru-catalyzed arylation of benzylic but also non benzylic sp3 C–H bonds with e.g. arylboronates as aryl donors directed by 3-substituted pyridin-2-yls. This catalytic method is compatible with a variety of substituted arene donors. Aryls containing electron-donating substituents gave higher yields at shorter reaction times compared to aryl donors containing electron withdrawing groups which is in agreement with previous literature observations.

ORGN 423

Effect of ligand conformational flexibility on palladium-catalyzed cross-coupling reactions

Kevin H Shaughnessy, [email protected]. Department of Chemistry, The University of Alabama, Tuscaloosa, AL 35487-0336, United States

Sterically demanding, electron rich phosphines have been identified as privileged ligands for metal-catalyzed cross-coupling reactions. Our group has shown that neopentylphosphines provide active catalysts for cross-coupling reactions. The neopentyl substituent is a conformationally flexible, sterically demanding substituent. In low coordination number palladium complexes (i.e., Pd(DTBNpP)2, DTBNpP = di(tert- butyl)neopentylphosphine), the neopentyl substituent has a significant steric effect. In the four-coordinate complex Pd(DTBNpP)2Cl2, the neopentyl group adopts a conformation with a smaller steric effect. Calculated cone angles based on LPd(0) complexes predicted that trineopentylphosphine (TNpP) would be much larger (227°) than DTBNpP (198°). Coordination studies and catalytic results show that TNpP has a smaller effective steric demand than DTBNpP, however. Catalysts derived from TNpP show higher reactions rates with sterically hindered substrates than with unhindered substrates. This unusual reactivity appears to be due to differences in the nature of the oxidative addition products as a function of aryl halide steric demand.

ORGN 424

Visible light-mediated living radical polymerization Brett P. Fors, [email protected], Craig J. Hawker.Materials Research Laboratory, California NanoSystems Institute, Department of Materials, and Department of Chemistry and Biochemistry, University of California, Santa Barbara, Santa Barbara, CA 93106, United States

This presentation will detail the development of a living free radical polymerization process that is regulated by visible light. This new polymerization method displays excellent control over polymer molecular weight and molecular weight distribution and can be efficiently activated/deactivated by an external stimuli (visible light). Further, this polymerization allows for the synthesis of highly controlled block copolymers. Lastly, insight into the mechanism of this process will be described.

ORGN 425

Mechanism of the [1,2]-Stevens and [2,3]-sigmatropic rearrangements in the generation and reactions of oxonium ylides

Deana M. Jaber1,2, [email protected], Ryan N. Burgin1, Michal P. Doyle1. (1) Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States (2) Department of Chemistry, Marymount University, Arlington, Virginia 22207, United States

Rh(II) catalyzed oxonium ylide generation of trans-3-styryltetrahydropyranone-5- diazoacetoacetates 1 and their subsequent rearrangements unexpectedly form two diastereoisomers through both the [1,2]-Stevens and [2,3]-sigmatropic processes. The distribution of diastereoisomeric products is independent of substituents and of dirhodium catalyst. The formation of a second diastereoisomer for the symmetry- allowed concerted [2,3]-sigmatropic rearrangement process supports the hypothesis that the presence of two conformational isomers for diazoacetoacetate 1 lead to the formation of two non-interconvertable oxonium ylide diastereoisomers.

ORGN 426 Copper-mediated trifluoromethylation and perfluoroalkylation of aromatic substrates

Nichole D. Litvinas, [email protected], John F. Hartwig. Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, United States

Perfluoroalkyl groups are often introduced to candidate pharmaceuticals because these moieties can favorably affect the physical and biological properties of a compound. In recent years, synthetic methods have been developed to prepare perfluoroalkyl arenes from aryl iodides and aryl chlorides; however, methods to prepare these compounds from aryl bromides and arenes are notably deficient. We have developed a class of reagents that are capable of effecting the perfluoroalkylation of a diverse range of aromatic substrates including aryl bromides, aryl iodides, and arenes. The trifluoromethylation of aryl bromides and arenes proceeds through an intermediate aryl boronate ester that is generated in situ via iridium- or palladium-catalyzed borylation. The development and scope of this reaction will be discussed.

ORGN 427

Development of air-stable, iron-based Shvo-type catalysts

Timothy W Funk, [email protected]. Department of Chemistry, Gettysburg College, Gettysburg, Pennsylvania 17325, United States

Shvo's catalyst is an air-stable, diruthenium bridging hydride that catalyzes assorted oxidative and reductive transformations. In 2007 Casey and Guan reported the catalytic activity of a known iron hydride structurally similar to Shvo's catalyst. The iron hydride exhibited reactivity analogous to the diruthenium bridging hydride. Unfortunately the iron catalyst is air-sensitive, which may explain the fact that there are surprisingly few reports exploring its versatility. We have been focused on developing air-stable pre- catalysts with the same activity and reactivity as the air-sensitive iron hydride. Our progress in the activation of (cyclopentadienone)iron tricarbonyl precursors with trimethylamine N-oxide and in the application of nitrile-ligated (cyclopentadienone)iron compounds to catalysis will be presented.

ORGN 428

Metal-catalyzed trifluoromethylation of alkenes

Pär G Janson, [email protected], Ibrahim Abou-Ghoneim, Kálmán J Szabó. Department of Organic Chemistry, Stockholm University, Stockholm, Sweden

Introduction of trifluoromethyl groups has become an increasingly important task in modern organic synthesis. Formation of C-CF3 bonds poses a challenge to synthetic organic chemists and there has been a surge in methodology development interest. Inspired by recent high oxidation state transition metal catalysis research performed in our group we have developed a series of oxidative metal-catalyzed trifluoromethylation reactions of alkenes. These reactions occur under mild conditions with good regio- and stereoselectivity.

ORGN 429

First total synthesis of (±)-Linoxepin via a palladium-catalyzed domino reaction

Svenia C. Schild, [email protected], Jérôme Clerc, Lutz F. Tietze. Department of Organic and Biomolecular Chemistry, Faculty of Chemistry, Georg-August-University Goettingen, Goettingen, Germany

Lignans are a well known class of phytoestrogens which have been studied for decades for their application in human cancer therapy. (+)-Linoxepin (1 ), which has been isolated by Schmidt et al. from the aerial parts of linum perenne, is a novel lignan with a so far unknown 2,8-dihydro-3H-benzo[e]naphtho[1,8-bc]oxepine skeleton.

The key step in the first total synthesis of (±)-linoxepin is the formation of the skeleton by a palladium-catalyzed domino process. First, a Sonogashira coupling of aryl iodide 3 and propargylic alcohol (4 ) leads to the corresponding alkyne, which undergoes a domino carbopalladation/Heck reaction to give the annulated oxepine 2 . This can be transformed into linoxepin very effectively in two steps. The domino reaction can be optimized to create 2 with an exocyclic double bond. The benzyl aryl ether 3 can easily be obtained in 9 steps starting from commercially available isovanillin and 2,3-dihydroxybenzaldehyde.

ORGN 430

Enantioselective recognition and identity determination of chiral carboxylic acids Leo A Joyce, [email protected], Eric V Anslyn. Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, Texas 78712, United States

We utilize an achiral copper (II) containing host for the enantioselective recognition of chiral carboxylic acids using circular dichroism (CD). This host adopts helical chirality that is indicative of the arrangement of groups on the stereocenter of the guest, and absolute configuration of the guest can be easily determined. Steric parameters have been applied to understand the magnitude of the CD signal, as different guests give signals of varying size. The distinct size and shape of each curve was suitable for identity determination using pattern recognition protocols. The enantiomeric excess (ee) was determined for samples of three different carboxylic acid guests with an average error of ±3.0%. This system has been successfully applied to other guests, namely amino acids. Examples of expanding this method toward examples from the synthetic community to expedite catalyst discovery will also be detailed.

ORGN 431

Toward the rational design of ditopic ion receptors based upon calix[4]arene strapped calix[4]pyrrole motifs

Neil J Young, [email protected], Benjamin P Hay. Chemical Science Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, United States

A novel approach to the rational design of ditopic ion-pair receptors based upon the calix[4]arene strapped calix[4]pyrrole motif is presented. The de novo design approach utilises HostDesigner to search a library of molecular fragments with the aim of identifying synthetically accessible structures, sorted by calculated binding energy, which will bind contact ion pairs. Such molecules have potential applications as molecular recognition devices for a number of industrial and medical applications.

ORGN 432 LNA/DNA nanocrawler: Controlled movement monitored by fluorescence

Irina Astakhova, [email protected], Karol Pasternak, Meghan Campbell, Jesper Wengel. Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense, Denmark

Fluorescent oligonucleotides are of high interest within modern nucleic acid nanotechnology since they can provide simple and effective monitoring of molecular interactions by emission signal at a certain wavelength (I. Astakhova et. al. Chem. Commun. 2010 , 8362). Herein a novel nano-machine built from fluorescent LNA/DNA oligonucleotides, a nano-crawler, will be discussed. Fluorescent 2′-amino-LNA nucleotides containing pyrenemethyl- and pyrenecarbonyl- moieties were multiply incorporated into the circular 39mer nano-crawler and a complementary linear "road". The amino-LNA monomers serve two goals: 1) interaction between pyrene dyes provide clear signal corresponding to stepwise movement of the nano-crawler along the road (λfl 370 nm and 480 nm for pyrene monomer and excimer signals, respectively); and 2) affinity enhancing LNA monomers provide thermodynamic gradiens for movement from previous step to the next one. Thus, the nano-crawler presented herein is a first example of DNA nano-device with combined advantages of fluorescence monitoring and controlled movement in a chosen direction.

ORGN 433

Novel acceptor-acceptor homo[2]catenane: A new class of stable organic radicals

Jonathan C. Barnes1,2, [email protected], Fraser Stoddart1,2. (1) Department of Chemistry, Northwestern University, Evanston, IL 60208, United States (2) Department of EEWS, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea

The mechanical interlocking of two cyclobis(paraquat-p-phenylene) rings by means of radical templation has resulted in the discovery of a remarkable new class of stable organic radicals which possess mixed-valencies. This mechanically interlocked molecular compound is completely stable in its monoradical form under ambient conditions and, upon full oxidation, affords a novel acceptor-acceptor homo[2]catenane. We envisage that this rigid redox-active homo[2]catenane could be an ideal candidate for application in site-directed spin labeling, organic radical frameworks, semiconductors, and energy storage devices.

ORGN 434

Pressure-accelerated cycloaddtion of azide and alkyne in crystalline state

Yuguo Ma, [email protected], Hao Chen, Fan Gao, Jiang Peng. College of Chemistry, Peking University, Beijing, China

Recently, pressure-induced/accelerated reaction has been more frequently applied in synthesis, especially in organic synthesis in solid state. Advantages of such reactions include high yield, convenient work-up, and “green” process. It is normally thought that pressure-induced/accelerated reaction works via the change of the cell volume, which tends to shrink under high pressure. Herein we developed a supramolecular system by using two non-covalent interactions--electrostatic and arene-perfluoroarene interaction-- to pre-organize the azide and alkyne functionality in crystalline state. Upon applying pressure, the cycloaddition reaction between azide and alkyne was accelerated. X-ray diffraction, Raman, FT-IR, NMR were used to characterize the structures of assembly and identify the interactions. This system provides a good example of pressure- accelerated reaction with high regioselectivity resulted from the suitable packing through careful design by using two non-covalent interactions.

ORGN 435

Self-assembly of dinuclear metal complexes from Tröger's base derived ligands

Arne Lützen, [email protected] of Organic Chemistry and Biochemistry, University of Bonn, Bonn, Germany

The formation of stereochemically defined oligonuclear metallosupramolecular aggregates through stereoselective self-assembly processes has become an increasingly important area of research in recent years. In most approaches, chiral ligands are employed to achieve enantio- or diastereoselective assembly, but these processes are non-trivial in predicting when racemic ligands are used. Here, we present the synthesis and self-assembly behaviour of racemic bis(pyrdiyl), bis(bipyridyl), and bis(nitrile) ligands based on the chiral Tröger's base scaffold.

Interestingly, the degree of stereoselectivity was found to be very much dependant on the substitution pattern of the central Tröger's base scaffold. Furthermore, we could demonstrate that the choice of the metal binding unit (and consequently the metal centres) in 2,8-functionalized Tröger's base ligands allows us to achieve diastereoselective self-assembly of either homochiral dinuclear metallosupramolecular assemblies in self-recognition processes or heterochiral assemblies in self- discrimination processes.

ORGN 436

Water soluble, deep-red fluorescent squaraine rotaxanes

Erin L Cole1, [email protected], Easwaran Arunkumar2, Shuzhang Xiao1, Bryan A Smith1, Bradley D Smith1. (1) Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, United States (2) Molecular Targeting Technologies Incorporated, West Chester, PA 19380, United States

Squaraine rotaxanes are intensely colored and highly fluorescent dyes with deep-red absorption/emission wavelengths. We have subsequently shown that squaraine rotaxanes can be employed as targeted fluorescent molecular probes for cell microscopy and whole-body imaging of disease models in small living animals. To date, most of the squaraine rotaxane probes have been lipophilic or partially water soluble compounds. However, there is a need for squaraine rotaxanes that are highly water soluble. Eight squaraine rotaxanes were prepared and assessed for chemical stability and suitability as water soluble, fluorescent tracers. The most stable squaraine rotaxanes have four large stopper groups attached to the ends of the encapsulated squaraine, and two members of this structural class have promise as highly fluorescent tracers with rapid renal clearance and very low tissue uptake in living mice.

ORGN 437

Design and synthesis of solid state structures with conjugate acid-base pair interactions

Sathyanarayana R. Perumalla, [email protected], Changquan C. Sun.Pharmaceutics, University of Minnesota, Minneapolis, MN 55455, United States Conjugate acid-base pairs are compounds that differ by one proton. Hydrogen bonds formed between these pairs are well known for their unusual features, such as very short bond distance and exceptional strength.[1] In the current literature extra attention has remunerated on obtaining new solid-state structures of Active Pharmaceutical Ingredients (APIs ) because of fundamental, practical, and legal interests.[2] However, structure design based on these interactions in APIs have generally not been well explored in the primary literature.

In this context, we have investigated potential problems in preventing the design of crystal structures based on the strong interactions between conjugate acid and base, using two well known APIs, i.e., Naproxen and Nicotinamide and the results obtained were discussed in this work.

[1] J. Clare Speakman, in Structure and Bonding, Vol. 12, Springer Berlin / Heidelberg, 1972 , pp. 141-199.

[2] O. Almarsson, M. J. Zaworotko, Chem. Commun. 2004 , 1889-1896.

ORGN 438

Self-assembled peptide nanostructures for template directed synthesis of 1D inorganic nanostructures

Mustafa O. Guler, [email protected]. UNAM-Institute of Materials Science and Nanotechnology, Bilkent University, Ankara, Turkey

We mimicked biomineralization process by using self-assembled peptidic nanostructures. We designed and synthesized an amyloid-like peptide self-assembling into nanostructures. The nanostructures were functionalized with chemically active groups to enhance affinity for metal ions. The metal chelating groups were used on the peptide scaffold to accumulate inorganic precursors on the self-assembled peptidic nanostructures. The self-assembly process and template effect were characterized by CD, FT-IR, UV-vis, fluorescence, TGA, SEM and TEM. The self-assembled organic nanostructures were used as a template to form various one-dimensional inorganic nanostructures by addition of appropriate precursors. Herein, a new bottom-up approach was demonstrated to form silica, titania, zinc oxide, zink sulfide ans cadmium sulfide nanostructures that can yield wide opportunities for producing high-aspect-ratio inorganic nanostructures with high surface area. The materials developed in this work have potential in catalysis, photovoltaics and semiconductor applications.

ORGN 439

Supramolecular catalysis with a light-responsive cavitand Orion B. Berryman, [email protected], Aaron C. Sather, Julius Rebek Jr..Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, United States

Supramolecular catalysis is a promising area of study. Host-guest systems that use noncovalent bonds to fine-tune catalyst/substrate interactions are unique. Typically the substrate is a guest for the host and the reaction is accelerated by increasing the effective concentration or stabilizing the transition state. Unfortunately, the product is often a superior guest which results in product inhibition. Here we detail an alternative strategy where the bound guest is an organocatalyst in a deep cavitand. The cavitand contains an azobenzene wall that adopts an introverted shape when irradiated with UV light. This invaginated conformation has been characterized in solution and the solid state and is used to control guest binding. By incorporating an organocatalyst guest, the rate of the Knoevenagel condensation is controlled with light.

ORGN 440

Discrimination of complex biological analytes using supramolecular hosts

Samuel A Minaker, [email protected], Fraser Hof. Department of Chemistry, University of Victoria, Victoria, BC V8N 3K4, Canada

Post-translational modifications (methylation, phosphorylation, acetylation, etc.) to histone N-terminal tails are collectively called the histone code, and are key epigenetic regulators of cellular function. The writer, reader, and eraser enzymes that place, read and remove these marks contribute to the biological complexity of these highly dynamic systems. Currently only antibodies are used to study these modifications. Antibodies suffer limitations of batch to batch reproducibility, epitope masking, and specificity. Chemical sensors offer advantages of reproducibility and synthetic modification allows tuning of specificity. We demonstrate a series of host/dye reporters that are capable of discriminating between sequences of modified histone tail peptide sequences. These sensors give a unique multi-dimensional fingerprint of fluorescent responses that discriminate the analytes without the need for antibodies.

ORGN 441

New cycloaddition strategies based on strained and unusual molecules

RIck L. Danheiser, [email protected]. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States

This talk will focus on the application of strained and unusual molecules as building blocks for the construction of complex carbocyclic and heterocyclic compounds. The synthetic utility of highly unsaturated, conjugated molecules such as vinylketenes, conjugated enynes, vinylallenes, allenylimines, and iminoacetonitriles will be described, as well as their application in the total synthesis of natural products.

ORGN 442

Developing the basic science and applications of boron(B)-nitrogen(N)-containing heterocycles

Shih-Yuan Liu Liu, [email protected]. Department of Chemistry, University of Oregon, Eugene, Oregon 97403-1253, United States

1,2-Dihydro-1,2-azaborines are a family of aromatic heterocycles that is isosteric with the ubiquitous and biologically important family of arenes. It's simplest member, 1,2- Dihydro-1,2-azaborine (“BN benzene”), is related to the quintessential aromatic compound benzene by replacement of a C=C bond unit of benzene with an isoelectronic B–N bond (BN/CC isosterism). The properties and reactivity of 1,2- dihydro-1,2-azaborines have not been extensively explored. We describe our contributions in the synthesis, characterization, and reactivity studies of this family of BN heterocycles. The diversity of structures generated by the BN/CC isosterism approach creates new opportunities in biomedical research and materials science, which will also be discussed.

ORGN 443

Catalytic C–H oxidation: Recent insights and advances Justin Du Bois, [email protected]. Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States

The invention of new reaction chemistry for the selective functionalization of saturated C-H centers and pi-bonds is a principal focus of our research program. We have successfully advanced both C-H amination and hydroxylation methods, and have demonstrated the utility of these reactions in complex chemical synthesis. Efforts to elucidate the mechanistic details that underlie these processes and to further expand their application potential will be discussed.

ORGN 444

New methods and strategies for the total synthesis of polycyclic natural products

Sarah E. Reisman, [email protected] of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, United States

Over the past century, natural products have played an important role in the discovery and development of new drugs. The chemical synthesis of natural products can enable the study of their biological properties, and can provide access to unnatural, synthetic derivatives that may have improved therapeutic properties. As importantly, these synthetic undertakings serve to drive innovation in, and deepen our fundamental understanding of, organic and organometallic chemistry. The overarching goal of our laboratory is to discover, develop, and study new chemical reactions within the context of natural product total synthesis. To this end, we have several ongoing research programs targeting the total synthesis of biologically active diterpenoid and epidithiodiketopiperazine (ETP) natural products. This seminar will describe our recent progress in these endeavors, including our synthetic studies toward the diterpenoid natural product maoecrystal Z and the dihydrooxepine-containing ETP acetylaranotin.

ORGN 445

Award Address (ACS Award for Creative Work in Synthetic Organic Chemistry sponsored by Aldrich Chemical Company, Inc.). Recent studies in asymmetric catalysis

Gregory C. Fu, [email protected]. Department of Chemistry, MIT, Cambridge, MA 02139, United States

We have been exploring the development of a wide array of enantioselective processes, including nickel-catalyzed cross-coupling reactions and nucleophile-catalyzed processes. In this lecture, I will discuss some of our recent progress.

ORGN 446

Graphene-based and graphene-derived materials Rod Ruoff, [email protected]. Department of Mechanical Engineering, The University of Texas at Austin, Austin, TX 78712-0292, United States

Graphene-based materials are promising because of their electronic and thermal transport, mechanical properties, high specific surface area, that they can act as an atom thick layer, barrier, or membrane, among other reasons. Our micromechanical exfoliation approaches [1,2] conceived of in 1998 yielded multilayer graphene and one paper described in detail how monolayer graphene could be obtained [1]. Three main research areas of our group are: (i) Growth of large area graphene on metal substrates, characterization and physical properties, and studies of devices having graphene as a central component; (ii) Generation, study, and use of graphene-based platelets (typically derived from graphite oxide) including as dispersed in liquids, and powders derived from such colloids or generated by microwave or thermal treatment of graphite oxide; (iii) Generation and study of new types of carbon derived from graphene-based precursors, such as “activated microwave expanded graphite oxide”, or 'aMEGO'[3]. I will briefly present each pioneering study (composites, thin films, transparent conductive films, electrical energy storage, large area monolayer CVD growth on copper, graphene as a protective coating, others) as well as discuss our on-going research in these areas.

1. Lu XK, Yu MF, Huang H, and Ruoff RS, Tailoring graphite with the goal of achieving single sheets, Nanotechnology, 10 , 269-272 (1999).

2. Lu XK, Huang H, Nemchuk N, and Ruoff RS, Patterning of highly oriented pyrolytic graphite by oxygen plasma etching, Applied Physics Letters, 75 , 193-195 (1999).

3. Zhu, Yanwu; Murali, Shanthi; Stoller, Meryl D.; Ganesh, K. J.; Cai, Weiwei; Ferreira, Paulo J.; Pirkle, Adam; Wallace, Robert M.; Cychosz, Katie A.; Thommes, Matthias; Su, Dong; Stach, Eric A.; Ruoff, Rodney S. Carbon-Based Supercapacitors Produced by Activation of Graphene. Science 332 , 1537-1541 (2011 ).

ORGN 447

Graphene-based electronics and optoelectronics

Phaedon Avouris, [email protected]. Department of Physical Sciences, IBM T.J. Watson Research Center, Yorktown Heights, New York 10598, United States

Graphene a two-dimensional, single atomic layer material with linear electron dispersion has rather unique electrical and properties1. There is currently strong interest in taking advantage of these properties for technological applications2. In my talk I will review some of the key properties of graphene, how these are affected by environmental interactions and how they can be utilized in electronics and optoelectronics. Specifically, I will discuss high frequency (>300 GHz) graphene transistors3,4, their fabrication and operation, as well as related device physics aspects, such as carrier transport mechanisms, electrical contacts, temperature effects, energy dissipation, etc. Simple integrated graphene circuits will also be presented5. I will then discuss key optical properties of graphene and how they can be combined with its excellent electrical properties and used in optoelectronics applications. Specific examples involving ultrafast graphene photodetectors6 and their applications in the detection of optical data streams7 will be presented.

[1] Geim, A.K. Science 3, 1530 (2009)

[2] Avouris, Ph., Nano Letters 10, 4285 (2010)

[3] Lin, Y.-M.; Dimitrakopoulos, C.; Jenkins, K.A.; Farmer, D.B., Chiu, H.-Y. ; Grill, A.; Avouris, Ph. Science 327, 662 (2010)

[4] Wu , Y.; Lin, Y.-M.; Bol, A.; Jenkins, K.; Xia, F.; Farmer, D.; Zhu. Y.; Avouris, Ph., Nature, 472, 47 (2011)

[5] Y.-M. Lin, A.Valdes-Garcia, S.-J. Han, D.B. Farmer, I. Meric,Y. Sun, Y. Wu, C. Dimitrakopoulos, A. Grill, Ph. Avouris, Wafer-scale Graphene Integrated Circuit, Science 332, 1294 (2011)

[6] Xia, F.; Mueller, T.; Lin, Y.-M.; Valdes-Garcia, A.; Avouris, Ph. Nature Nanotechnology 4, 839 (2009)

[7] Mueller, T.; Xia, F.; Avouris, Ph. Nature Photonics 4, 297 (2010)

ORGN 448

Pathways, coherences, interference, and hopping in molecular transport

Mark A Ratner, [email protected]. Department of Chemistry, Northwestern University, Evanston, Illinois 60208-3113, United States

The two phenomena of electron transfer in molecules and electron transport through molecules are closely related to one another. Some of the phenomena exhibited in one of these areas can be mirrored in the other, but there are also differences. In this talk, we discuss the transport situation and different mechanisms for transport that occur under different temperature conditions and with different molecular structures. In particular, we will examine transport through more complex organic molecules than usual, and the interference phenomena that can result from cross-coupling, from meta linkages, and from simultaneous transport through more than one molecule. Emphasis will be conceptual (no complicated equations, no harping on methodology), and some concepts of physical organic chemistry, and their relationship to transport, will be addressed.

ORGN 449

Chemically enhanced carbon-based nanoelectronic materials and devices Mark C. Hersam, [email protected]. Department of Materials Science and Engineering, Northwestern University, Evanston, IL 60208-3108, United States

Carbon nanomaterials have attracted significant attention due to their potential to improve applications such as transistors, transparent conductors, solar cells, batteries, catalysts, and sensors. This talk will highlight our latest efforts to develop strategies for purifying, functionalizing, and assembling carbon nanomaterials into functional arrays. For example, we have recently demonstrated and commercialized a scalable technique for sorting surfactant-encapsulated single-walled carbon nanotubes (SWCNTs) by their physical and electronic structure using density gradient ultracentrifugation (DGU). The resulting monodisperse SWCNTs enhance the performance of thin-film transistors, infrared optoelectronic devices, transparent conductors, photovoltaics, and sensors. The DGU technique also enables multi-walled carbon nanotubes to be sorted by the number of walls and solution phase graphene to be sorted by thickness, thus expanding the suite of monodisperse carbon nanomaterials. By extending our DGU efforts to carbon nanotubes and graphene dispersed in biocompatible polymers, new opportunities have emerged for monodisperse carbon nanomaterials in biomedical applications.

ORGN 450

Electrochemical routes to the reduction of resistance in single-walled carbon nanotube networks

Marcus D Lay, [email protected], Pornnipa Vichchulada, Darya Asheghali. Department of Chemistry, University of Georgia, Athens, GA 30602, United States

A novel method of creating ordered arrays of purified SWNTs with minimal defect density has been exploited to attain a higher level of control over the reproducibility of SWNT networks. This method uses unidirectional airflow to deposit SWNTs from aqueous suspensions onto various surfaces without allowing bundle formation during the deposition process. This facilitates the formation of a network with an inter-SWNT spacing that exceeds the electrochemical diffusion layer for each nanotube. Under these conditions, the current is increased due to the increased surface area of the electrode, yet the 2-D network retains the enhanced properties expected of nanoscaled electrodes; namely enhanced diffusion, and reduced capacitance. This will allow greater S/N ratios in trace analysis. The electrochemical behavior of these networks has been investigated with the impetus of reducing the inherent inter-SWNT and SWNT/metal electrode contact resistance in order to form more efficient electronic materials.

ORGN 451

From molecules to materials

Colin P Nuckolls, [email protected]. Department of Chemistry, Columbia University, New York, NY 10027, United States This talk will develop methods to bridge, both literally and figuratively, the tools for lithography and those for creating complex molecular structures. Through this combination, we create molecular devices that are ultrasensitive sensors and efficient photovoltaic materials.

ORGN 452

Designing, measuring, and controlling molecular and supramolecular devices

Paul S. Weiss, [email protected]. California NanoSystems Institute and Departments of Chemistry & Biochemistry and Materials Science & Engineering, UCLA, Los Angeles, CA 90095, United States

We use molecular design, tailored syntheses, intermolecular interactions, and selective chemistry to direct molecules into desired positions to create nanostructures, to connect functional molecules to the outside world, and to serve as test structures for measuring single or bundled molecules. Interactions within and between molecules can be designed, directed, measured, understood, and exploited at unprecedented scales. Such interactions can be used to form precise molecular assemblies, nanostructures, and patterns, and to control and to stabilize function. We selectively test hypothesized mechanisms by varying molecular design, chemical environment, and measurement conditions to enable or to disable function and control using predictive and testable means. Critical to understanding these variations has been developing the means to make tens to hundreds of thousands of independent single-molecule measurements in order to develop sufficiently significant statistical distributions, while retaining the heterogeneity inherent in the measurements. We measure the electronic coupling of the molecules and substrates by measuring the polarizabilities of the connected functional molecules. The next step in such devices is to learn to assemble and to operate molecules together, both cooperatively and hierarchically, in analogy to biological muscles. We discuss our initial efforts in this area, in which we find both interferences and cooperativity.

ORGN 453

From carbon to silicon oxide invisible memories

James M Tour, [email protected]. Department of Chemistry, Smalley Institute, Rice University, Houston, TX 77005, United States

Starting from carbon layers deposited atop silicon oxide, a host of two-terminal switching devices were generated that have the following properties: radiation hardness toward X-rays, protons and heavy ions, stability to >600C, non-volatility, and >10,000 to 1 ON/OFF ratios. Continued work revealed that the switching was inherent to the underlying silicon oxide structure due to the formation of metallic silicon nanofilaments. These filaments have now be imaged in situ by transmission electron microscopy using a home-build imaging probe system. These memories are simple to fabricate en mass, have been built into crossbar architectures, and can be transparent in the visible region affording “invisible memory” on glass and plastic substrates.

ORGN 454

Synthesis of 2-arylidenecalix[4]arenes

Jordan L. Fantini, [email protected]. Department of Chemistry and Biochemistry, Denison University, Granville, Ohio 43023, United States

2-Arylidenecalix[4]arenes are a new class of calixarenes accessed by selective modification of a single methylene group of the calixarene. These molecules hold promise as components of sensors in which the photophysical properties of an arylidenecalix[4]arene will depend on molecular conformation which in turn is affected by the binding of an analyte. Synthetic routes to 2-arylidenecalix[4]arenes will be described.

ORGN 455

Facile synthesis of thieno[3,2-c]pyrazole using the Jacobson reaction

Philip M. Weintraub, [email protected], Kwon Musick, John Airey, Matthieu Barrague, Michael L. Edwards, Michael Ferro, Dirk Friedrich, John G. Jurcak, Wuu-Yung Lin.sanofi-aventis, Bridgewater, NJ 08807, United States

Pyrazoles are an important class of biomolecules. Condensed pyrazoles such as indazole have become important pharmaceutical scaffolds. Less well known are thienopyrazoles such as 1H-thieno[3,2-c]pyrazole. It is known that thiophene is an acceptable bioisostere for benzene, thus 1H-thieno[3,2-c]pyrazole should be a scaffold substitute for indazole. A practical synthesis of multigram quantities of 1H-thieno[3,2- c]pyrazole utilizing the Jacobson Reaction is presented.

ORGN 456

Highly selective Ru0-catalyzed H-D exchange reactions on heteroarenes – proof of principle for a tritiation protocol Michael Schnürch, [email protected], Birgit Gröll, Marko D. Mihovilovic.Intitute of Applied Synthetic Chemistry, Vienna University of Technology, Vienna, Austria

A highly selective deuteration method for N-containing heterocycles is reported employing Ru3(CO)12 as catalyst and using t-BuOD as deuteration reagent. The reactions takes place at 100°C under argon atmosphere within 30min. In contrast to established methods a much lower amount of deuteration reagent is required. After evaporation of the solvent the deuteration grade can be determined via 1H-NMR spectroscopy and GC-MS. In some cases two deuteration steps were sufficient to achieve deuteration grades greater than 90%. However, in most cases a third step was required to reach high deuteration grades. Several electron-rich and electron-poor N- containing heteroarenes could be deuterated selectively in ortho- and/or meta-position to the nitrogen atom. Examples include indoles, azaindoles, deazapurines, benzimidazoles, quinolines, isoquinolines, pyridines and pyrazine. We could also demonstrate that this reaction can be used for tritiation reactions in principal.

ORGN 457

Rapid and flexible methods for the syntheses of heteroatom-containing stereotriads

Jennifer M. Schomaker, [email protected], Jared W. Rigoli, Luke A. Boralsky, Christopher S. Adams, Cale D. Weatherly, John C. Hershberger. Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, United States

The beneficial biological activity of many molecules relies on the proper spatial presentation of various functional groups to a receptor protein. In particular, the position and chirality of arrays of carbon-heteroatom bonds strongly influences the binding of a molecule to its target. Current methods to prepare complex nitrogen-containing stereotriads and tetrads can often involve inefficient, multi-step processes that result in mixtures of regio- and stereoisomers. Our solution has been to develop new methods for allene oxidation that allow for the introduction of three or more heteroatom-bearing chiral centers into a simple allene substrate in a single flask. These methods demonstrate significant flexibility in the choice of the heteroatom (N, O, S, Cl, F, Br), allowing for rapid syntheses of libaries of novel stereotriads. These reactions also occur with excellent regio- and stereocontrol, due to our ability to transfer the axial chirality of the allene to all three new chiral centers.

ORGN 458

Synthesis of cyclic N-aryl hydroxamates via partial nitro group reduction- application to the synthesis of Kynurenine aminotransferase (KAT) II inhibitors

Laura A McAllister, [email protected], Bruce M Bechle, Amy B Dounay, Edelweiss Evrard, Xinmin Gan, Somraj Ghosh, Ji-Young Kim, Vinod D Parikh, Jamison B Tuttle, Patrick R Verhoest.Neuroscience Chemistry, Pfizer Worldwide R&D, Groton, CT 06340, United States

Cyclic aryl and heteroaryl hydroxamates have been identified as potent inhibitors of KAT (Kynurenine aminotransferase) II; a potential new target for treatment of cognitive impairment associated with schizophrenia. This presentation will describe the development of novel methodology to overcome the challenge of preparing diverse aromatic and heteroaromatic cyclic hydroxamates. A generalized approach to stereocontrolled synthesis of substituted cyclic hydroxamates by selective reduction of substituted 2-nitrophenylalanine substrates was developed. The nitrophenyl alanine intermediates are prepared enantioselectively; by phase transfer catalyzed alkylation; or by an optimized Negishi coupling of bromo-nitroarenes. The scope and limitations of the reductive cyclization transformation were explored with attention to the effects of substitution pattern and electronics on reaction efficiency and by-product formation. A novel activated trifluoroethyl ester cyclization strategy was developed to access the most sterically demanding systems and heterocyclic systems. This work has led to a versatile, robust and scalable route to a diverse set of hydroxamates.

ORGN 459

Kilo-scale synthesis of trifluoromethylpyrimidine-based kinase inhibitors via zinc- promoted C2-selective amination

Martin A Berliner, [email protected], Nandell F Keene. Chemical Research and Development, Pfizer Global Research and Development, Groton, CT 06340, United States

A common method for functionalizing pyrimidines is via regioselective addition of nucleophiles to 2,4-dichloropyrimidines. This approach results in no selectivity for the electron-deficient 5-trifluoromethyl-2,4-dichloropyrimidine, which has been used as a core for a series of kinase inhibitors discovered at Pfizer. In this talk, we describe the kilogram-scale implementation of a zinc(2+)-mediated functionalization for the C-2 selective amination of 5-trifluoromethyl-2,4-dichloropyrimidine and its application to the synthesis of two APIs that have been advanced into clinical studies.

ORGN 460

WITHDRAWN

ORGN 461 Process chemistry for the first GMP delivery of SSTR3 antagonist MK-4256

Rebecca T Ruck1, [email protected], Mark A Huffman1, Gavin Stewart2, Edward Cleator2, Wynne A Kandur1, Mary M Kim1, Dalian Zhao1. (1) Department of Process Chemistry, Merck & Co. Inc., Rahway, NJ 07065, United States (2) PRPL, Merck Sharp and Dohme, Hoddesdon, United Kingdom

Substituted β-carboline derivatives, including MK-4256, have been shown to be selective antagonists of the somatostatin subtype receptor (SSTR3) and useful for treatment of Type 2 diabetes and its associated conditions. The medicinal chemistry synthesis of MK-4256 provided a convergent route to API. This talk will focus on the chemistry developed to allow processing on the necessary 3 kg scale for the first GMP delivery. Developments include: a green protocol for pyrazole iodination, a one-pot oxadiazole synthesis, and efficient ketone Pictet-Spengler reaction, and an epimerization procedure to recycle the undesired diastereomer formed in the Pictet- Spengler reaction.

ORGN 462

Synthesis of diverse chiral spiro-azetidinepiperidines and their derivatives as ghrelin inverse agonists

Suvi T M Orr, [email protected], Kimberly O Cameron, Samit Bhattacharya, Kim F McClure, Daniel Kung, Shawn Cabral, Wenhua Jiao, Dilinie Fernando, Jeffrey Kohrt, Jana Polivkova, David Perry. Cardiovascular and Metabolic Disease Research Unit, Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States

A variety of chiral spirocyclic azetidinepiperidines 3 have been obtained by utilizing an expedient one-pot reaction of piperidinechloroaldehyde 1 with chiral amines 2 in the presence of a reductant. The reaction sequence involves a tandem reductive amination/nucleophilic substitution which proceeds with retention of the stereochemistry of the starting chiral amine thereby enabling rapid access to enantiomerically pure 3 . Subsequent modifications to convert an aryl bromide to a biaryl group via one-pot borylation/cross-coupling reaction followed by Boc-deprotection and amidation allowed rapid analogue synthesis to access ghrelin inverse agonists of general structure 4 .

ORGN 463

Friedel-Crafts acylation with amides

Erum K. Raja, [email protected], Daniel J. DeSchepper, Douglas A. Klumpp. Department of Chemistry, Northern Illinois University, DeKalb, Illinois 60115, United States

Acyl-transfer reactions involving amides and weak nucleophiles are exceptionally rare. However, we have found a series of N-aryl amides capable of providing aryl ketones by Friedel-Crafts acylation (eq 1-2). When Brønsted acid catalysts are used, the nitro- substituted aryl groups activate the acyl group towards nucleophilic attack. The results of these studies will be presented.

ORGN 464

Extreme oxatriquinanes: From protonating oxonium cations to record long C-O bonds

Gorkem Gunbas1, [email protected], Evgenii Stoyanov2, Nema Hafezi1, Mark Mascal1, Irini Stoyanova2, Fook Tham2, William Shepperd1, Christopher Reed2. (1) Chemistry, University of California Davis, Davis, CA 95616, United States (2) Chemistry, University of California Riverside, Riverside, CA, United States

The term "oxonium ion" evokes images of fleeting intermediates or highly reactive alkylating agents. Oxatriquinane, a rigid, tricyclic oxonium salt, has been synthesized and shows remarkable stability under conditions that would quickly decompose alkyl oxonium ions, and can even be recrystallized from boiling water. This unusual stability encouraged us to attempt the synthesis of an oxadionium (R3OH2+) ion by the protonation of oxatriquinane. It was shown that oxatriquinane forms strong hydrogen bonds with the superacid CHB11Cl11, providing the first direct evidence for basicity of an oxonium lone pair. X-ray crystal structures and calculations show that oxatriquinanes possess unusually long carbon-oxygen bonds. A crystal structure of tri- tertbutyloxatriquinane revealed a world record 1.62 Å C-O bond length.

ORGN 465 Molecular multifunctionalization via electronically coupled lactones

Matthew B Baker, [email protected], Jonathan Tasseroul, Andrew J Lampkins, Alexandre Al Abbas, Yan Li, Khalil A Abboud, Ion Ghiviriga, Ronald K Castellano. Department of Chemistry, University of Florida, Gainesville, FL 32611, United States

The aminolysis of benzotrifuranone (BTF, 1 ) occurs in a highly selective, stepwise fashion at low temperature (selectivities above 98%); this methodology allows the construction of fully differentiated star shaped molecules in an iterative manner under mild conditions with perfect atom economy and without protecting groups. Recent studies of structurally related systems (e.g., ring expanded, α-substituted) have identified the electronic (inductive) coupling of the lactones as the origin of this reactivity.

ORGN 466

Palladium catalyzed oxaheterocyclization of alcohols and hemiacetals: Stereoselective synthesis of cyclic ethers

Surendra Dawadi, [email protected], Christopher D. Spilling. Department of Chemistry and Biochemistry, University of Missouri-St. Louis, St. Louis, MO 63121, United States

Tetrahydrofuran (thf) and tetrahydropyran (thp) moieties are found in many biologically active natural products. Consequently, new methods for the construction of these fragments are of considerable importance. Palladium(0) catalyzed cyclization of primary alcohol (R', R'' = H) with allylic diacetate leads to the formation of 2-substituted cyclic ethers.1 This widely studied reaction proceeds via a Pd π-allyl complex. On the other hand, aldehydes and ketones in methanol form hemiacetals (R' = OMe, R'' = H, CH3) in the equilibrium mixture, which, although they are weak nucleophiles, react with Pd π- allyl to give 2,5 and 2,6 disubstituted thf and thp, respectively. Chiral ligands like (R,R)- DACH-phenyl Trost ligand is employed for non-racemic cyclizations.2 The vinyl acetate (R', R'' = H) thus obtained was treated with ozone followed by reductive workup with sodium borohydride to produce tetrahydrofurfuryl alcohol. Specific rotation of this alcohol was measured and compared with the literature values to determine absolute configuration at C-2 of the ring. It was found that (R)-tetrahydrofurfuryl alcohol was obtained by employing the (R,R)-DACH-phenyl Trost ligand. The stereocontrolled formation of chiral cyclic ethers is thus achieved from olefinic alcohols and hemiacetals.

ORGN 467

Asymmetric phase-transfer catalyzed electrocyclic reactions

Craig P Johnston, [email protected], Martin D Smith. Department of Chemistry, University of Oxford, Oxford, Oxfordshire OX1 3TA, United Kingdom

Electrocyclic reactions are powerful transformations which are seldom exploited in organic synthesis due to the lack of asymmetric methodologies. Our research aims to develop a range of new electrocyclic substrates which can be cyclized under asymmetric phase-transfer conditions to generate densely functionalized products. By exploiting tight-ion binding in an organic solvent a chiral counterion can block one π- face of the delocalized anion. This new methodology can generate substrates with up to three contiguous stereocentres comprising a diverse array of functionality.

ORGN 468

Direct carbonyl functionalization of carboxylic acids: Phosphorus-mediated synthesis of amides

Andrew D Kosal, [email protected], Erin E Wilson, Brandon L Ashfeld. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, United States

Our research has focused on new methods/chemical transformations of simple or readily available starting materials towards the rapid construction of complex synthetic intermediates and targets. Recently, we have shown that carboxylic acids can be used as an acyl surrogate in amidation reactions utilizing phosphorus and a functionalized azide. By exploiting phosphorus' ability to activate carboxylic acids in situ and reveal the latent nucleophilicity of azides via Staudinger-like reactivity, a highly chemoselective method for the formation of new C-N bonds directly from carboxylic acids was achieved.

ORGN 469

Facile synthesis of alkyl, aryl, heteroaryl boronic acids: Reaction of diisopropylaminoborane with corresponding halides mediated by magnesium under ambient Grignard and Barbier conditions

Christopher L Bailey, [email protected], Jacob Clary, Terry J Rettenmaier, Scott Eagon, Chris L Murphy, Bakthan Singaram. Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064, United States

Grignard reagents react with diisopropylaminoborane, BH2N(iPr)2, at ambient reaction conditions yielding the corresponding boronic acid. This reaction is general and can accommodate aliphatic, aromatic, and heteroaromatic halides. One equivalent of Grignard reacts with one equivalent of BH2N(iPr)2 in THF, the reaction is complete within one hour affording the product in good to excellent yield. Boronic acids can also be produced under Barbier-type conditions. An array of simple alkyl and aryl substrates were synthesized by this method.

ORGN 470

Metal-free aminofluorination and diamination of alkenes

Dmitry V Liskin, [email protected], Forrest E. Michael. Department of Chemistry, University of Washington, Seattle, Washington 98195, United States

Metal-free intramolecular oxidative cyclizations of sulfonamido- and hydroxyalkenes have been developed. Reactions employ hypervalent iodine (III) as oxidant and a strong Bronsted acid as promoter. Changing the Bronsted acid allows for incorporation of fluoride or nitrogen-containing groups, resulting in the formation of fluoroamines, fluoroethers and diamines.

ORGN 471

Microwave assisted one-pot synthesis of diaryl chalcogenides

Jin Jin, [email protected], Shaozhong Zhang, Kranthi Karra, Adam M Koe. Department of Chemistry, Western Illinois University, Macomb, IL 61455, United States

Diaryl chalcogenides have proven to be valuable building blocks in organic synthesis and also exhibit interesting biological activities. Here we report a copper-catalyzed new protocol to prepare diaryl chalcogenides assisted by microwaves. The one-pot synthesis of diaryl tellurides employs aryl halides, Te and KCN as starting materials in the presence of Cs2CO3 and a catalytic amount of CuI/NH2CH2CH2NH2. For diaryl selenides, commercially available KSeCN is used as one of the starting materials. The reactions are highly efficient with reaction times from 40 min to 1 h and reaction yields from 50-90%.

ORGN 472

Efficient one-pot synthesis of substituted quinolines from commercially-available starting materials

Courtney E. Meyet, [email protected], Catharine H. Larsen. Chemistry, UC Riverside, Riverside, CA 92521, United States

Quinolines have been long known to embody a range of important pharmacological and physical properties, from antimalarial and anti-inflammatory, to nano and meso structures with enhanced photonic and electronic properties. A facile one-pot strategy to rapidly access alkyl and/or aryl multi-substituted quinoline derivatives in high yields from commercially available starting materials has been developed. This catalytic process proceeds efficiently in air, tolerates up to 10 equivalents water, and is operable in a variety of solvents, creating a methodology with high atom economy and catalytic efficiency.

ORGN 473

Catalytic route to ketone-derived propargylamines via commercially available materials

Conor J Pierce, [email protected], Catharine H Larsen, Courtney E Meyet. Department of Chemistry, University of California Riverside, Riverside, CA 92521, United States

While an important method for accessing nitrogen-containing building blocks, research in the area of imine alkynylation is dominated by the alkynylation of aldimines to construct propargylamines. The few examples of ketimine alkynylation in literature require the use of multiple catalysts or stoichiometric amounts of zinc and base, each providing products of limited scope. We have developed a catalytic one-pot reaction to yield ketone-derived propargylamines to provide fully substituted nitrogen-bearing carbon centers.

ORGN 474

Simple ways to gold carbene catalysts and their application

A. Stephen K. Hashmi, [email protected]. Department of Chemistry and Earth Sciences, Universität Heidelberg, Heidelberg, Germany

Following the one-step synthesis of saturated five-membered gold carbene catalysts1 and the one-step synthesis of new N-heterocyclic oxo-carbene complexes,2 we now report the simple synthesis of unsaturated NHC complexes of gold(I). The method is further extended to six-membered carbene complexes of gold and other related but hitherto unkown systems. The structural properties of these new, previously unknown catalysts will be discussed in detail. The results of different new catalysts obtained by this method in different gold(I)- catalyzed organic transformation will be reported and it will be discussed where the new types of catalysts are superior to known catalysts.

References (1) Hashmi, A. S. K.; Lothschütz, C.; Böhling, C.; Hengst, T.; Hubbert, C.; Rominger F. Adv. Synth. Catal. 2010, 352, 3001-3012. (2) Hashmi, A. S. K.; Lothschütz, C.; Graf, K.; Häffner, T.; Schuster, A.; Rominger F. Adv. Synth. Catal. 2011, 354, 1407-1412.

ORGN 475

New synthetic strategies for the construction of N-hydroxyureas and N,N'- dihydroxyureas

Neal A. Yakelis, [email protected], Melrose T. Mailig, Jeremy S. Thomas, Samuel D. Whedon. Department of Chemistry, Pacific Lutheran University, Tacoma, WA 98447, United States

N-Hydroxyurea is an approved chemotherapeutic agent for several forms of cancer and the alleviation of sickle cell anemia crises. N'-Substituted-N-hydroxyureas have the potential to be more active or more selective donors of the bioactive metabolites nitric oxide (NO) or nitroxyl (HNO). Classic routes to N'-substituted-N-hydroxyureas involve reactions of amines and/or hydroxylamine with phosgene, isocyanates, or carbamates. Our more versatile, water-tolerant methodology makes use of the phosgene synthetic equivalents S,S'-dimethyldithiocarbonate and phenyl chloroformate. Surprisingly, the synthesis of N,N'-dihydroxyurea has been reported previously in low yield in two literature accounts using phosgene and triphosgene, respectively. Noting the instability of this compound at higher pH, a new higher yielding synthetic route for this fundamental compound will be highlighted. O-Protecting groups such as tetrahydropyranyl and o-nitrobenzyl ethers also enable our versatile synthesis of N',N'- disubstituted-N-hydroxyureas and N-/O-substituted-N,N'-dihydroxyureas.

ORGN 476

Organocatalyzed synthesis of bisheterocycles with various aldehydes and ketones

Melissa Padilla, [email protected], Robert W Harrison, Catharine H Larsen. Department of Chemistry, Universtiy of California, Riverside, Riverside, CA 92507, United States Dipyrrolomethanes are a common motif found in many biologically significant compounds but their synthesis from pyrroles and aldehydes usually requires strong acid. We have developed a new organocatalyst capable of coupling heterocycles including pyrroles, indoles, and thiophenes with not only aldehydes but ketones as well.

ORGN 477

QCI//DFT studies of heterocyclic di-N-oxides with antitumor activity: Mechanistic insights from tirapazamine analogs

Jian Yin1, [email protected], Rainer Glaser1, Kent S Gates2. (1) Department of Chemistry, University of Missouri, Columbia, MO 65211, United States (2) Department of Biochemistry, University of Missouri, Columbia, MO 65211, United States

Tirapazamine (TPZ, 3-amino-1,2,4-benzotriazine 1,4-N-dioxide) can cause hypoxia- selective, redox-activated DNA strand cleavage and nucleobase damage in solid tumors. Although actively studied for over two decades, the nature of the species responsible for DNA damage under hypoxia remains under investigation. To elucidate the mechanism of TPZ activity and to improve its in vivo efficacy, a series of TPZ analogs were synthesized and studied in the Gates laboratory and possible reaction channels for their activation are being studied with modern electronic structure methods by the Glaser group.

In the present work, higher-level correlated methods (QCI//DFT) were employed to investigate the homolytic fragmentation processes of TPZ analogs and to identify and characterize their major metabolites. The new results suggest that the redox-activation mechanism of tirapazamine (X(C3) = NH2) also applies to the parent system (X = H) as well as the 3-methyl (X = CH3) and 3-cyclopropyl (X = C3H5) analogs. On the other hand and in agreement with experimental observations, the PES analysis of 3-amino-2- quinoxalinecarbonitrile 1,4-di-N-oxide shows a reversal of the regiochemical preference of N-OH homolysis as compared to TPZ.

ORGN 478

Low-temperature copper-catalyzed formal Bergman cycloaromatizations of bis(2- arylethynyl)benzenes

Thomas S. Hughes, [email protected], E.S. Arun Thmaban, Stephen A. Jannetti. Department of Chemistry and Biochemistry, Siena College, Loudonville, NY 12211, United States Thermal Bergman cycloaromatizations usually require high temperatures, particularly when large substituents are located at the 1- and 6-positions of the enediyne system. We have recently found that bis(2-arylethynyl)benzenes with terminal ortho-formyl substituents undergo copper(I) catalyzed cycloaromatizations to give 6-5-6-6 tetracyclic benzo[a]fluorenones at temperatures as low as 85 °C. Although these reactions are formal Bergman cycloaromatizations because they convert enediyne moieties into new 6-carbon aromatic rings, they are accompanied by the formation of a new five- membered ring, and most likely do not proceed via the 1,4-benzyne mechanism because of the low temperatures and metal required. Studies of the scope and mechanism of this reaction indicate that the copper(I) is required, and that a variety of aromatic substituents are tolerated. For instance, if two ortho-formyl groups are present, the cycloaromatization gives a benzoxepin and a 6-5-6-5-6 ketoalcohol via tricyclization.

ORGN 479

Ultrafast irreversible phototautomerization of o-nitrobenzaldehyde

Ferran Feixas1, [email protected], Annapaola Migani1,2, Verónica Leyva3, Inés Corral4, Leticia González3, Lluís Blancafort1. (1) Department of Chemistry and Institut de Química Computacional, Universitat de Girona, Girona, Catalonia 17071, Spain (2) Centro de Física de Materiales, CSIC-UPV/EHU, Donosti-San Sebastian, Spain (3) Institut für Physikalische Chemie, Friedrich Schiller Universität Jena, Jena, Germany (4) Department of Chemistry, Universidad Autónoma de Madrid, Madrid, Spain

This theoretical work based on CASPT2//CASSCF methodology aims to elucidate the reaction mechanism underlying the transformation of o-nitrobenzaldehyde (NBA) to o- nitrosobenzoic acid. This reaction initially involves excited-state intramolecular hydrogen-atom transfer (ESIHT) from the aldehyde to the nitro group giving the ketene intermediate, which in turn is converted in the ground state into the o-nitrosobenzoic acid. Recently, it has been shown that the ketene intermediate is obtained with a 50% quantum yield by exciting NBA with a wavelength of 260 nm[1]. The ketene intermediate is in this case formed within 400 fs. Figure 1 shows the proposed mechanistic scenario. There are two product formation paths, one along the two S1/S0 conical intersections (CI), and one along the CI cascade [2]. Internal conversion to S1 and stepwise ESHT along path 1 will be the dominant route after excitation at 258 nm. In addition, ab initio surface-hopping dynamical calculations have been performed to simulate ESIHT dynamics of NBA in gas phase from the electronic S1 excited state [3].

[1] Laimgruber, S.; Schreier, W.J.; Schrader, T.; Koller, F.; Zinth, W.; Gilch, P. Angew. Chem. Int. Ed. 2005, 44, 7901.

[2] Migani, A.; Leyva, V.; Feixas, F.; Schmierer, T.; Gilch, P.; Corral, I.; González, L.; Blancafort, L. Chem. Comm. 2011, 47, 6383

[3] Leyva, V.; Corral, I.; Feixas, F.; Migani, A.; Blancafort, L.; González-Vázquez, J.; González, L. Phys. Chem. Chem. Phys. 2011, 13, 14685

ORGN 480

Solvent and substituent effects on the photochemistry of 1- acylaminoanthraquinones

Sarah J Schmidtke, [email protected]. Department of Chemistry, The College of Wooster, Wooster, OH 44691, United States

1-Acylaminoanthraquinones serve as models for biological systems with intramolecular hydrogen bonds between adjacent carbonyl and amino groups. We seek to gain a fundamental understanding of the impact of structure and solvent environment on photochemistry in these systems. Updated syntheses were applied to make the compounds, providing easier sample purification relative to past methods. The acyl substituent is varied to tune the extent of excited state proton transfer observed, ranging from a nearly complete charge transfer to no charge transfer. The proton transfer is traced through fluorescence spectroscopy, as both the locally excited state and charge transfer tautomer are fluorescent. Temperature-dependent fluorescence spectroscopy is used to evaluate the reaction thermodynamics in a series of solvents to assess the impact of solvent interactions upon the proton transfer. The results are correlated with kinetics studies providing a more complete understanding of factors that impact the photochemical properties.

ORGN 481 Substituent-induced π-facial stereoselectivities in Diels-Alder cycloadditions involving 5-substituted cyclopentadienes

Lufeng Zou, [email protected], K. N. Houk. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, United States

Stereospecific Diels-Alder cycloaddition plays a vital role in organic synthesis. In the synthesis of a natural product, aconitine, by the late David Gin's group,1 π-facial stereoselectivity leads to the desired natural product rather than its diastereomer. To trace its origin, a computation analysis based on distortion/interaction theory is conducted with SCS-MP2/6-311++G(d,p)//B3LYP/6-31G(d), which agrees well with the high-level ab initio theory G4.

In addition to verify that distortion energy plays the main role in the activation energy,2 we found that the activation and reaction energies are affected substantially by the 5- substituents and characterized by the C5-X out-of-plane angle to the C1-C4-C5 plane. Due to the bending of C5-X in the 5-substituted cyclopentadienes, attack of the dienophile syn to a donor and anti to an acceptor is favored. The bending of C5-X out- of-plane angle results from the interactions between the π orbitals of diene and the 5- substituent.

1. J. T. Wilmot, PhD thesis with D. Y. Gin 2010 .

2. J. D. Xidos, R. A. Poirier, C. C. Pye and D. J. Burnell, J. Org. Chem. 1998 , 63:105.

ORGN 482

Classification of low barrier hydrogen bonding molecules

Hou Ung1, [email protected], Jos Oomens2, Thomas H Morton1. (1) Department of Chemistry, University of California Riverside, Riverside, CA 92521, United States (2) FOM Institute for Plasma Physics, Nieuwegein, The Netherlands

Low barrier hydrogen bonds (LBHB) display characteristic properties of structure and vibrational spectroscopy. Mono- and diprotonated tetra(aminomethyl)benzene ions have been produced using ESI to explore whether the dication exhibits LBHBs.

Figure 1 shows stable tautomers of the diprotonated tetraamine. DFT predicts exothermic dissociation of the doubly charged parent ion into two singly charged daughter ions (loss of protonated dimethylamine), while expulsion of neutral Me2NH to form the doubly charged daughter ion is endothermic. Infrared Multiple Photon Dissociation (IRMPD) spectra were collected using the free electron laser for infrared experiments (FELIX) in the Netherlands. Experimental results show the endothermic dissociation pathway is preferred. Replacing H+ with D+ doesn't change the IRMPD of the monoprotonated ions, suggesting their N-H-N stretch occurs outside the range of FELIX (600-1800cm-1). Diprotonated ions show bands around 1150-1200cm-1 that can be assigned as its N-H-N vibrations. Theoretical and experimental results suggest the diprotonated tetraamine contain no LBHBs.

ORGN 483

Quantum chemical investigations into the photochemistry of urocanic acid

Deniz Tuna1, [email protected], Andrzej L. Sobolewski2, Wolfgang Domcke1. (1) Department of Theoretical Chemistry, Technische Universität München, Garching, Bayern 85747, Germany (2) Institute of Physics, Polish Academy of Sciences, Warsaw, Poland

Urocanic acid is a bioorganic molecule found in human skin. It acts as a UV-filter, presumedly protecting DNA from radiation-induced damage. Upon UV-irradiation, it is able to undergo E/Z-isomerization.

Urocanic acid exhibits a noteworthy wavelength-dependent E/Z-isomerization quantum yield. Upon absorption in the short-wavelength region of the absorption spectrum the quantum yield for isomerization amounts to only 5%, whereas absorption of longer wavelengths has the quantum yield rise up to 50%. We propose that this behavior originates from the topography of excited state potential energy surfaces.

The detailed mechanism of photochemical isomerization has not been elucidated up to this day. We will show CASSCF potential energy surfaces (corrected by various perturbational methodologies) along the isomerization coordinate as well as other internal coordinates. Possible mechanisms for photophysical deactivation of urocanic acid associated with retention of the (E)- (or (Z)-) configuration and for photochemical isomerization will be outlined.

ORGN 484

Synthees and structures novel fluoro- and chloro-isoindenonone derivatives: Polycycles meet fleeting intermediates

Markus Etzkorn1, [email protected], Tiffany B. Meyers1, Steven D. Smeltz-Zapata1, Tyler Warmack1, Michael Gerken2, Xin Yu2. (1) Department of Chemistry, The University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States (2) Department of Chemistry and Biochemistry, University of Lethbridge, Lethbridge, Alberta T1K 3M4, Canada

Although the parent and several alkyl-/aryl-substituted isoindenones have been described in the literature, there is no report on the generation of fluoro- or chloro- isoindenone derivatives. Starting from a readily available dienedione precursor, we will present the synthesis of two polycyclic tetrachloro-isoindenone derivatives along a short synthetic sequence. Their thermal isomerization and an alternative approach through the generation of tetrachloro-isoindenone will be discussed. Furthermore, we will describe our efforts to generate tetra- and hexafluoro-isoindenone derivatives and to dimerize or scavange the novel species.

ORGN 485

Examination of the cyclization mechanism for titanated vinylallenes

Bruce N. Hietbrink, [email protected], Frank Cucunato, James Parra, Nathan Sanford.The Department of Chemistry, The Richard Stockton College of New Jersey, Galloway, NJ 08205-9441, United States

The electrocyclic ring closure of 1,2,4-pentatriene, or vinylallene, is not a synthtically viable transformation, as it is both high energy and reversible. Delas, Urabe and Sato demonstrated (J. Am. Chem. Soc. 2001 , 123, 7937) an organometallic analog that gives reasonable yield at low temperatures. Our intial examination of this proecess using denstity functional theory suggests that this is not a simple pericyclic reaction, but rather a cationic process. Loss of a ligand from the titanium opens up a coordination site that then brings together together the two ends of the carbon framework. Cyclization through a transition state resembling a titanocycle proceeds much more readily than the parent hydrocarbon ring closure. Our ongoing examination seeks to clarify this mechanism and also goes on to look at the effect of substituents and stereochemical considerations.

ORGN 486

Origins of stereoselectivity in the organocatalyzed Diels-Alder reaction between 3-vinyl indole and activated methyleneindolinones

Gonzalo Jimenez-Oses1, [email protected], Bin Tan2, Gloria Hernandez- Torres2, Carlos F. Barbas III2, K. N. Houk1. (1) Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California 90095, United States (2) The Skaggs Institute for Chemical Biology and Departments of Chemistry and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, United States

Despite rapid progress in organocatalyst development, practical and efficient asymmetric approaches remain in high demand. An ideal asymmetric reaction would be atom-economical and rapid, performed under mild conditions to yield quantitative and enantiomerically pure products with catalyst and solvent recycling. Very recently, an unusually efficient organocatalytic asymmetric Diels-Alder reaction of 3-vinyl indole 1 and methyleneindolinone 2 using bisthiourea H-bonding catalyst 3 to yield carbazolespirooxindole skeletons 4 with up to three stereocenters, has been described.1

In this communication, a thorough theoretical study on the mechanisms of asymmetry induction is reported. A detailed conformational search of the rather flexible bisthiourea organocatalyst both in the free and complexed states, as well as the substrate- organocatalyst coordination modes, was necessary to account for the experimentally observed stereoselectivity levels. The inclusion of dispersion forces in the theoretical method was key to properly describe the reaction potential energy surface.

1 B. Tan, G. Hernández-Torres, C. F. Barbas, III, J. Am. Chem. Soc., 2011 , 133, 12354.

ORGN 487

Preparation of homogeneous Ir complexes containing a bidentate "NHC-OH" ligand and its application to alkylation of amines with alcohols

Agnieszka Bartoszewicz1,3, [email protected], Rocío Marcos1,3, Suman Sahoo1,2,3, Kentaro Inge2,3, Belén Martín-Matute1,3, Xiaodong Zou2,3. (1) Department of Organic Chemistry, Stockholm University, Stockholm, Stockholm 106 91, Sweden (2) Inorganic & Structural Chemistry, Stockholm University, Stockholm, Sweden (3) Berzelii Centre EXSELENT on Porous Materials, Stockholm University, Stockholm, Sweden

Alkylation of amines is of particular interest for the pharmaceutical industry due to the numerous drugs that contain alkylamino functionalities. As part of our research on the development of efficient, atom economical and environmentally friendly processes, we were searching for a highly active catalyst for the alkylation of amines using alcohols as latent electrophiles. We have designed and prepared a series of new Ir-NHC-OH complexes and test their catalytic activity. The reaction parameters were optimized and catalyst 1 provided the best catalytic performance. A large variety of secondary and tertiary amine products have been obtained in high yields. A low catalyst loading can be used, and the reactions are run under base-free conditions. An excess of any of the reagents is not needed. A solid supported version of the catalyst has been prepared.

ORGN 488

Rhodium-catalyzed conjugate addition with functionized boronate: Divergent access to various building blocks with lead-like molecular properties

Ho Yin Li1, [email protected], Joachim Horn1, Rachel J Shearer1, Stephen P Marsden1, Adam Nelson1, Amanda J Campbell2, David House2, Gordon G Weingarten2. (1) School of Chemistry, University of Leeds, Leeds, United Kingdom (2) Medicines Research Centre, GlaxoSmithKline, Stevenage, United Kingdom An efficient and convergent synthesis of various heterocycles including tetrahydroquinolines, dihydroquinolinones, chromans and chromenes via Rh-catalyzed conjugate addition of 2-substituted aryl pinacolboronates to α,β-unsaturated carbonyl compounds. The use of Duanphos ligand allowed the synthesis of tetrahydroquinolines with excellent yield and enantioselectivity.

Thanks to the air and water stability of the catalyst, this method is easily applicable in parallel synthesis format and provides convenient access to libraries of skeletally diverse scaffolds with lead-like properties due to the high chemo- and regioselectivities, mild reaction conditions and readily accessible starting materials.

ORGN 489

Schlenk equilibrium effects on iron-catalyzed cross-coupling reactions of aryl chlorides with alkyl Grignard reagents

Marc C. Perry, [email protected], Amber N. Gillett. Department of Chemistry, Point Loma Nazarene University, San Diego, CA 92106, United States

Research in our group has recently focused on the use of N-heterocyclic carbenes as ligands for the iron-catalyzed cross-coupling of non-activated aryl chlorides with primary and secondary alkyl Grignard reagents. Even though it is well known that Grignard reagents exist as an equilibrium mixture of alkylmagnesium halide and dialkylmagnesium species, there has been no study reported that determines which of these species is/are responsible for the cross-couplings observed in iron-catalyzed systems. An understanding of which species is/are responsible for such cross-coupling reactions would allow for the optimization of reaction conditions. We report on the studies performed aimed at exposing whether the alkylmagnesium halide, the dialkylmagnesium, or both species are responsible for observed cross-coupling behavior.

ORGN 490

Rapid synthesis of eneynearomatics and their reactions

Kevin A Lavender, [email protected], Scott T Handy. Department of Chemistry, Middle Tennessee State University, Murfreesboro, TN 37132, United States For several years, we have been studying the application of multiple couplings in a one- pot and regioselective fashion on polyhaloaromatics. To date, however, these polycouplings have always been of the same type (ie two Suzuki couplings or two Sonogashira couplings). Even greater versatility could be accessed if the type of coupling was different in the two (or more) stages. Identifying reaction conditions compatible for both couplings is not necessarily a trivial task. Recently, we have been exploring an option for a sequential Sonogashira/Suzuki sequence in which one palladium catalyst is used for both couplings, but the solvent is changed between the two reactions. The details of this reaction sequence and some applications of the reaction products will be discussed.

ORGN 491

New metallao-ligands for catalysis

James Lynch, [email protected], Jonathan M. J Williams. Chemistry, University of Bath, bath, United Kingdom

Phosphine ligand complexes have been utilized in the formation C-H, C-C and even C- X bonds. These bidentate phosphate ligands can be extremely difficult to modify, increasing cost also limiting use and tunability. We have looked to develop simple monodentate phosphines from commercially available chemicals. These can then be coordinated in situ to a metal scaffold to form complex and tuneable bidentate ligands.

ORGN 492

Evolution of a catalyst for secondary C-H borylation

Carl W. Liskey1,2, [email protected], John F. Hartwig1. (1) Department of Chemistry, University of California-Berkeley, Berkeley, CA 94618, United States (2) Department of Chemistry, University of Illinois-Urbana-Champaign, Urbana, IL 61801, United States

One of the greatest challenges in C-H functionalization reactions is achieving high selectivity for the functionalization of a single C-H bond. Rhodium and ruthenium- catalyzed borylation of aliphatic C-H bonds is controlled by the steric properties of the substrate, leading to functionalization of terminal methyl groups; however, these catalysts have been unreactive towards secondary C-H bonds. Using knowledge gained from our studies on the iridium-catalyzed borylation of arenes, we have identified an Ir- catalyst for the borylation of secondary C-H bonds of cyclic ethers, with high selectively for functionalization at the position beta to oxygen. The same catalyst also mediates the borylation of cyclopropanes, with selectivity for functionalization of the methylene position over a terminal methyl group. The development and scope of these reactions will be presented.

ORGN 493

Direct Matteson homologation of aldehyde diboration products: Facile synthesis of β-hydroxyboronate esters

Timothy B. Clark, [email protected], Cameron M. Moore, Casey R. Medina, Peter C. Cannamela. Department of Chemistry and Biochemistry, University of San Diego, San Diego, CA 92110, United States

The incorporation of boron substituents alpha to heteroatoms provides direct entry into substrates analogous to those formed and utilized in the Matteson homologation reaction. The diboration of aldehydes with bis(pinacolato)diboron using the (ICy)CuOt- Bu catalyst developed by Sadighi and co-workers leads directly to α-hydroxyboronate esters. To utilize these unique intermediates, Matteson homologations were explored. The resulting diboration products were amenable to direct homologation (of the crude diboration products) using Matteson homologation conditions with excess ClCH2Li to provide β-hydroxyboronate esters in moderate to high yields. Replacement of bis(pinacolato)diboron with bis[(+)-pinanediolato]diboron provides α- and β- hydroxyboronate esters with high asymmetric induction. The resulting products have been subjected to further reactions involving the C–B bond, demonstrating the synthetic versatility of these intermediates.

ORGN 494

Magnetically recoverable Nano-Fe-Glut-Cu and Nano-Fe-DOPA-Cu catalysts for Huisgen 1, 3-dipolar cycloadditions and coupling of thiols with aryl halides

Nasir Baig R B, [email protected], Rajender S Varma.Sustainable Technology Division, National Risk Management Research Laboratory, U. S. Environmental Protection Agency, Cincinnati, Ohio 45268, United States

Two novel bimetallic magnetic nano-ferrites using Fe3O4 as a robust, readily available, high-surface-area heterogeneous nano-magnetic support (Nano-Fe-Glut-Cu and Nano- Fe-DOPA-Cu) were synthesized and their applications in one-pot multi-component azide-alkyne-cycloaddition (AAC) reaction in aqueous media has been demonstrated. The C-S coupling of aryl halides with thiols, using microwave as a nonconventional energy, has been accomplished using these catalysts.

ORGN 495

Towards more sustainable chemical synthesis via multifaceted catalysis

Jason E Camp, [email protected]. School of Chemistry, University of Nottingham, Nottingham, United Kingdom

A multifaceted catalysis (MFC) approach to synthesis, in which one metal catalyses multiple mechanistically distinct steps in a synthetic process, is a powerful tool for the sustainable construction of added-value compounds from simple starting materials. This method allows for catalytic activation under mild, base free conditions. Our research into novel MFC processes for the synthesis of biologically active compounds, including reaction design, substrate scope and mechanistic details will be presented.

ORGN 496

Alcohol oxidations and asymmetric ketone reductions with (cyclopentadienone)iron carbonyl complexes

Tarn C Johnson, [email protected], Martin Wills, Guy J Clarkson. Department of Chemistry, University of Warwick, Coventry, West Midlands CV4 7AL, United Kingdom

A range of iron derivatives of the Shvo catalyst have been synthesised and applied to the Oppenauer-type oxidation of alcohols. The synthesis of further derivatives containing both point and planar chirality and their use in asymmetric ketone reductions is described.

1) For a comprehensive review of the Shvo catalyst see B.L. Conley, et. al. Chem. Rev. 2010, 110 , 2294-2312.

2) T.C. Johnson, et. al. Organometallics, 2011, 30, 1859-1868.

ORGN 497

Rhodium-catalyzed [4+2+2] cycloaddition reactions for the synthesis of eight- membered ring compounds

Gino Martin R. Canlas, [email protected], Scott R. Gilbertson. Department of Chemistry, University of Houston, Houston, Texas 77204-5003, United States

Intermolecular cycloadditions such as [4+2+2] cycloisomerizations are considered efficient due to the fact that multiple bonds are formed in a single step. Metal complexes, usually those of the late transition metals, have been employed for this purpose. Recently, a rhodium-BozPHOS based complex, has been found to be catalytically-competent in allowing the creation of cyclooctatrienes in moderate to good yields. The crystal structure of this complex will be reported, along with a number of reactions including the formation of tricyclic products through the cycloaddition of cyclic dienes. Such structures should have application in the synthesis of natural products containing eight-membered rings, such as asteriscanolide and the abyssomycins.

ORGN 498

Development of palladium-boron nitride (Pd/BN) as a novel semihydrogenation catalyst of alkynes Yuki Yabe, [email protected], Tsuyoshi Yamada, Saori Nagata, Yoshinari Sawama, Yasunari Monguchi, Hironao Sajiki. Department of Organic Chemistry, Gifu Pharmaceutical University, Gifu, Gifu 501-1196, Japan

Semihydrogenation of alkynes to alkenes is an important class of chemical transformations and its development are challenging field due to the difficult reaction control between alkynes (especially terminal alkynes which are easily over-reduced by Lindlar's catalyst) and alkenes, and the over-hydrogenation to alkanes is usually observed. We have developed a novel Pd supported on boron nitride catalyst (Pd/BN) possessing selective hydrogenation activity toward azide, alkyne and alkene functionalities in the presence of other reducible functionalities.

Such catalyst activity is derived from the coordination effect of BN nitrogen atoms to act as an efficient catalyst support and appropriate catalyst poison. Consequently, the combination of Pd/BN and diethylenetriamine (DETA) enabled the efficient semihydrogenation of terminal as well as internal alkynes to the corresponding alkenes.

It is noteworthy that DETA bears the acceleration effect for the semihydrogenation, while the over-reduction to alkane is completely suppressed.

ORGN 499

Effect of diazocine bridgehead modification on the folding of the Wilcox molecular torsion balance

Mark R Ams1, [email protected], Brijesh Bhayana2, Timothy Grabnic1. (1) Chemistry, Allegheny College, Meadville, PA 16335, United States (2) Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 16335, United States

Torsion balances are useful for measuring CH-pi interactions in a single molecule. Our 1 preliminary data show that replacing the methano (NCH2N) bridgehead with an ethano (NCH2CH2N) bridgehead affects the conformational equilibrium of the torsion balance, and suggests the CH-pi interaction distance is decreased. This talk will discuss our efforts to experimentally determine the relationship between CH-pi interaction strength and distance using the torsion balance approach.

1 Bhayana, B.; Ams, M. R. J. Org. Chem. 2011 , 76, 3594-3596

ORGN 500

Using serum albumin for the differential sensing of hydrophobic analytes

Michelle Adams Ivy, [email protected], Eric V Anslyn. Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, Texas 78712, United States

There has been a growing interest in the use of differential sensing, in which an array of non-selective receptors are used to detect a variety of analytes. The protein serum albumin is a good potential receptor for differential sensing because a variety of species of serum albumin are commercially available and have significant differences in amino acid sequences, thereby having variable binding affinities to analytes. Serum albumins also have multiple binding sites capable of binding a large range of molecules. Thus, we have developed several sensing ensembles for hydrophobic analytes, such as terpenes and fatty acids, which include several species of serum albumin, hydrophobic indicators, and assay additives. The fluorescence modulation is measured upon analyte addition to the sensing ensemble, which is statistically analyzed to generate a fingerprint, indicative of a particular analyte. We apply these sensing assays to pattern mixtures of analytes, such as perfumes and edible oils.

ORGN 501

Enemy brothers: Gathering cation-π and anion-π interactions for zwitterions recognition

Olivier Perraud, [email protected], Alexandre Martinez, Jean-Pierre Dutasta. Department of Chemistry, Ecole Normale Supérieure de Lyon, LYON, F 69007, France

Hemicryptophanes are chiral hosts constructed from one cyclotriveratrylene unit facing another C3-symmetric subunit. These heteroditopic molecules were found to be efficient receptors and supramolecular catalysts.

Herein we report on the synthesis of new hemicryptophanes and their properties toward efficient and selective encapsulation of ion-pairs and selected zwitterionic neurotransmitters in competitive aqueous media. 1H NMR experiments and quantum chemistry calculations are presented to emphasize the key-role played by the different endohedral interactions (particularly cation-π and anion-π interactions) in the binding selectivity.

ORGN 502

Employing pedal motion within the organic solid state to enhance photoreactivity

Ryan H. Groeneman1, [email protected], Elizabeth Elacqua2, Leonard R. MacGillivray2. (1) Department of Chemistry, Jefferson College, Hillsboro, Missouri 63050, United States (2) Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, United States

The ability to perform organic synthesis within the solid state has gained greater attention in the past decade. In this contexnt, motion within the organic solid state is common; however, it is often overlooked. A reactant molecule will often need to move within a crystal lattice to achieve reaction. In certain cases the reactant will need to undergo conformational changes prior to reaction. Conformational changes of olefins in solids, based on pedal motion, can lead to reactivity since the motion will convert the reactants to a more photoreactive material. In this contribution, we will discuss a series of [2+2] photocycloaddition reactions of olefinic esters in co-crystals wherein pedal motion enhances reactivity. The overall co-crystal structure, the photoproducts, and the observed pedal motion will be discussed. In addition, we will illustrate the enhanced reactivity associated with certain molecules due to the conformational changes. This work is generously supported by the National Science Foundation and PRISSM.

ORGN 503

Revival of the chemistry of hemicryptophanes

Alexandre Martinez, [email protected], Jean-Pierre Dutasta. Department of chemistry, Ecole Normale Superieure de Lyon, Lyon, F 69364, France Among the C3 symmetrical host molecules, two classes are built from cyclotrivératrylène (CTV) unit (figure 1-(a)): cryptophanes and hemicryptophanes (figure 1-(b) and (c) respectively).

The cryptophane hosts, which are constructed from two cyclotriveratrylene (CTV) units, can encapsulate a wide variety of guests, and have remarkable binding properties toward neutral or charged guests and efficient chiral recognition properties. The hemicryptophanes, combining a CTV unit with another C3 symmetrical moiety, are ditopic host molecules. Although their synthesis was described for the first time by A. Collet and J.-M. Lehn in 1982, their complexation properties and their catalytic activities have received little attention so far.

Here, we will described new aspects of the chemistry of hemicryptophanes since recently they were found to be efficient supramolecular catalysts, ion-pairs, zwitterions, or enantioselective carbohydrates receptors, and led to the design of novel molecular mechanical components as propellers or gyroscope.

ORGN 504

Protease-directed manipulation of micellar architectures using polymer-peptide amphiphiles

Lyndsay M Randolph, [email protected], Michael E Hahn, Matthew P Thompson, Nathan C Gianneschi. Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, United States

Nanoscale materials provide an ideal platform for the development and implementation of in vivo imaging probes. Herein an approach for the manipulation of nanoscale objects that contain the proper size and photophysical properties needed to elicit a response from disease-associated enzymes will be presented. The family of matrix metalloproteinases (MMPs) are known to be overexpressed in tumorigenesis and have therefore been extensively studied in all phases of cancer progression. For this reason, we designed polymer-peptide amphiphiles (PPAs) that contain an MMP peptide substrate to enzymatically trigger a switch in self-assembly and/or aggregation. In order to confirm the enzymatic switch of this material, various labels have been incorporated as tags to monitor an aggregation event. Specifically, methods utilizing Förster resonance energy transfer (FRET) pairs and TEM have provided confirmation of a variety of controlled switched in aggregation states. ORGN 505

Supramolecular preorganization induced by anions for the easy and efficient access to pseudopeptidic macrocyclic structures and cages

Santiago V. Luis, [email protected]. Department of Inorganic and Organic Chemistry, University Jaume I, Castellon, Castellon E-12071, Spain

Macrocyclic structures and cages are of interest in many fields of chemistry whose efficient synthesis is often a challenging target. In the case of C2 symmetrical pseudopeptides, efficient [n+m] macrocyclization processes can be obtained by preorganizing the open-chain precursos in a folded conformation. Although in some cases structural and configurational preorganization can be obtained, the interaction of those precursors with anions, either organic or inorganic can be used to direct the process to the formation of the desired product. Anions can act both as kinetic and thermodinamic templates. A change in the anion present can also be used to modify the nature of the final compound obtained. Thus, it is possible to obtain [2+2] or [3+3] macrocyclizations as the major product by a proper selection of the conditions. The use of C3 open-chain pseudopeptidic precursors, on the other hand, opens the way for the efficient preparation of pseudopeptidic cages.

ORGN 506

Incorporating rigidity into biomimietic aromatic cages for cation binding

Amanda L Whiting, [email protected], Fraser Hof. Department of Chemistry, University of Victoria, Victoria, BC V8W 3V6, Canada

Aromatic cages are an important motif in biology due to their ability to selectively bind quaternary ammonium ions. They interact with biological cations such as methylated lysine, and use cation-binding events to participate in protein-protein interactions. Mimicking the structure of aromatic cages with synthetic hosts allows us to study the interplay of cation-pi interactions, the hydrophobic effect, and preorganization on host- guest binding in water.

Our previous experience with making synthetic cages has shown that while electron- rich, aromatic hosts are suited for cation-binding, selectivity suffered greatly with increased host flexibility. Indeed, crystal structures of cation-binding proteins in bound and free states reveal almost no movement of the aromatic cage side chains, suggesting a highly rigid and preorganized binding pocket. To address this, our second generation of cage mimics incorporates bicyclic heterocycles as rigidifying elements. The effect of host rigidification on guest binding in water and directions for future modifications will be discussed.

ORGN 507 Unraveling the structural energetics of self-assembling protein cages and their application to nanomaterials

Brendan P Orner, [email protected], Yu Zhang, Maziar Ardejani, Thomas Cornell.Division of Chemistry and Biological Chemistry, Nanyang Technological University, Singapore, Singapore, Singapore

Self-assembly can govern higher order protein structure, and protein-protein interactions are fundamental to this assembly. By the use of domain swapping, alanine shaving, and computer-based design, we investigate the role of protein-protein interactions in the formation of hollow, nano-scaled ferritin cage proteins. These mutagenesis studies have resulted in the identification of key domains and residues that strongly influence the assembly and overall protein stability. These studies have also provided insight into the general self-assembly process allowing us to rationally design cages with enhanced stability. Furthermore, we describe a novel and general two step reduction technique for the clean and homogeneous production of gold nano-particles and gold/silver mixed nano-particles inside unmodified nano-cage proteins.

ORGN 508

Highly cooperative self-assembly of porphyrin nanoring complexes

Johannes K Sprafke1,2, [email protected], Harry L Anderson2. (1) Materials Research Laboratory, University of California Santa Barbara, Santa Barbara, California 93106-5121, United States (2) Department of Chemistry, University of Oxford, Oxford, United Kingdom

Fully π-conjugated porphyrin nanorings feature strained, highly symmetric and “end- free” π-systems that lead to unusual electronic structures with excited states being delocalized around the whole ring. Star-shaped hexapyridyl templates can direct the selective synthesis of such nanorings by either classical (6-ring, c-P6 ) or Vernier templating (12-ring, c-P12 ). This talk will mainly focus on the highly cooperative template binding in these systems as well as on the formation of multicomponent assemblies such as the sandwich complex (c-P12 )2:(DABCO)12 shown below.

ORGN 509

Sulfate recognition by a subcomponent self-assembly receptor

Song Yi, [email protected], Burjor Captain, Angel E Kaifer. Department of Chemistry, University of Miami, Miami, FL 33146, United States

The design and preparation of artificial receptors for sulfate recognition has become an area of great interest due to their importance in environmental and biological systems. Herein, we describe a tetrahedral metal-organic cage (1 ), formed via subcomponent self-assembly, which is capable of tightly and selectively binding sulfate anions. The formation of the cage with encapsulated sulfate was demonstrated using NMR spectroscopic, high-resolution ESI mass spectrometric, and X-ray crystallographic data. This self-assembled cage is highly soluble in aqueous solution (~30g/L) and could be readily disrupted and recovered, thus releasing and trapping sulfate anions, by adjusting the pH of the solution. Other metal-organic cages prepared through subcomponent self- assembly will be introduced briefly as well.

ORGN 510

Enhancing molecular gelation using functional polymers

Yash Adhia1, [email protected], Anne J McNeil2. (1) Macromolecular Science and Engineering, University of Michigan, Ann Arbor, MI - Michigan 48109, United States (2) Chemistry, University of Michigan, Ann Arbor, MI - Michigan 48109, United States

This presentation will highlight our recent efforts towards enhancing the gelation ability of a class of molecular gelators using polymer-based additives. Low concentrations (ca. 0.2 wt%) of poly(acrylic acid) (PAA) were found to significantly lower the critical gelation concentration (cgc) and increase the gel strength. Detailed studies revealed that PAA adsorbs onto the growing fibers, resulting in a reduced growth rates and thinner fibers. These morphological changes lead to improved gel properties by an increase in the fiber-fiber entanglements. Similar studies performed with other polymers showed that the polymer structure is important, wherein the polymer containing a complementary functional group relative to the gelator (e.g., H-bond donor/acceptor) provided the lowest cgc.

ORGN 511

Catalyst diversity via substrate induced five-component catalyst assembly

Wynter E. G. Osminski, [email protected], Zhenjie Lu, William D. Wulff. Department of Chemistry, Michigan State University, East Lansing, MI 48824, United States

A thorough study was performed on the catalyst diversity in the five-component catalytic asymmetric aziridination reaction mediated by boroxinate catalysts prepared from vaulted ligands, imines, borane, water, and various alcohols or phenols.

A diversified family of catalysts have been generated and examined by altering one or more of the five components. Furthermore, these modified catalysts help to give an insight into the aziridination mechanism in terms of the role played by the alcohol in the substrate-catalyst binding.

ORGN 512

Catalytic asymmetric synthesis of pyrrolidines using a diverse chiral copper catalysts derived from a single chiral source

Jian-Yuan Li, [email protected], Hunyoung Kim, Kyungsoo Oh. Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States

Continuing efforts are made in the development of catalytic asymmetric systems to pyrrolidines due to their unique biological activities as well as their high potential as organocatalysts. Previously, we reported a versatile chiral catalyst system that provided chrial pyrrolidines with orthogonal enantioselectivity under different metal catalysts. In this present poster, we disclose the full detail of copper(I)-catalyzed enantioselective [3 + 2] cycloaddition reactions of glycine imines with a diverse array of alkene derivatives, where high enantio- and diastereoselectivity have been achieved under different chiral copper catalysts derived from a brucine-diol ligand .

ORGN 513

Stereospecific distal epoxidation of dienols: Application to nigricanoside

Jawahar L Jat, [email protected], Ganesh Kumar, Saroj Ranjan De, Adeniyi M Adebesin, John R Falck.Biochemistry, UT Southwestern Medical Centre, Dallas, Texas 75390, United States

Enantiomerically enriched vinyl epoxides offer enticing synthetic versatility and also occur as labile metabolites in many biosynthetic pathways of medicinal significance. Herein, we describe an efficient, highly stereo- and regiospecific mono-epoxidation of conjugated dienols using a Ti(IV) catalyst and hydrogen peroxide at rt.

The utility of this methodology will be validated in a total synthesis of the potent anticancer agent nigricanoside and analogs.

ORGN 514

Enantioselective C-C bond-forming reactions using vanadium(V) complexes

Shinobu Takizawa, [email protected], Junpei Kodera, Doss Rajesh, Tomomi Katayama, Hiroaki Sasai.The Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan

We have successfully developed dinuclear vanadium(V) complex (Ra,S,S)-1 for enantioselective oxidative coupling of 2-naphthols. Simultaneous activation of two molecules of 2-naphthol by the two vanadium metals in the chiral template led to the smooth homocoupling reaction with high enantiocontrol. This “dual activation” mechanism was supported by kinetic analysis of the catalytic reaction. In this presentation, we will also discuss simple and convenient one-pot preparation of the dinuclear vanadium(V) complex and its application to enantioselective Friedel-Crafts reactions.

ORGN 515

Synthesis of a Diels-Alder cycloadduct, 8-aza-1,4-oxidobicyclo[4.3.0]non-2-ene: Using trityl chloride as a steric buttress

Nandeo Choony, [email protected], David Dragano, [email protected]. Chemistry, University of South Carolina Aiken, Aiken, South Carolina 29801, United States

A tritylated cycloadduct (8-aza-1,4-oxidobicyclo[4.3.0]non-2-ene) was synthesized by reaction of N-allylfurfurylamine with triphenylchloromethane followed by heating under reflux in toluene. The triphenyl group acted as a steric buttress enhancing the intramolecular Diels-Alder cycloaddition reaction of the N-allylfurfuryl amine. After its removal, 8-aza-1,4-oxidobicyclo[4.3.0]non-2-ene was isolated. Addition reactions were done on the double bond before deprotection, thus forming new compounds.

ORGN 516

Synthesis of complex amino acids of microsclerodermins

Akshat H Rathi, [email protected], Timothy J Donohoe. Department of Chemistry, University of Oxford, Oxford, Oxon OX13DP, United Kingdom

The microsclerodermins are a family of cyclic peptides, all of which possess intriguing antifungal activity with some showing potent antitumour properties. The core of the targets microsclerodermins F, G, H & I has been disconnected into two fragments; a pentapeptide 1 and an unusual amino acid 2. The pentapeptide 1 presents a significant challenge with an unusual hydroxypyrrolidinone unit. The amino acid 2 features five contiguous stereocentres, two of which are installed via a tethered aminohydroxylation (TA) reaction.

ORGN 517

Asymmetric C-C bond forming method for the synthesis of smoking cessation agents

Naga Durgarao Koduri, [email protected], Syed R Hussaini. Department of Chemistry and Bio-chemistry, University of Tulsa, Tulsa, Oklahoma 74104, United States

Our attempts towards the asymmetric synthesis of enantiopure analogs of nicotine and related alkaloids are reported here. Asymmetric synthesis is carried out by organocatalytic action of chiral urea catalysts. The urea catalyst will act as a bis- hydrogen bond donor allowing the alkyl radical to be delivered selectively from one face of imine. Later, these amines will be subjected to allylation or vinylation at nitrogen. Ring closing metathesis (RCM), reduction of double bond and N-alkylation of these substrates will provide the analogs of nicotine in enantiopure form.

ORGN 518

La(III)-mediated asymmetric 1,2-reduction of enones featuring a chiral sulfoxide auxiliary

Toshinori Nakakita1,2, [email protected], Kouichi Nagase1, Motofumi Miura1, Masaharu Toriyama1, Mikhail V Barybin2, Shigeyasu Motohashi1. (1) School of Pharmacy, Nihon University, Funabashi, Chiba 274-8555, Japan (2) Department of Chemistry, The University of Kansas, Lawrence, Kansas 66045, United States

Our novel convenient method for the preparation of chiral allylic alcohols of high optical purity involves 1,2-reduction of the corresponding (Z)-β-sulfinyl enones complexed to La(III) ions followed by removal of the sulfoxide fragment via an oxidation/desulfurization protocol. The handedness of the desired chiral allylic alcohol is easily controlled by employing either sodium borohydride in methanol or diisobutylaluminum hydride in THF as reducing agents. The scope of the above asymmetric reduction of (Z)-β-sulfinyl enones as well as mechanistic considerations pertaining to the stereochemical outcomes of this process will be discussed.

ORGN 519

Enantioselective preparation of P-chiral phosphine oxide organocatalysts and their application in asymmetric synthesis

Christopher JA Warner, [email protected], Simon Jones. Department of Chemistry, University of Sheffield, Sheffield, South Yorkshire S3 7HF, United Kingdom

Non-symmetrically substituted phosphorus compounds are omnipresent throughout asymmetric synthesis, both as chiral ligands and in their own right as organocatalysts. Despite their frequent use, the synthesis of such species still remains a challenge. Herein, we report a mild and highly enantioselective route to the preparation of a diverse range of diaryl and dialkyl P-chiral phosphine oxides using the N-phosphoryl oxazolidinone 1 . The application of these P-chiral species as catalysts in a range of asymmetric transformations will also be presented.

ORGN 520

α-Functionalised aldehydes as alternative bench stable ketene surrogates

James Douglas, [email protected], Andrew Smith. Department of Chemistry, University of St Andrews, St Andrews, Fife KY16 9ST, United Kingdom

Since its recent birth organocatalysis has grown to become one of the most desirable methods for the expedient synthesis of complex functionality. Within this field N- Heterocyclic carbenes (NHCs) are recognised to promote a range of diverse reaction types, the union of ketenes and NHCs previsouly utilized as efficient d2 enolate synthons. This poster summarises recent advancements in the synthetic development and application of α-functionalised aldehydes as alternative bench stable ketene surrogates.

ORGN 521

Brønsted acid catalyzed-alkylation of aldehydes and ketones: Dual role of the acid catalyst

Chong Xing, [email protected], Yonggui Robin Chi.Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological University, Singapore, Singapore 637371, Singapore

The use of Brønsted acid as the sole catalysts for alpha-functionalization of aldehydes and ketones will be discussed. One specific example is the Brønsted acids-catalyzed SN1-type α-alkylation of aldehydes with diaryl alcohols. The acid catalysis approach offers a broader substrate scope in this type of transformations, compared to the previously used enamine catalysis methods. Diaryl alcohols that generate less-stable carbocation intermediates can behave as effective substrates, as well as the α,α- disubstituted aldehydes. The acid plays two important roles: one is to mediate the alcohol dehydration for carbocation formation; the other is to accelerate the rate- determining aldehyde enolization.

ORGN 522

Selective boron-tethered Diels–Alder reactions

Katie E Scholl, [email protected], Lindsey G DeRatt, Jeremy B Morgan. Department of Chemistry and Biochemistry, University of North Carolina at Wilmington, Wilmington, NC 28403, United States Methods that generate complex organic structures in a stereoselective manner are essential for bio-active molecule synthesis. Vinyl boronic acids undergo a boron- tethered Diels–Alder reaction to generate valuable cyclohexene diols. Attempts to generate an enantioselective product by control of facial selectivity have never been reported. We will present a catalytic, enantioselective variant of this transformation utilizing organocatalysts, which leads to enantioenriched cyclohexenes containing four contiguous stereocenters. The functionalization of the intermediate carbon–boron bond is also being investigated.

ORGN 523

Development of catalysts for enantioselective halolactonization of alkenes

Wei Zhang, [email protected], Na Liu, Casi M Schienebeck, Kyle Decloux, Suqing Zheng, Weiping Tang. School of Pharmacy, University of Wisconsin, Madison, Madison, WI 53705, United States

A new catalyst was developed for enantioselective chlorolactonization of olefins. This catalyst was designed based on our previous studies on enantioselective 1,4-syn- bromolactonization of conjugated enynes. The tosyl group connected to the urea part of the catalyst was critical for enantioselectivity. Good yields and enantioselectivity were obtained with various aryl substituted olefins.

ORGN 524 Efforts towards cinchona alkaloid conformations and their catalytic functions in asymmetric synthesis: Exploitation of trifluoromethyl moiety as a conformational stabilizer and a probe

G. K. Surya Prakash, Fang Wang, [email protected], Jingguo Shen, Martin Rahm, Chuanfa Ni, Ralf Haiges, Golam Rasul, George A Olah.Loker Hydrocarbon Research Institute, Department of Chemistry, University of Southern California, Los Angeles, California 90089, United States

Cinchona alkaloids and their derivatives are widely utilized in asymmetric catalysis. Although close conformation-catalytic activity relationships have been established in several cinchona alkaloid-mediated catalytic processes, conformational behavior of cinchona alkaloids is still not fully understood. To address such an inherent problem, the CF3 moiety has been incorporated as a conformational stabilizer and a probe, which allows feasible conformational studies via 19F NMR spectroscopy. Facilitated by this unique strategy, a wealth of conformational information, otherwise inaccessible, has been revealed. A further case study exploiting the CF3 probe has manifested catalytically active conformations in the enantioselective cyclopropanation of phenyl vinyl ketone.

ORGN 525

Synthesis of 5- and 6-membered cyclic hydrazides as organocatalysts for cycloaddition reactions

Robyn A Biggs1, [email protected], Xuehong Luo2, William W Ogilvie1. (1) Department of Chemistry, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada (2) Department of Medicinal Chemistry, AstraZeneca Canada Inc., Montreal, Quebec H4S 1Z9, Canada The favorable environmental and reactivity qualities of organocatalysts are contributing to the popularization of this method for the acceleration of enantioselective reactions. Research in our group1 has been focused on the synthesis of camphor-derived hydrazide based organocatalysts for enantioselective cycloaddition processes. Recent results2 suggest that the presence of an exocyclic electron withdrawing group on the hydrazide moiety, as well as the incorporation of the hydrazide moiety into a 6- membered ring, may have a beneficial effect on the kinetics of the catalysts. Efforts are currently underway to synthesize and test a variety of camphor-based cyclic hydrazides, varying both the ring size and placement of the electron withdrawing group.

1Lemay, M.; Ogilvie, W. W. Org. Lett. 2005 , 7, 4141.

2 Brazier, J. B.; Cavill, J. L.; Elliott, R. L.; Evans, G.; Gibbs, T. J. K.; Jones, I. L.; Platts, J. A.; Tomkinson, N. C. O. Tetrahedron, 2009 , 65, 9961.

ORGN 526

Highly enantioselective Diels-Alder reactions of chalcones and formylcyclopropanes catalyzed by chiral N-heterocyclic carbenes

Hui Lu, [email protected], Yonggui Robin Chi.Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological University, Singapore, Singapore 637371, Singapore

The catalytic generation of chiral ester enolates or their equivalents with small organic catalysts for enantioselective carbon-carbon bond-forming reaction is a powerful strategy in reaction discovery and synthesis.We present herein highly enantioselective Diels-Alder reactions of chalcones and formylcyclopropanes catalyzed by chiral N- Heterocyclic Carbenes. We captured the challenging NHC-bounded enolate intermediates from formylcyclopropanes for new C-C bonding formation reactions, and significantly expands the scope of reverse-electron-demand hetero-Diels-Alder reactions that were previously limited to highly activated heteodienes. The reaction products could be easily transformed to optically pure multi-substituted cyclohexane derivatives.

ORGN 527

Catalytic activation of stable carboxylate esters via chiral N-heterocyclic carbenes Lin Hao, [email protected], Yonggui Robin Chi.Division of Chemistry & Biochemistry, School of Physical & Mathematical Science, Nanyang Technological University, Singapore, Singapore 637371, Singapore

In N-Heterocyclic Carbenes (NHC) catalysis, the activation of aldehydes, enals, and ketenes has led to a diverse set of interesting reactions. For example, the activation of enals, after a few transformations typically involving homoenolate and enolate intermediates, ends up as the corresponding ester forms. We have attempted to achieve the reverse activation processes starting from stable carboxylate esters. Here our recent success in activate esters to generate catalytic enolate intermediates for highly selective reactions will be discussed.

ORGN 528

Enal β-substituents-directed enatioselective Diels-Alder reactions and Stetter reactions of enals and modified chalcones catalyzed by N-heterocyclic carbenes

Xingkuan Chen, [email protected], Yonggui Robin Chi.Division of Chemistry & Biological Chemistry, Nanyang Technological University, Singapore, Singapore 637371, Singapore

The N-heterocyclic Carbene (NHC)-mediated unconventional activation of enals often leads to homoenolate equivalents as the reactive intermediates. Here we report selective catalytic generation of enolate and acyl anion equivalents from simple enals that undergo highly enantioselective intermolecular Diels-Alder and Stetter reactions respectively with alkylidene diketones. The enal β-substituents play an important role in directing the two reaction pathways: β-aryl enal favors the Diels-Alder reactions, while β-alkyl enals exclusively undergo Stetter reactions. No products resulted from the typical homoenolate equivalent intermediates were observed under a range of conditions.

ORGN 529

β-Lactam synthesis via NHC mediated organocatalysis

Stuart M Leckie, [email protected], Andrew D Smith. Department of Chemistry, University of St Andrews, St Andrews, Fife KY16 9ST, United Kingdom β-Lactams are a privileged structure within organic chemistry. NHC 1 undergoes nucleophilic attack upon alkylarylketenes to form azolium enolate 2 . This enolate can react with a range of imines 3 to give the corresponding β-lactams 4 . This poster will discuss recent progress in this area.

ORGN 530

Development of an asymmetric trimethylenemethane cycloaddition: Application in the enantioselective synthesis of highly substituted carbocycles

Steven M Silverman, [email protected], James P Stambuli, Nicolai Cramer, Barry M Trost. Department of Chemistry, Stanford University, Stanford, CA 94305, United States

A protocol for the enantioselective [3+2] cycloaddition of trimethylenemethane with electron-deficient olefins has been developed. The synthesis of novel phosphoramidite ligands was critical in this effort, evolving from acyclic amine-derived structures to cyclic pyrrolidine and azetidine-derived ligands. The conditions developed to effect an asymmetric TMM reaction using 2-trimethylsilylmethyl allyl acetate were shown to be tolerant of a wide variety of alkene acceptors, providing the desired methylenecyclopentanes with high levels of enantioselectivity. The donor scope was also explored and substituted systems were tolerated, including those bearing nitrile and alkyne moieties. These donors were reactive with unsaturated oxindoles and acylpyrroles, giving the product cyclopentane rings bearing three contiguous stereocenters with high chemo-, diastereo- and enantioselectivity.

ORGN 531

Synthesis and applications of chiral ligands based upon an indole core

Yu Wang, Noora Kuuloja, Robert Franzen, [email protected]. Department of Chemistry and Bioengineering, Tampere University of Technology, Tampere, Finland Although the indole core has been investigated for over a century, it has gained attention as a ligand only very recently. Excellent results for the utility of achiral indolylphosphine ligands in Pd-catalyzed reactions, such as Suzuki-Miyaura couplings, Hiyama cross-couplings, cross-couplings utilizing organotitanium nucleophiles, and aminations have been reported. However, only a few chiral indole ligands have been prepared until today. In comparison with other benzofused heterocycles, the selective modification methods for indole are much more diverse and thus offer more possibilities for tuning the electronic and steric properties. Also due to the accessible diversity, tunability, and potential activity in asymmetric reactions, we have recently developed many indole-phosphine oxazoline (IndPHOX) 1,2 and indole-olefin oxazoline (IndOlefOx) 3 ligands as valuable additions to oxazoline ligands. This presentation will focus on these novel ligands as alternatives in enantioselective transformations

(1) Wang, Y.; Hämäläinen, A.; Tois, J.; Franzén, R. Tetrahedron: Asymmetry, 2010 , 21, 2376.

(2) Wang, Y.; Vaismaa, M.; Hämäläinen, A.; Tois, J.; Franzén, R. Tetrahedron: Asymmetry, 2011 , 22, 524-529.

(3) N. Kuuloja; Tois, J.; Franzén, R. Tetrahedron: Asymmetry, 2011 , 22, 468-475.

ORGN 532

Syntheses and applications of chirally pure phosphine ligands from the natural lignan hydroxymataresinol

Yury Brusentsev, [email protected], Patrik Eklund. Department of Natural Sciences, Åbo Akademi University, Åbo, Finland

Recent advances in isolation of the lignan hydroxymataresinol (HMR) from Norway Spruce (Picea abies) promped us to use it (HMR) as a novel chiral starting material for syntheses of chiral phosphine DIOP-type ligands. Highly efficient routes for syntheses of various phosphines were developed. The routes include different modifications of the lignan skeleton followed by the reduction of the lactone ring, preparation of the dimesylate derivative and substitution of the mesylates with the phosphide anion (Fig. 1 and 2).

Several rhodium(I) complexes were prepared (Figure 2). There use as asymmetric transition metal catalysts is under development in our laboratory.

ORGN 533

Towards the chemoenzymatic dynamic kinetic resolution of more complex secondary and tertiary chiral alcohols

Richard Lihammar, [email protected], Ylva Wikmark, Renaud Millet, Jan-Erling Bäckvall. Department of Organic Chemistry, Arrhenius Laboratory, Stockholm, Sweden

In a chemoenzymatic dynamic kinetic resolution (DKR) a racemic substrate mixture is converted in nearly 100% to a single product enantiomer. The method has provided excellent results for basic building blocks such as 1-phenyl ethanol and derivatives thereof, but more complex molecules still remains a challenge.

In this work, research to resolve more complex molecules like amino-, allylic- and tertiary alcohols have been conducted. The results show that the scope of the DKR method can be broadened to more advanced structures.

ORGN 534

Toward a catalytic, asymmetric aza-Cope rearrangement—Mannich cyclization

Ian M Pendleton, [email protected], Harriet A Lindsay. Department of Chemistry, Eastern Michigan University, Ypsilanti, MI 48197, United States

The aza-Cope rearrangement—Mannich cyclization is a 3,3-sigmatropic rearrangement that provides an efficient method of synthesizing both complex and simply-substituted acylpyrrolidines. One limitation of this reaction has been the difficulty in controlling stereochemistry in substrates where there is conformational mobility of the intermediates. Previous work has indicated that varying the Lewis acid catalysts in the reaction can have a significant impact on stereochemistry, offering good stereoselectivity in some but not all cases. In other sigmatropic rearrangements, use of chiral Lewis acid catalysts has resulted in high enantioselectivity for substrates. However no application of this sort has been attempted for the aza-Cope Mannich reaction. To address this shortcoming, we have evaluated the use of several chiral Lewis acids in the reaction of conformationally mobile substrates.

ORGN 535

Memory of chirality test: Asymmetric induction in the catalytic aza-Cope rearrangement—Mannich cyclization

Elizabeth Miguet, [email protected], Harriet A Lindsay. Department of Chemistry, Eastern Michigan University, Ypsilanti, MI 48197, United States

The aza-Cope rearrangement—Mannich cyclization has been used for both the synthesis of complex alkaloids and for the formation of simpler acyl pyrrolidines. In many cases, excellent stereocontrol is observed, likely due to conformational restraints arising from structural complexity of substrates. However, in the absence of such complexity, stereocontrol is much less common. Nonetheless, we have recently discovered that, using borontrifluoride catalysis, excellent stereoselective may be realized in reactions involving conformationally mobile substrates, largely through the phenomenon of memory of chirality. Application of this catalytic, asymmetric aza- Cope—Mannich reaction to the synthesis of pyrrolizidine and indolizidine alkaloids will be presented.

ORGN 536

Highly asymmetric cyclopropanation reactions by co(II)-based metalloradical catalysis

Xue Xu, [email protected], Hongjian Lu, Shifa Zhu, Xin Cui, Peter Zhang. Department of Chemistry, University of South Florida, Tampa, FL 33620, United States

Metal-catalyzed asymmetric olefin cyclopropanation with diazo reagents stands as one of the most general approaches for the synthesis of optically active cyclopropane derivatives. Cobalt (II) complexes of D2-symmetric chiral amidoporphyrins [Co (D2- Por*)] were first introduced in 2004, now they have emerged as a new class of catalysts for asymmetric cyclopropanation. These metalloradical catalysts have been shown to be highly effective for both asymmetric inter- and intra-molecular cyclopropanation with different classes of carbene sources, particularly including acceptor/acceptor- substituted diazo reagents, in excellent diastereoselectivity and enantioselectivity.

ORGN 537

Organocatalytic desymmetrization of a citric acid derived anyhydride

Sean Roberts, [email protected], Kaz Skubi, Alex Lai, Milan Cvitkovic, Anna Brezny, Kenneth Lum, David G. Alberg, Gretchen E. Hofmeister. Department of Chemistry, Carleton College, Northfield, Minnesota 55057, United States

One of our research aims is to generate useful chiral synthons from inexpensive commodity chemicals. Desymmetrization of the citric acid-derived anhydride 1 [1] via enantioselective alcoholysis and thiolysis using cinchona alkaloid derived organocatalysts [2] would provide a useful alternative to the traditional resolution of 2 [1] or enzymatic resolutions of citrate derivatives.[3] Here we report the optimization of this reaction, which has yielded enantiomerically enriched reaction products in up to 85% ee.

[1] Ancliff, R. A.; Russell, A. T.; Sanderson, A. J. Tetrahedron: Asymmetry 1997 , 8, 3379-3382.

[2] Atodiresei, I.; Schiffers, I.; Bolm, C. Stereoselective anhydride openings. Chem. Rev. 2007 , 107, 5683-5712.

[3] Oves-Costales, D.; Song, L.; Challis, G. L. Chem. Commun. 2009 , 1389-1391, and references cited therein.

ORGN 538

Copper-catalysed asymmetric 1,4-conjugate addition of alkylzirconium compounds

Rebecca M Maksymowicz, [email protected], Philippe M Roth, Stephen P Fletcher. Department of Chemistry, University of Oxford, Oxford, United Kingdom

Asymmetric carbon-carbon bond formation by addition of an organometallic reagent is a powerful strategy in chemistry. The use of Grignard and organozinc reagents as nucleophiles can now give high levels of asymmetric induction, but these methods have a number of disadvantages. We have developed a catalytic asymmetric 1,4-conjugate addition of alkylzirconium compounds, which overcomes a number of these limitations. The system uses mild conditions to achieve high levels of enantioselectivity. The reaction shows broad substrate scope and a high tolerance to different reaction conditions while still maintaining good selectivity.

ORGN 539

Enantioselective catalysis and expanding molecular diversity for spirocyclic oxindoles

Abel Silva-Garcia, [email protected], Joseph J Badillo, Benjamin Shupe, Jacob MacDonald, Annaliese K Franz. Department of Chemistry, University of California, Davis, Davis, CA 95616, United States

Spirocyclic oxindoles are an important class of biologically active compounds that contain a privileged spirocyclic architecture found in a large number of natural products and pharmaceutically relevant molecules. Here we present the efficient preparation of spirooxindole structures using a catalytic enantioselective Pictet-Spengler reaction followed by diversification via incorporation of triazoles. We demonstrate that a series of chiral Brønsted acid catalysts promote high enantioselectivity (up to 98:2 er) for the reaction of tryptamine and isatin derivatives affording spirooxindole products in excellent yields (up to 99%). We will discuss the optimization for spirooxindole formation using a range of different asymmetric catalysts, additives, solvents, and temperatures. Using a series of propargylated isatins, we then diversify these spirooxindole scaffolds using the copper-catalyzed azide-alkyne cycloaddition reaction to provide spirooxindole-triazoles

ORGN 540

Total synthesis of haminol A: An analysis of vinylpyridine metathesis reactivity

Brianne R King, [email protected], Jennifer M Storvick, Gregory W O'Neil. Chemistry, Western Washington University, Bellingham, WA 98225, United States

The total synthesis of haminol A has been completed featuring a masked-alkene metathesis reaction followed by bis-acyloxysulfone elimination to install the 1,3,8-triene subunit. During the course of our synthesis, the metathesis reactivity of 3-vinylpyridine was evaluated and our data suggest the rapid formation of a ruthenium pyridylalkylidene that no longer participates in productive metathesis.

ORGN 541

Synthesis of trans-epoxy quinol via Noyori asymmetric transfer hydrogenation of meso-epoxy diketone

Brian Walker, [email protected], Matthias McIntosh, David Clay. Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, United StatesDepartment of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, United StatesDepartment of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, United States

trans-epoxy quinols (e.g. 3 ) are present in the natural products bromoxone, harveynone, panepoxydon and others. For our purposes, trans-epoxy quinol 3 was identified as an early intermediate in the asymmetric total synthesis of antascomicin B. Racemic epoxy quinol has been prepared in four steps from benzoquinone. However, the existing asymmetric synthesis of the corresponding silyl ether required eight steps, high enzyme loading, and long reaction times. Our goal was to prepare large quantities of the trans-epoxy quinol 3 with an efficiency comparable to the racemic synthesis. We will describe the successful realization of this goal using Noyori asymmetric transfer hydrogenation of meso-epoxy diketone (figure 1). The overall asymmetric route is equal in length and higher in reduction diastereoselectivity than the racemic route.

ORGN 542 Phosphate tether-mediated ring-closing metathesis studies: The role of stereochemistry and application in natural product synthesis

Rambabu Chegondi, [email protected], Soma Maitra, Jana Markley, Paul R Hanson. Department of Chemistry, University of Kansas, Lawrence, Kansas 66045- 7582, United States

Temporary phosphate tether-mediated diastereoselective ring-closing metathesis studies will be discussed probing a number of parameters including ring size, stereochemistry and conformation. Synthetic efforts towards the total synthesis of the 14-membered cytotoxic marine marolide (–)-lyngbouilloside (1 ) are also reported. Overall, an integrated platform employing phosphate-mediated processes will be detailed, which have led to the synthesis of dolebelide C, (–)-tetrahydrolipstatin, (–)- salicylihalamide A as well as the construction of the advanced intermediates enroute to (–)-bitungolide F, fostriecin, and neopeltolide.

ORGN 543

Study of dynamic kinetic resolution in the synthesis of chiral β-substituted [3.3.0]-bicyclic lactams

Phillip A Campos, Joe D Ferraro, [email protected], Paul T Buonora. Chemistry and Biochemistry, California State University - Long Beach, Long Beach, California 90840, United States

5,5- and 5,6-Bicyclic lactams can form through the cyclocondensation of 1,2- aminoalcohols and 1,3- or 1,4-dicarbonyls. Dynamic Kinectic Resolution (DKR) allows one to control the reaction diastereoselectivity. As part of our continuing studies, we have investigated the influence of substituent size on the dicarbonyl as a mitigating factor in the synthesis of 5,5-bicyclic lactams. The substituent beta to the lactam influences the diastereoselectivity, although to a lessor extent than the aminoalcohol.

ORGN 544

Chiral aryl iodides as catalysts for stereoselective oxidative dearomatization reactions

Kelly A. Volp, [email protected], Alison M. Thorsness, Andrew M. Harned. Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, United States

Oxidative dearomatization reactions have proven to be a general entry into the cyclohexadienone framework. Hypervalent iodine reagents have proven to be quite general oxidants for these reactions. However, enantioselective variants have been slow to develop. While recent examples have emerged, the demonstrated scope has been limited to nucleophile additions at the ortho position of the phenolic starting material. For the first time, we have found that the use of chiral aryl iodide catalysts can be extended to reactions that take place para to the phenol. Using these catalysts we can perform stereoselective hydroxylations, spirocyclizations, and C–C bond forming reactions. Our early work on catalyst development and recent results will be presented.

ORGN 545

Synthesis of chiral sulfonamides and their evaluation as catalysts in aldol reaction

Haydee Rojas Cabrera, [email protected], Gabriela Huelgas Saavedra, Cecilia Anaya de Parrodi.Departamento de Ciencias Químico-Biológicas, Universidad de las Américas Puebla, Cholula, Puebla 72820, Mexico

New organocatalysts bearing both sulfonamide and prolinamide moieties were design to promote the asymmetric aldol reaction between acetone and varied aldehydes. Reaction of acetone with 4-nitrobenzaldehyde was used for screening different reaction conditions suitable for our organocatalysts. The desired aldol product was obtained in 82-98% yield and 68-88% ee of (S) configuration in reaction times from 1 to 4 hours. ORGN 546

Organoaluminum and zwitterionic effect on stereoselectivity in tropanes

Juliet Hahn, [email protected]. Department of Chemistry, New Mexico Tech, Socorro, NM 87801, United States

Tropanes are a class of natural products with neurobiological effects and are potential pharmaceuticals for diseases like Alzheimer's and Parkinson's. Organoaluminum catalysis and a zwitterionic effect on stereoselectivity in tropanes will be discussed

ORGN 547

Novel synthesis of darunavir and atazanavir

Joseph M.D. Fortunak, Joseph Williams Jr., [email protected]. Department of Chemistry, Howard University, Washington, DC 20059, United States

Darunavir and Atazanavir are two Protease Inhibitors important for the treatment of symptomatic HIV/AIDS. The critical synthetic motif of each is the establishment of two adjacent chiral centers with control of relative and absolute stereochemistry. Small organic ligands are increasingly being used as catalysts to provide such synthetic control via the aldol, Henry, and related reactions. We will report on novel chemistry to achieve new, less expensive syntheses of these molecules with a consequent potential impact on increasing access to these drugs in Less-Developed Countries.

ORGN 548

Esterification of fatty acids catalyzed by BrØnsted acidic ionic liquids

Hector Palencia1, [email protected], Fang-Xia Yang2, Nolan W Broekemier1, Milford A Hanna2, Stephanie Sotelo-Canales1. (1) Department of Chemistry, University of Nebraska at Kearney, Kearney, NE 68849, United States (2) Industrial Agricultural Products Center, University of Nebraska at Lincoln, Lincoln, NE 68583-0730, United States

The esterification and transesterification are important reactions in organic synthesis. Lately they have attracted the interest of researchers because their role in the synthesis of biofuels. BrØnsted acidic ionic liquids catalyze several reactions and they have been used in esterification/transesterification reactions. We had synthesized and new BrØnsted acidic ionic liquids and screen them as catalyst for esterification of fatty acids with methanol. The esterification is catalyzed with 3 mol% of the catalyst with good yields in 2 h. One of the catalyst can be reused up to 3 times, with a drop in the yield of 6% after the second cycle.

ORGN 549

Dual control of selectivity in the synthesis of donor-acceptor cyclopropanes via the addition of oxygen and nitrogen based nucleophiles to in situ generated cyclopropenes

Pavel G Ryabchuk, [email protected], Jonathon P Matheny, Ivan A Babkov, Andrew S Edwards, Jack Xu, Marina Rubina, Michael Rubin. Department of Chemistry, University of Kansas, Lawrence, KS 66045-4401, United States

A highly diastereoselective protocol for the synthesis of stereodefined densely substituted donor-acceptor cyclopropanes from tetrasubstituted 1- bromocyclopropylcarboxamides (1) will be described.

Existing stereogenic center at C-2 of the bromocyclopropane sets two other stereocenters on the cyclopropane ring via the sterically controlled addition of nucleophile across the double bond of in situ generated cyclopropene (2), followed by thermodynamically driven epimerization of the resulting enolate intermediate (3). Scope and limitations of this methodology will be discussed in detail and the mechanistic implicationswill be provided.

ORGN 550

Pd0-catalyzed formal 1,3-diaza-Claisen rearrangement Yanbo Yang, [email protected], José Madalengoitia. Department of Chemistry, University of Vermont, Burlington, Vermont 05405, United States

Our previous work has shown that isocyanates react with azanorbornenes and azabicyclo[2.2.2]octanes under thermal condition to afford zwitterionic intermediates that undergo a thermal 1,3-diaza-Claisen rearrangement to give both ureas and isoureas. However, some azanorbornenes and azabicyclooctanes failed to rearrange or proceeded in low yields. To address these challenging substrates for the thermal 1,3- diaza-Claisen rearrangement, we have developed a Pd0-catalyed formal 1,3-diaza- Claisen rearrangement. Interestingly, under Pd0-catalyzed condition, both isocyanates with electron-withdrawing groups and isocyanates without electron-withdrawing groups react with azanorbornenes and azabicyclo[2.2.2]octanes to provide ureas as the only products in high yields. More importantly, the reactions that failed under thermal conditions were all successful under Pd0-catalysis. In addition to azanorbornenes and azabicyclo[2.2.2]octanes, other ring systems were also investigated. Pd0 catalysis has broadened the scope of tertiary allylic amines that react with isocyanates to afford 1,3- diaza-Claisen rearrangement products.

ORGN 551

Michael additions of β-nitrostyrenes to 1,2-cyclohexanedione

Chad Simpkins, [email protected], David A. Hunt. Chemistry, The College of New Jersey, Ewing, NJ 08628-0718, United States

While the synthetic utility of 1,3-cyclohexanediones has been thoroughly studied, comparatively little is known regarding the 1,2-cyclohexanedione system. Recent reports have shown that bicyclic adducts 5a and 5b result upon the reaction of 1,2- cyclohexanedione with β-nitrosyrenes in the presence of catalytic chiral bases. We have found that the use of stoichiometric achiral bases afford the adducts 3 and 4 . Based on this preliminary work, we are investigating the potential of this reaction to serve as a source of precursors for the preparation of a variety of fused ring heterocyclic systems.

ORGN 552 Novel preparation of dibenzo-fused seven-membered ring heterocyclic ketones

John Farrokh, [email protected], David A. Hunt. Chemistry, The College of New Jersey, Ewing, NJ 08628-0718, United States

Dibenzo-fused 7-membered heterocyclic ketones have been shown to possess central nervous system (CNS) pharmacological activity. Current methods for synthesizing these compounds involve highly acidic or extreme reaction conditions. These reaction conditions prohibit the integration of particular functional groups. The goal of this work is to develop a new method of preparing these compounds which would enable the preparation of these compounds under milder conditions and permit acid-labile functional group substitutions on the aromatic rings.

ORGN 553

Reactions of functionalized aryllithium reagents with N-substituted isatoic anhydrides

Sarah Thornton, [email protected], David A. Hunt. Chemistry, The College of New Jersey, Ewing, NJ 08628-0718, United States

Novel synthetic routes for o-aminobenzophenones are useful since these compounds are precursors to biologically active 1,4-benzodiazepines. Organometallic reagents such as organolithiums and Grignard reagents are known to react with N-methylisatoic anhydride. The current study extends this research to explore the reactivity of N- substituted isatoic anhydride derivatives with similar functionalized aryllithium reagents. This method offers an efficient way to synthesize a variety of highly substituted o- aminobenzophenones.

ORGN 554 Novel green pathway toward the combinatorial library synthesis of benzoxazole derivatives: Utilizing anodic coupling reaction

Chinghao Pan, [email protected], Yachen Shih, [email protected], Chenyi Ke, [email protected], Yung-tzung Huang, [email protected]. Department of Applied Chemistry, National University of Kaohsiung, Kaohsiung, Taiwan, R.O.C. 81148, Taiwan Republic of China

The N,O-heterocyclic benzoxazole rings are wildly found in many natural products, synthetic pharmaceutical drugs, fluorescence materials and etc. Among the reported data, most methods use a variety of toxic chemical reagents to synthesize such ring. Instead, we report a green pathway toward the synthesis of the benzoxazole derivatives, which utilizes electrochemical method and avoids the usage of those toxic chemicals. Through intramolecular anodic coupling and combinatorial library synthesis,

a series of benzoxazole derivatives were synthesized efficiently. Detail information and mechanisms studies will be discussed.

ORGN 555

Montmorillonite K10 clay-catalyzed synthesis of silicon-tethered molecules

Matthew R. Dintzner, [email protected], Nathan D. Brown, Kara Brasovan, Matthew M. Zuziak. Chemistry, DePaul University, Chicago, Illinois 60614, United States

An environmentally friendly, Montmorillonite K10 clay-catalyzed syntheis of silicon- tethered organic molecules is presented.

ORGN 556

In situ anionic shielding for regioselective metalation: Directed peri-metalation and iterative functionalization routes to polysubstituted 7-azaindoles

Anton A Toutov, [email protected], Cedric Schneider, Emilie David, Victor Snieckus. Department of Chemistry, Queen's University at Kingston, Kingston, Ontario K0H 1X0, Canada

We wish to report on a) the unusual peri(C-4)metalation reactivity of N-unprotected 7- azaindole 3-DMG (1 in below scheme) dianion frameworks using a new anionic shielding C-2 protection concept (2 ) and its generalization for the synthesis of 4 substituted derivatives, b) the use of the thereby derived powerful C-4 CONEt2 DMG for further DoM leading via Suzuki cross-coupling and directed remote metalation (DreM) chemistries, to new annulated heterocyclic systems and c) the use of a ring-walk metalation platform for the regioselective construction of polysubstituted 7-azaindoles (3 ). The reported results constitute, to the best of our knowledge, the first observation of peri-metalation of CONEt2 and SO2NEt2 DMG system.

1. J. J. Song, J. T. Reeves, F. Gallou, Z. Tan, N. K. Yee, C. H. Sennayake, Chem. Soc. Rev. 2007, 36, 1120 2. T. Fukuda, H. Akashima, M. Iwao, Tetrahedron 2005, 61, 6889 3. M. Iwao, Heterocycles 1993, 36, 29

ORGN 557

Pyridine as an organocatalyst for the reductive ozonolysis of alkenes

Rachel A Willand-Charnley, [email protected], Thomas J Fisher, Bradley Johnson, Patrick H Dussault. Department of Chemistry, University of Nebraska at Lincoln, Lincoln, Nebraska 68588, United States

Ozonolysis of alkenes under traditional conditions generates peroxide intermediates that must be decomposed in a separate step in order to obtain the carbonyl product(s). However, ozonolysis in the presence of stoichiometric pyridine results in the direct formation of the carbonyl product(s), without generation of the peroxide byproducts and without consumption of pyridine. The reaction is postulated to involve the decomposition of carbonyl oxides via the pyridine-promoted conversion to a previously unobserved class of intermediates that fragment to release the carbonyl product and regenerate pyridine.

ORGN 558

Metal nitrite: A powerful oxidizing reagent

Mahiuddin Baidya, [email protected], Hisashi Yamamoto. Department of Chemistry, The University of Chicago, Chicago, IL 60637, United States

A safe, readily available source of nitroso reagents based on the combination of a Lewis acid and a metal nitrite (Lewis base) was developed. This nitroso source was applied to the α- and/or α,α'-oxidation of carbonyl compounds under very mild conditions. For α,α- disubstituted ketones, the resultant α-nitroso compounds undergoes smooth C-C bond cleavage when treated with O- and N-nucleophiles to generate polyfunctional amides. This methodology was used for the rapid synthesis of amino acid and peptide derivatives.

ORGN 559

Iron-catalyzed efficient synthesis of amides from aldehydes and amine hydrochloride salts

Subhash Chandra Ghosh, [email protected], Joyce Shi Yun Ngiam, Anqi Chen.Organic Chemistry, Institute of Chemical and Engineering Sciences, A*STAR, Singapore, Singapore

A practical, cost-effective and environmentally benign method for the synthesis of amides has been developed by iron-catalysed oxidative amidation of aldehydes with amine hydrochloride salts. A wide range of aldehydes and amine hydrochloride salts have been coupled to afford the corresponding amides in good to excellent yields under mild conditions.

The application of this novel amide formation reaction has been successfully demonstrated in an efficient synthesis of antiarrhythmic drug N-acetyl procainamide.

ORGN 560 One-pot three-step conjugate addition-oxidation-Diels–Alder reactions of ethyl propiolate

Ana M Neferu, [email protected], Christina Vivelo, Smaranda Craciun, C. Wade Downey. Department of Chemistry, University of Richmond, Richmond, VA 23173, United States

Through an efficient one-pot reaction sequence, ethyl propiolate can be transformed into a complex, usefully functionalized bicyclic product. Trialkylamine-catalyzed thioconjugate addition is followed by in situ oxidation to the sulfone and Li-catalyzed Diels–Alder cycloaddition to provide useful product yields. No purification is necessary until after the final step in the sequence.

ORGN 561

Domino cascade ring annulation via intramolecular Michael cyclization

Dorine Belmessieri, [email protected] of Chemistry, University of St Andrews, St Andrews, Fife KY169ST, United Kingdom

We describe a highly diastereo and enantioselective asymmetric carbocycle forming protocol via organocatalytic generation of ammonium enolates directly from carboxylic acids. This transformation allows the synthesis of syn polycyclic lactones in high enantioselectivity (up to 99% ee) and diastereoselectivity (up to 99 : 1 dr) using Lewis base organocatalysts. A one pot synthesis of enantioenriched complex molecules from readily available starting materials will also be discussed.

ORGN 562

Hofmann rearrangement of carboxamides using catalytic hypervalent iodine with oxone as terminal oxidant

Akira Yoshimura, [email protected], Kyle R Middleton, Matthew W Luedtke, Viktor V Zhdankin. Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN 55812, United States

Many reactions of hypervalent iodine reagents have been used in organic chemistry and new reactions and new methodology have been recently found with these reagents. Hofmann rearrangement was also performed with hypervalent iodine and some procedures were created for that reaction. However, hypervalent iodine compounds are expensive reagents and more than one equimolecular PhI is produced as waste after the reaction. To solve that problem, recyclable hypervalent iodines were prepared and those were used in Hofmann rearrangement. Very recently, our group reported on Hofmann rearrangement using hypervalent iodine species generated in situ from PhI and Oxone, but we could not find catalytic condition. Herein, we disclose a catalytic Hofmann rearrangement with Oxone as terminal oxidant. Even though amounts of PhI were only 20 mol% in reaction condition, rearrangements of various amides (21 examples) efficiently proceeded and we obtained carbamates in good yields (70-98 %).

ORGN 563 Allylic oxidation of steroids with pyridinium chlorochromate (PCC) and pyridinium dichromate (PDC)

Edward J Parish1, Yu-Chen Lo2, [email protected], Hiroshi Honda3. (1) Department of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849, United States (2) Department of Biomedical Engineering, University of California, Los Angeles, Los Angeles, CA 90095, United States (3) Department of Bioengineering, Northwestern Polytechnic University, Fremont, CA 94539, United States

Pyridinium chlorochromate (PCC), in refluxing benzene, or dimethyl sulfoxide, and pyridinium dichromate (PDC) in pyridine have been found to be effective reagents for the allylic oxidation of steroids.

ORGN 564

Synthesis of triazole-based unnatural amino acids via regioselective ring opening of sulfamidates

Nasir Baig R B, [email protected], Rajender S Varma.Sustainable Technology Division, National Risk Management Research Laboratory,, U. S. Environmental Protection Agency, Cincinnati, OhiO 45268, United States

Cyclic sulfamidates, 1 , bearing nitrogen atom as a part of the five-membered ring system are synthetic equivalent of aziridines 2 with certain advantages in terms of ring opening reactions namely, a) They have only one preferred site of attack (C1 ) towards the incoming nucleophiles whereas such reactions in aziridines are dependent on the size of R1 and R2; b) The reactivity of sulfamidates is independent of the nature of N- protecting group used; in contrast, the aziridines are classified as activated and non- activated based on R-group attached to the nitrogen atom. In view of the limited applications of sulfamidates in organic synthesis and in our quest for development of greener methodology, herein we describe a simple and high yielding protocol for the synthesis of chiral triazole-based unnatural amino acids using sulfamidates. This one- pot multi-component reaction proceeds via regioselective ring opening of sulfamidate with NaN3 followed by Cu-azide-alkyne cycloaddition reaction

ORGN 565 Steroidal allylic oxidation with chromium (VI) reagents in the presence of pyrazole

Edward J Parish1, Wan-Yuan Huang2, [email protected], Hiroshi Honda2. (1) Department of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849, United States (2) Department of Bioengineering, Northwestern Polytechnic University, Fremont, CA 94539, United States

The allylic oxidation of cholesteryl benzoate chosen as a model had previously been studied and our results were compared with those used with the acetate derivatives. Pyrazole when complexed with chromium trioxide, arguments the allylic oxidation of cholesteryl benzoate.

ORGN 566

Novel, efficient and greener protocol for the syntheses of hydantoin, thiohydantoin and iminohydantoin from common precursor

Vinod Kumar, [email protected]. Chemistry and Biochemistry, The University of Texas at Austin, Austin, Texas 78712, United StatesProcess Technology Development Division, Defence Research and Development Establishment, Gwalior, MP 474002, India

We have developed a novel strategy from simple and readily available substrates for the synthesis of N-1 substituted hydantoin, thiohydantoin and iminohydantoin under solvent-free reaction conditions. The products were obtained in quantitative yields with high purity. Syntheses of wide varieties of hydantoin, thiohydantoin and iminohydantoin bearing primary, secondary, tertiary cyclic and aryl groups were successfully achieved, and product isolation was very straightforward. Convenient syntheses of bicyclohydantoins and bis-hydantoins are one of the most striking features of this reaction. Our approach may be useful to chemists seeking novel synthetic fragments with unique properties for medicinal chemistry programs.

ORGN 567 Alumina as a support and catalyst for the synthesis of benzothiazoles in solvent- free condition

Shaw-Tao Lin, [email protected]. Department of Chemistry, Providence Univeristy, Taichung, Taiwan 43301, Taiwan Republic of China

Arylbenzothiazole (4 ) and benzothiazolylcoumarins (5 ) were prepared by the condensation of 2-aminothiophenol (1 ) and hydroxybenzaldehydes (2 ) and 3- ethoxycarbonylcoumarinnin (3 ), respectively, in solvent-free condition. Of the solid support used, γ-Al2O3 demonstrated the best activity. In general, good yields (>80% yield) were obtained for the formation of 4 . Conversely, yields of 5 were poor, because of γ-Al2O3 catalytic decomposition of 3 to form 2 (without P2O5) and coumarin (with P2O5).

ORGN 568

Chemical synthesis of ketones from organoboranes using pyridinium chlorochromate

Edward J Parish1, Hiroshi Honda2, [email protected], Jiann-Tsyh Lin3. (1) Department of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849, United States (2) Department of Bioengineering, Northwestern Polytechnic University, Fremont, CA 94539, United States (3) Department of Crop Improvement & Utilization Research, Agricultural Research Services, USDA, Albany, CA 94710, United States

Oxidation of organoboranes with chromic acid is standard methodology for the synthesis of ketones. This paper presents that pyridinium chlorochromate in refluxing methylene chloride is able to accomplish the direct oxidation of organoboranes to ketones under mild reaction conditions.

ORGN 569

Rapid and convenient synthesis of phenanthridine derivatives

Anna M Linsenmeier1,2, [email protected], Craig M Williams2, Stefan Braese1. (1) Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), Karlsruhe, Baden-Württemberg 76131, Germany (2) School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia

Phenanthridine cores play an important role in a large number of natural products. The diversity of these molecules is huge and far reaching from almost completely unsubstituted phenanthridine cores to more complex structures. We herein report an improved photochemical method for producing the prolifically bioactive phenanthridine system. A wide variety of derivatives were obtained in two steps in yields ranging from 31-95%.

[i] Linsenmeier, A. M.; Williams, C. M.; Bräse, S. J. Org. Chem. 2011 , Article Asap (DOI: 10.1021/jo201542x).

ORGN 570

Selectivity in palladium catalyzed transformations of enones: The oxidative-Heck reaction and conjugate addition of Iodoarenes

Aditya L Gottumukkala1, [email protected], Adriaan J Minnaard1, Johannes G de Vries1,2. (1) Department of BioOrganic Chemistry, Stratingh Institute for Chemistry, University of Groningen, Groningen, Groningen 9747AG, The Netherlands (2) DSM Innovative Synthesis BV, Geleen, The Netherlands

Heck reactions performed on enones usually result in a mixture, of the expected Heck product and the reduced Heck product (formally, the conjugate addition product). This results from two possible pathways a σ –alkyl Pd complex can follow upon migratory insertion into an alkene, namely β-hydride elimination and reductive cleavage (Scheme1).

In this poster communication, two cases are presented in which the reaction conditions are modified effectivily to afford either the Heck product or the conjugate addition product selectively.

In the first section, a discussion about Pd(OAc)2-BIAN (Bisaryl- acenapthaquinonediimine) is presented. Pd(OAc)2-BIAN was found to be an excellent catalyst for the base-free oxidative Heck reaction, in which molecular oxygen is the sole oxidant,. The system was found to be selective for the formation of the expected Heck product, while phenol and biphenyl were detected only in trace quantities (Scheme2).

In the second section, selectivity between conjugate addition and the Mizoroki-Heck reaction is discussed, in the addition of iodoarenes. Herein, a novel catalyst system is presented, which by mere choice of the base, affords the conjugate addition or the Mizoroki-Heck product selecitively. Only 1.5 mol% of a commerically available Pd- carbene is required for this procedure, and the system has been shown to be applicable for a variety of linear and cyclic enones. Further, these reactions can be performed conveniently under microwave irradiation, without loss of yields or selectivity.

ORGN 571

Nickel(0)-catalyzed cyclization of N-benzoylaminals for isoindolinone synthesis

Mary P. Watson, [email protected], Danielle M. Shacklady-McAtee, Srimoyee Dasgupta. Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, United States

We have discovered a novel nickel(0)-catalyzed cyclization of N-benzoylaminals to form 3-substituted isoindolinones. This method relies on the use of catalytic nickel(0) and stoichiometric Lewis acid to obtain the desired isoindolinone products. This reaction likely proceeds via an α-amidoalkylnickel(II) intermediate, which then may cyclize via either an electrophilic aromatic substitution or an insertion pathway. This method enables benzoyl chloride, primary amine and aldehyde to be transformed to the isoindolinone core in an efficient two-step procedure.

ORGN 572

Polymer functionalization via acylnitroso ene reactions

Nicolas J. Treat, [email protected], Brett P. Fors, Javier Read de Alaniz, Craig J. Hawker.Materials Research Laboratory, Department of Materials, Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, California 93106, United States

This presentation will disclose the development and applications of a method for the functionalization of polymers via acylnitroso ene reactions. Two approaches to polymer functionalization using this chemistry were taken. First, polymers containing alkenes were reacted with in situ generated acylnitroso compounds. Second, polymers containing protected acylnitroso groups were appended with various alkenes. These two systems allowed for the efficient and general functionalization of a variety of polymeric systems.

ORGN 573

Kinetic studies on the NHC-catalysed benzoin and Stetter reactions

Christopher J Collett1, [email protected], Richard S Massey2, [email protected], Andrew D Smith1, AnnMarie C O'Donoghue2. (1) School of Chemistry, University of St Andrews, St Andrews, Fife KY16 8XH, United Kingdom (2) Department of Chemistry, University of Durham, Durham, United Kingdom

Using NMR spectroscopy and HPLC a comprehensive study has been undertaken on the NHC (N-heterocyclic carbene)-catalysed benzoin and Stetter reactions in order to monitor the build up and consumption of reactants, intermediates and products present over time. This data allows the calculation of rate constants for the individual reaction steps for a series of NHC precursors.

ORGN 574

Development of a new photocleavable protecting group toolbox

Pengfei Wang, [email protected]. Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States

We have recently developed a series of robust photocleavable protecting groups (PPGs) for protection of carbonyl and hydroxyl groups. These new PPGs share advantageous features, including structural simplicity, ease of preparation, high installation and removal efficiencies, and remarkable chemical stabilities. In particular, their unique structural features led to neutral protecting protocols and for the first time both protection and deprotection reactions can be conducted under neutral conditions without using any other chemical reagents. For carbonyl protection, we have achieved selective removal of different carbonyl PPGs by control of irradiation wavelength. We have also demonstrated that deprotection of both carbonyl and hydroxyl PPGs can be successfully carried out with irradiation of sunlight without requirement of photochemical devices. Most recent advance expands the scope of the new PPGs to applications in aqueous environments. The new PPG toolbox provides unique opportunities for a wide spectrum of applications in different fields.

ORGN 575

Microwave-assisted method for the synthesis of assymetrical fluoroazobenzenes

Cristina Fonseca, [email protected], Elisa Leyva, Edgar Moctezuma. Centro de Investigación y Estudios de Posgrado, Universidad Autónoma de San Luis Potosí, San Luis Potosí, San Luis Potosí 78210, Mexico

A microwave-assisted method for the synthesis of assymetrical fluoroazobenzenes is described. The method is environmentally friendly since it does not require the use of organic solvents. It is faster and gives better yields than other procedures reported. It has proven to be versatile to obtain different mono- and di- substituted fluoroazobenzenes that are not obtainable by other methods, such as photochemical synthesis. Fluoroazobenzenes have applications in non-linear optics, have been used as dyes, and are intermediates in the preparation of hydroxyfluoroazobenzenes, which have been evaluated as inhibitors of steroid biosynthesis.

ORGN 576

Diastereocontrol of intramolecular aldol condensation of 1,2,6-triketoesters, synthesis of highly functionalized cyclopentanones

Phong M Truong, [email protected], Michael P Doyle. Department of Chemistry and Biochemistry, University of Maryland at College Park, College Park, MD 20740, United States

Control of diastereoselectivity is essential for the efficient synthesis of complex molecules and continues to be a challenging task in organic synthesis. We were able to access to 1,2,6-triketoesters via oxidation of functionalized α-diazo-β-ketoacetates, formed by zinc triflate catalyzed Mukaiyama-Michael addition. This system undergoes intramolecular aldol reactions to afford highly functionalized α-hydroxycyclopentanone- carboxylates having two chiral centers. Diastereoselectivity in product formation is controlled by using either Lewis acids for the formation of the anti-isomer or Bronsted acids for the formation of the syn-isomer.

ORGN 577

General epoxide-based methodology for the synthesis of the hemiacetal rings in the plecomacrolide family

Elizabeth M. Valentín, [email protected], Jorge A. Vargas, José A. Prieto. Department of Chemistry, University of Puerto Rico, Río Piedras Campus, San Juan, PR 00931-3346, Puerto Rico

The plecomacrolildes are unusual macrocyclic secondary metabolites that are produced by different Streptomyces species and have received considerable medicinal, as well as synthetic interest. Key examples include the bafilomycins, formamicinone, and elaiolide. Our laboratory has focused on a reiterative methodology for the synthesis of polypropionates based on epoxide chemistry that has shown success in the assembly of several fragments, including the C14–C25 bafilomycin A1 polypropionate chain. This approach was extended to the syntheses of the C12–C16 and C20–C24 fragments of elaiolide and formamicinone, respectively. These transformations include regioselective cleavage of trans-epoxides with alkynyl aluminum reagents and diastereoselective epoxidation of homoallylic alcohols. An Ireland-Claisen rearrangement generates a γ,δ- unsaturated acid that, upon iodolactonization/methanolysis, yields the required syn-anti configuration for both fragments. These variations have enabled a general methodology for the synthesis of the polypropionate chain included in the plecomacrolide family. Supported by NIH-RISE (1R25-GM-61151-01A1) and NIH-SCORE (2S06GM-08102- 29).

ORGN 578

Pericyclic rearrangements of tethered allene azides

Oleksandr Zhurakovskyi, [email protected], Jeremy Robertson. Department of Chemistry, University of Oxford, Oxford, United Kingdom

Allenes are attracting growing attention in organic synthesis due to their ability to participate in a wide variety of reactions, particularly those initiated by cycloaddition or electrophilic activation. We report the intramolecular reactions of allenes tethered to an azide group by two- and three-carbon linking chains. We show that these compounds undergo substantially different transformations depending on both the substrate structure and the reaction conditions (thermal – both batch and flow – and microwave) and that these reactions can be 'tuned' towards specific outcomes. In some cases, the obtained products represent novel heterocyclic systems that were not previously synthetically accessible.

ORGN 579

Synthesis of novel 4H-pyrido[1,2-a]pyrimidines via a one-pot three-component reaction

Jinbao Xiang, [email protected], Kai Yang, Qun Dang, Xu Bai, [email protected] Center for Combinatorial Chemistry and Drug Discovery, The School of Pharmaceutical Sciences and The College of Chemistry, Jilin University, Changchun, Jilin 130021, China

Multicomponent reations (MCRs) have emerged as a powerful tool in the creation of molecular complexity and diversity from simple substrates.1 We have extended our previously reported one-pot three-component condensation reaction2 to the preparation of a series of highly substituted 4H-pyrido[1,2-a]pyrimidines by use of 2-aminopyridines, aldehydes and ketones. The details of this study will be discussed.

Reference:

(1) (a) Dömling, A. Chem. Rev. 2006 , 106, 17–89. (b) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996 , 29, 123–131. (c) Touré, B. B.; Hall, D. G. Chem. Rev. 2009 , 109, 4439–4486.

(2) Xiang, J.; Li, H.; Yang, K.; Yi, L.; Dang, Q.; Bai, X. Mol. Divers. revision.

ORGN 580

Pd-catalyzed cyanation of non-activated alkynes

Shigeru Arai, [email protected], Yuka Koike, Tomohiro Igarashi, Xiaofei Yang, Atsushi Nishida.Pharmaceutical Sciences, Chiba University, Chiba, Chiba 260-8675, Japan A new protocol for nucleophilc cyanation to non-activated simple alkynes is described. Cyano grroup is a versatile functionality so that its introduction has been major challenge in synthetic organic chemistry. CN anion basically attack electron deficient multiple bonds however our protocol enables to use simple CC triple bonds under Pd catalysis with TMSCN & O2. Furhter application to use reaction intermediate (organopalladium species) established the new protocol for dicyanative 5-exo-, and 6- endo cyclizations and [4+2] cycloaddition. Stereochemistry for all the products were critically controlled and multicyclic carbocyclic system could be easly constructed.

ORGN 581

Chirality transfer in oxindole synthesis: A novel pericyclic cascade

Edward Richmond1, [email protected], Andrew D Smith1, Kenneth B Ling1, Kendall N Houk2, Yu-hong Lam2, Nihan Çelebi-Ölçüm2. (1) Department of Chemistry, University of St Andrews, St Andrews, Fife KY16 9ST, United Kingdom (2) Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, United States

Pericyclic cascade reactions are of increasing value in organic synthesis due to their potential for expedient generation of molecular complexity, often with predictable and exquisite stereocontrol. An efficient, enantioselective route to 3,3-disubstituted oxindoles from chiral nitrones (1 ) and disubstituted ketenes (2 ) will be discussed, along with computational work which has elucidated a plausible pericyclic cascade featuring chirality transfer between the constituent steps which rationalizes the observed enantioselectivity.

ORGN 582

Synthesis of tetrasubstituted alkenes via palladium-catalyzed domino- carbopalladation/C-H-activation

Tim Hungerland, [email protected], Lutz F. Tietze. Department of Organic and Biomolecular Chemistry, Faculty of Chemistry, Georg-August University Goettingen, Goettingen, Germany

The concept of domino reactions represents an innovative and beneficial tool towards the synthesis of complex organic molecules. Moreover, C-H bond functionalizations bear a high potential in comparison to traditional cross-coupling reactions. We have combined the two aspects in the synthesis of overcrowded alkenes which have gotten great attention due to their photophysical properties, for instance as molecular switches or light driven motors.

Tetrasubstituted alkenes of type 1 (n = 1, X = O/CH2) were obtained from 2 in excellent yields using a Pd-catalyzed domino process consisting of a carbopalladation and a C-H activation. To investigate the influence of substituents on the C-H-activation, substrates 2 with R either H, F or CF3 have been employed in the reaction; moreover, also electron- withdrawing and -donating groups R1 in 2 were introduced. Furthermore, the process also allows the synthesis of tetrasubstituted alkenes 1 with a five- or seven-membered ring as B .

ORGN 583

Mechanistic investigations of a silylation based kinetic resolution of secondary alcohols

Ravish K Akhani, [email protected], Sheryl L Wiskur. Department of Chemistry & Biochemistry, University of South Carolina, Columbia, South Carolina 29208, United States

A silylation based kinetic resolution of monofunctional secondary alcohols has been developed by the Wiskur group. This methodology has achieved a high level of selectivity using triphenylsilyl chloride as the silicon source. For further expansion, a deeper understanding of the mechanism will provide detailed insight into our methodology. We will discuss our efforts towards this through the use of linear free energy relationships revolving around the silicon protecting group. The effects of electronics and sterics at silicon will be elucidated.

ORGN 584

Synthesis of α-substituted chalcones, malononitriles, and cinnamates

Paul R Leger, [email protected], Stephen R Sieck. Department of Chemistry, Grinnell College, Grinnell, Iowa 50112, United States

A fast and efficient methodology utilizing microwave irradiation for the promotion of a Knoevenagel condensation reaction is described. The one-pot synthesis of α-cyano chalcones from various benzoylacetonitriles and aromatic aldehydes has been studied extensively and has afforded high yielding solids after facile purification. This methodology has been successfully extended to the synthesis of benzylidenemalononitriles as well as methyl and ethyl α-cyano cinnamates. Further extension of this methodology towards α-nitro and α-bromo substituted chalcones will be discussed.

ORGN 585

Hydrocarboxylation of styrenes via transition metal-free CO2 carboxylation

Robert D Grigg, [email protected], Jared W. Rigoli, Samuel Neale, Jennifer M Schomaker. Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, United States

Carbon dioxide's low cost and renewability makes it an attractive C1 feedstock for construction of complex molecules. However, the activation of CO2 is challenging due to its thermodynamic stability. Recently, transition metal catalysis has emerged as a major strategy towards CO2 carboxylations at aryl and alkenyl positions. However, few reports have described these transformations at sp3-type positions. We report a transition metal-free CO2 carboxylation that displays excellent regioselectivity and surprising functional group tolerance. Alkyl carboxylic acid derivatives can be readily accessed from styrenes through a facile tandem process that eliminates the use of harsh, reactive organometallic reagents. The methodology allows for the rapid installation of CO2 at a chiral center. The scope of this hydrocarboxylation methodology has been explored, in addition to transformations that utilize electrophiles besides CO2.

ORGN 586

Synthesis of 1,3-diamino-2-ols via allene oxidation

Cale D Weatherly, [email protected], Jared W Rigoli, Jennifer M Schomaker. Department of Chemistry, University of Wisconsin - Madison, Madison, WI 53703, United States A one-pot, diastereoselective synthesis of 1,3-diaminoketones from allenic carbamates has been developed. This synthesis proceeds through novel 1,3-diazaspiro-[2.2]- pentanes previously reported by our lab, followed by aziridine ring opening with carboxylic acids and Bi(OTf)3-catalyzed rearrangement to 1,3-diaminoketones in high yield. These structures subsequently undergo diastereoselective reduction with Na(OAc)3BH to the corresponding 1,3-diamino-2-ols, allowing the formation of three vicinal carbon-heteroatom stereocenters in two pots. The deployment of this methodology in the total synthesis of manzacidin B is currently underway.

ORGN 587

Epoxide approach towards the synthesis of Dolabriferol

Keyla F Morales, [email protected], Raúl R Rodríguez, Jose A Prieto. Department of Chemistry, University of Puerto Rico-Rio Piedras, San Juan, Puerto Rico 00931, Puerto Rico

Dolabriferol is a polypropionate natural product isolated from a Dolabrifera mollusk, which possesses remarkable biological and pharmacological activity. Its structure consists of two related polypropionate subunits linked by an ester functionality. A polypropionate chain consists of an array of alternating methyl and hydroxy groups on an aliphatic chain with a particular configuration. In our laboratory, we have developed a reiterative epoxide-based methodology for the construction of polypropionates. Our approach consists of three steps: a regioselective epoxide cleavage with an alkynyl aluminum reagent, reduction of the alkyne, and the stereoselective epoxidation of the resulting alkene. Applying this, we have engaged in a divergent synthesis of dolabriferol in which the same precursor is used for the elaboration of the two polypropionates fragments. Using this approach, we have been able to synthesize the polypropionate fragments containing the C1-C5 and C8-C12 segments of dolabriferol with the correct configuration. Work supported by NIH SCORE 2S06GM-08102-29.

ORGN 588

Kinetic resolution of N-acylaziridines

Jennifer A Cockrell, [email protected], Christopher A Wilhelmsen, Heather N Rubin, Allen D Martin, Jeremy B Morgan. Department of Chemistry and Biochemistry, University of North Carolina Wilmington, Wilmington, North Carolina 28403, United States

Aziridines are of significant importance as intermediates for the synthesis of nitrogen- containing molecules. We will present a boron-catalyzed kinetic resolution that produces enantioenriched terminal aziridines. Synthetically useful enantiomeric excess values of > 99%and s-values ranging from 32-236 are observed with a range of substrates. The chiral modifier can be cleaved from the byproduct and isolated in excellent yield. The utility of the resolved aziridines is demonstrated through several stereoselective transformations to provide access to functionalized small molecules.

ORGN 589

1,3-Dibromo-5,5-dimethylhydantoin and TBD: A sustainable approach to the Hofmann Rearrangement

Caitlyn Wonski1, [email protected], Isabel Larraza2, [email protected]. (1) Department of Chemistry and Physics, Saint Mary's College, Notre Dame, IN 46556, United States (2) Department of Chemistry, North Park University, Chicago, IL 60625, United States

A green protocol for the microwave-assisted Hofmann Rearrangement of primary amides mediated by DBDMH and TBD in methanol is described. Under these conditions the methyl carbamates from a wide variety of aliphatic and aromatic amides were obtained in high yields, short reaction times, and excellent purity. This new protocol constitutes a convenient alternative to the traditional method that uses NBS/DBU.

ORGN 590

Selenium dioxide-mediated oxidative amidation of arylglyoxals to synthesize α- ketoamides and their use in the production of quinoxalinones and diazepinones

Arthur Y. Shaw, [email protected], Christopher Hulme. Department of Pharmacology and Toxicology, University of Arizona, Oro Valley, AZ 85737, United States

A facile and expeditious synthetic approach to prepare α-ketoamides, quinoxalinones and diazepinones is described. A series of α-ketoamides synthesized from selenium dioxide-mediated oxidative amidation of arylglyoxals and secondary amines under microwave irradiation were obtained in moderate to good yields. Moreover, as an application of the oxidative amidation, we will present its use in a sequential process of oxidative amidation/Boc deprotection/cyclization to prepare quinoxalinones and diazepinones. This method provides an efficient strategy for preparing pharmacologically relevant chemotypes to facilitate drug discovery.

ORGN 591 Ugi/Robinson-Gabriel reactions directed synthesis of 2, 4, 5-trisubstituted oxazoles

Arthur Y Shaw, Breland Smith, [email protected], Christopher Hulme. Department of Pharmacology and Toxicology, University of Arizona, Oro Valley, AZ 85737, United States

Isocyanide Multi-component reactions (MCRs) are a powerful transformation in which three or more starting materials are incorporated in a one-pot manner to produce a highly functionalized product. This poster reveals concise, operationally friendly, unique chemical methodology to afford collections of oxazoles in a mere two synthetic operations utilizing the Robinson-Gabriel reaction to form the final oxazole from an appropriately functionalized Ugi product. It is expected the novel two step one pot procedure will be widely embraced in lead generation groups.

ORGN 592

Concise one-pot preparation of bis-pyrrolidinone tetrazoles

Steven Gunawan1, [email protected], Joachim Petit2, Nathalie Meurice2, Christopher Hulme1. (1) Department of Pharmacology and Toxicology, University of Arizona, Oro Valley, AZ 85737, United States (2) CADD Laboratory, TGen, Phoenix, AZ 85004, United States

A one-pot, two-step synthesis of bis-pyrrolidinone tetrazoles ('pyrrotets') has been established via the TMSN3-modified Ugi reaction using methyl levulinate, primary amines, isocyanides and azidotrimethylsilane with subsequent acid treatment to catalyze γ-lactam formation. The efficiency offered by this protocol allowed the procedure to advance to 96-well plate production in a proficient manner where an assembly of an 84 member array of 'pyrrotets' was successfully accomplished using an assortment of 24 primary amine inputs and 4 isocyanide inputs. Virtual libraries for the 'pyrrotets' were compared with a collection of over 400,000 chemically diverse small molecules in the National Institutes of Health (NIH) molecular libraries small molecule repository (MLSMR) and principle component analysis exhibited the unique spatial occupancy of the 'pyrrotets' scaffold with no substructure match in the MLSMR and minor overlap in similarity space with its 942 nearest neighbors of the MLSMR.

ORGN 593

Practical and scalable synthesis of α-fluorobis(phenylsulfonyl)methane as a versatile nucleophilic monofluoromethylating reagent

G. K. Surya Prakash, Nan Shao, [email protected], Fang Wang, Chuanfa Ni.Loker Hydrocarbon Research Institute, Department of Chemistry, University of Southern California, Los Angeles, California 90089, United States α-Fluorobis(phenylsulfonyl)methane (FBSM) has been developed as a useful monofluoromethylating reagent in recent years. Conventional synthetic approaches toward FBSM, such as the electrophilic fluorination of bis(phenylsulfonyl)methide anion using Selectfluor®, significantly suffer from unsatisfactory chemoselectivity. Column chromatographic technique is thus inevitable and impedes large-scale preparation (usually <5 g scale). To address this synthetic challenge, our laboratory has developed a practical and scalable synthetic protocol utilizing readily available starting materials. The novel preparative method can be feasibly performed on up to 100 g scales to afford the product in almost quantitative yield. In particular, efficiently purified by simple extraction and crystallization technique, the product can be obtained in high purity without chromatography.

ORGN 594

Facile synthesis of α-monofluoromethyl alcohols: Nucleophilic monofluoromethylation of aldehydes using TMSCF(SO2Ph)2

G. K. Surya Prakash, Zhe Zhang, [email protected], Nan Shao, Chuanfa Ni, Fang Wang, Ralf Haiges, George A Olah.Loker Hydrocarbon Research Institute, Department of Chemistry, University of Southern California, Los Angeles, California 90089, United States

A feasible synthetic protocol toward β-monofluorinated alcohols has been achieved using α-trimethylsilyl-α-fluorobis(phenylsulfonyl)methane [TMSCF(SO2Ph)2, TFBSM] as a novel monofluoromethylating reagent. Initiated by a catalytic amount of fluoride, the reagent can be readily added to a variety of aldehydes providing the desired products in high yields. Computational and experimental mechanistic studies have revealed the exceptional lability of the Si-C bond in TFBSM compared with other fluoromethylsilane counterparts.

ORGN 595

Selective preparation of difluoromethyl aromatics via Mg(0)-mediated C-F activation of aromatic trifluoromethyl compounds

G. K. Surya Prakash, Socrates Munoz, [email protected], Nan Shao, Chuanfa Ni, Donald R Bellew, Fang Wang, Thomas Mathew, George A Olah.Loker Hydrocarbon Research Institute, Department of Chemistry, University of Southern California, Los Angeles, California 90089, United States

Various synthetic protocols have been developed recently for the preparation of trifluoromethylated arenes. In contrast, CF2H-containing aromatic compounds are almost exclusively achieved through deoxofluorinations of aromatic aldehydes. As a continuation of our synthetic efforts in organofluorine chemistry, a facile preparative method has been explored towards difluoromethylated aromatics from readily available trifluoromethyl arenes. Mediated by Mg(0) under mild conditions, a series of bis(trifluoromethyl)aromatics can be selectively converted into the corresponding difluoromethyl products by the present protocol in practical yields.

ORGN 596

Silver-catalyzed tandem heterocyclization/alkynylation of 1-((2- tosylamino)aryl)but-2-yne-1,4-diols to 2-alkynyl indoles

Srinivasa Reddy Mothe, [email protected], Prasath Kothandaraman, Philip Wai Hong Chan. Department of Chemistry and Biological Chemistry, Nanyang Technological University, Singapore, Singapore A highly efficient and versatile approach to 2-alkynyl indoles via silver-catalyzed 1-(2- tosylamino)aryl)but-2-yne-1,4-diols is reported herein.1 The novel and non-coupling intramolecular AgOTf-catalyzed reaction offers synthetic route to these diverse heterocycle building blocks in moderate to excellent yields (45-94 %) under mild conditions that does not require metal-catalyzed cross-coupling approach.

ORGN 597

Application of Cl3CCONH2/PPh3 towards the glycosylation of glycosyl hamiacetals

Pawarun Chitchirachan, Wanchai Pluempanupat, [email protected]. Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Kasetsart University, Bangkok, Thailand

Reaction of glycosyl chlorides, generated in situ from glycosyl hamiacetals using trichloroacetamide and triphenylphosphine, and acceptor alcohols could be proceeded in the presence of zinc(II) bromide to furnish the desired glycosides in high yields.

ORGN 598

In-catalyzed isomerization of donor-acceptor-acceptor cyclopropenes

Lien H Phun, [email protected], Stefan France, Joel Aponte-Guzman. School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30318, United States

A common structural motif that bridges medicinal chemistry, organic materials, and even ligands in metal catalysts are substituted biheteroaryls. Given the versatility of these compounds, we employ donor-acceptor-acceptor (D-A-A) cyclopropenes as a synthetic equivalent in the formation of the benzannulated skeleton. Herein, we wish to report an In-catalyzed isomerization of D-A-A cyclopropenes for the formation of highly substituted benzo-fused heteroaromatic compounds.

ORGN 599 Montnmorillonite K10 clay-catalyzed, microwave-assisted synthesis of 4- aryltetrahydropyrans and 4-aryltetrahydrofurans

Matthew R. Dintzner, [email protected], Neal P. Herink, Daniel E. Portillo, Maqsood Khan. Chemistry, DePaul University, Chicago, IL 60614, United States

The Montmorillonite K10 clay-catalyzed, microwave-assisted synthesis of 4- aryltetrahydropyrans and 4-aryltetrahydrofurans is presented as a one-pot, multicomponent, environmentally friendly Prins-Friedel-Crafts-type reaction.

ORGN 600

Chemoselective transfer of allyl or phenyl group from allyl(phenyl)germanes in Pd-catalyzed reactions with aryl halides

Yong Liang, [email protected], Jean-Philippe Pitteloud, Stanislaw F Wnuk. Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, United States

Reaction of allyl(phenyl)germanes 1 with aryl halides (Pd/NaOH/H2O/dioxane) resulted in Heck-type transfer of the allyl group providing allylated aryls 2 (32-88%) in addition to (α-methyl)styryl isomers (4-12%). Conversely, reaction of 1 with SbF5 in toluene yielded (phenyl)germanyl fluorides. Subsequent treatment with TBAF generates hypervalent fluoro(phenyl)germanates that undergo Stille-like coupling with ArX in toluene to provide 3 (43-82%). The SbF5/TBAF combination allowed transfer of two or three phenyl groups from germanes 1 . The yield of 3 increased when couplings were performed with addition of a measured amount of water (~10-30 equiv).

ORGN 601

Bromination at C-5 of pyrimidine and C-8 of purine nucleosides with 1,3-dibromo- 5, 5-dimethylhydantoin

Ramanjaneyulu Rayala, [email protected], Stanislaw F Wnuk. Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, United States

Halogen-substituted nucleosides have been utilized as intermediates for a variety of synthetic transformations. We now present a general procedure for bromination at C-5 of pyrimidine and C-8 of purine nucleosides with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH). Treatment of uridine, cytidine, adenosine or guanosine with DBDMH in DMF at ambient temperature (0.5 – 24 h) and crystallization of the crude reaction mixtures gave the corresponding 5- or 8-bromo substituted nucleosides (40-76%). Treatment of the protected nucleosides including 2'-deoxyuridine and 1-(β,D-arabinofuranosyl)uracil with DBDMH in CH2Cl2 (1.5 - 24 h) at ambient temperature also produced C-5 or C-8 brominated nucleosides (51-95%) with purity >90% after only aqueous work-up. Combination of DBDMH with Lewis acids (e.g. TMSOTf, TsOH) resulted in better yields and shorter reaction times. Bromination with DBDMH is compatible with typical protection groups use in nucleoside chemistry (acyl, silyl, isopropylidene). Effects of temperature, time, solvent and acid catalysts on the bromination reaction will be discussed.

ORGN 602

Flexible synthesis of C-X/C-N/C-Y stereotriads from allenes

Christopher S Adams, [email protected], Luke A Boralsky, Jennifer M Schomaker. Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, United States

The transformation of simple allene carbamates and sulfamates to diverse stereotriads of the form C-X/C-N/C-Y is described (X,Y = OR, SR, NR2, halogen). The key step involves an intramolecular aziridination to form an unusual strained bicyclic methylene aziridine. Further diastereoselective functionalization of this reactive intermediate can be carried out with a range of nucleophiles and electrophiles to yield three new heteroatom-bearing chiral centers with excellent chemo- and regioselectivity, as well as high diastereoselectivity in many cases. This process can be carried out in one pot to generate three adjacent stereocenters from the three carbons of the allene. Furthermore, single enantiomers of product can be obtained through the use of an enantioenriched allene substrate. This method holds great promise for constructing three or more adjacent, defined stereocenters in a single step.

ORGN 603

Transition-metal-free direct arylation of arenes

Thanh V Truong, [email protected], Olafs Daugulis. Department of Chemistry, University of Houston, HOUSTON, TX 77004, United States

An efficient method for base-promoted direct C-arylation of arenes has been developed. Under basic conditions, a variety of arenes can be arylated by aryl chlorides. Yields are comparable to methods that employ transition metals. The reactions are carried out at mild temperatures and proposed to proceed via aryne intermediates.

ORGN 604 Oxidative addition of heteroaromatic halides to the Negishi reagent: Novel heteroaromatic zirconium reagents and their application in organic synthesis

Caleb F Harris, [email protected], Shouquan Huo. Department of Chemistry, East Carolina University, Greenville, North Carolina 27858, United States

We have recently discovered that the oxidative addition of heteroaromatic halides such as 2-chloroquinoline and 1-chloroisoquinoline to zirconocene equivalent “Cp2ZrBu2” (Negishi reagent) produce cleanly the corresponding heteroaromatic zirconium reagents. This novel reagent can participate in the palladium catalyzed cross-coupling reactions with functionalized aromatic halides and other coupling partners. For example, in the presence of 1 equivalent of copper (I) chloride and 5% of Pd(PPh3)4, the cross coupling of 2-quinolinylzirconocene with ethyl 3-bromobenzoate produced ethyl 3-(2- quinolinyl)benzoate in 91% isolated yield. The organometallic reagents derived from heteroaromatics are very much underdeveloped because of their instability, particularly because the heteroaromatics themselves are prone to nucleophilic attack by organometallic reagents. Heteroaromatic compounds are important building blocks for constructing natural products, medicinally or biologically important molecules, and ligands for coordination complexes. The use of novel heteroaromatic zirconium reagents represents an efficient and user-friendly method for introducing the heteroaromatic motif to functionalized molecules.

ORGN 605

PAMAM G0 and G1 dendrimer cyclization by DMAD and 2- benzylidenemalononitrile

Hooshang Vahedi, [email protected], Abdolhossien Massoudi, Sara Hoseini. Department of Chemistry, Payame Noor University, Tehran, Tehran, Iran (Islamic Republic of)

The reaction of PAMAM (G0 or G1) with DMAD and 2-benzylidenemalononitrile was carried out and the cyclized products were obtained in high yields, without using special procedure for purification.

ORGN 606

Continued studies on the development of a novel synthesis of aziridines

Justin T Worthing, [email protected], Lynn M Bradley. Department of Chemistry, The College of New Jersey, Ewing, NJ 08628-0718, United States

Preliminary work has demonstrated dimerization for a series of aziridines (1) to symmetrical, substituted benzyl piperazines (2). The addition of benzyl bromide to 2- bromoethylamine hydrobromide in triethylamine led to initial formation of the desired aziridine. This, over time, dimerized to form benzyl piperazines; the presence of both compounds has been confirmed via GC/MS. Continuing efforts include altering variables within the reaction with the intent of preventing the dimerization and isolating the aziridine intermediate as the final product.

ORGN 607

Synthesis of aromatic silyl ketones and studies of their cyclization reactions

Katrina Wunderlich, [email protected], Lynn M Bradley. Department of Chemistry, The College of New Jersey, Ewing, NJ 08628-0718, United States

The ongoing goal of this research is to analyze the mechanism for the reactions of silyl ketones to form cyclic compounds. The nature of the starting silyl ketone determines the stability of the resulting carbanion intermediate, which in turn influences whether the compound undergoes a Brook Rearrangement or a simple ring closure to provide a cyclic ether. This research presents a new method of creating a series of benzoyl silanes that will be used to further study these cyclizations.

ORGN 608

Synthesis of 4,5-dihydropyrrolo[1,2-a]quinoxaline and pyrrolo[1,2-a]quinoxaline derivatives

Metin Zora1, [email protected], Arif Kivrak1,2. (1) Department of Chemistry, Middle East Technical University, Ankara, Turkey (2) Department of Chemistry, Yüzüncü Yıl University, Van, Turkey

4,5-Dihydropyrrolo[1,2-a]quinoxalines and pyrrolo[1,2-a]quinoxalines have gained considerable interest in recent years owing to their wide variety of biological and pharmacological properties, including antiallergic, antiparacitic, antibacterial, antimalarial, antiulcer, antituberculosis and anticancer activities. Lewis acid catalyzed cyclizations have recently emerged as valuable tool in organic synthesis due to their high efficiency for new carbon-carbon and carbon-heteroatom bond formation. We have found that depending on the conditions, InCl3-catalyzed reactions of 1-(2- aminophenyl)pyrrole (1 ) with aldehydes and ketones 2 afford 4,5-dihydropyrrolo[1,2- a]quinoxalines 3 and pyrrolo[1,2-a]quinoxalines 4 in good to excellent yields. These reactions have also been utilized in the synthesis of complex heterocyclic systems by employing functionally substituted aldehydes and ketones. The scope, limitations and mechanism of these reactions will be discussed.

ORGN 609

Insertion of an alkene into an ester: An intramolecular oxyacylation reaction of alkenes directed by phenoxy group

Giang T Hoang, [email protected], Christopher J Douglas. Department of Chemistry, University of Minnesota, Twin Cities, Minneapolis, MN 55455, United States

Recently, we reported a novel strategy of synthesizing β-alkoxy ketones from reaction between an alkene and an ester. In this atom economic reaction, one C–C and one C– O bonds are formed in one single operation, emphasizing the potential utility of the method. In the initial example, quinoline was employed as a directing group for activation of the ester group. Herein, we report our recent development in expanding the scope of this reaction. In particular, a phenoxy group in salicylate esters has been shown to be an efficient directing group for intramolecular oxyacylation reaction.

ORGN 610 Depsipeptidic anticancer natural products and analogs via improved latent thioester mediated solid-phase methodology

Wade S. Perkins, [email protected], Xiaoyu (Janice) Zang, [email protected], Leila Peraro, [email protected], Heli K. Shah, Nicole M. Zanghi, Justin S. Miller, [email protected]. Department of Chemistry, Hobart and William Smith Colleges, Geneva, NY 14456, United States

Improved methods are described for accessing cyclic, cysteine-containing, depsipeptidic HDAC inhibitor natural products and their analogs via solid-phase synthesis. The solid-phase tactics described here have been used to generate protected, linear, depsipeptidic precursors suitable for chemoselective macrocyclization. The central development involves new organic reaction conditions for exploiting the latent thioester solid-phase linker that is crucial for the endgame macrocyclization. The target depsipeptides belong to a class of HDAC inhibitors, and are thus intended as potential treatments for cancer and other ailments implicating HDAC. Due to the variety of analogs available through this methodology, the synthetic targets will also be used to evaluate factors affecting HDAC inhibitory activity.

ORGN 611

Phase transfer activation of catalysts for olefin metathesis

Zhenxing Xi1,2, [email protected], John Gladysz1, Hassan Bazzi2. (1) Department of Chemistry, Texas A&M University, College Station, College Station, Texas 77840, United States (2) Department of Chemistry, Texas A&M University at Qatar, Doha, Qatar, Qatar

During the processes that employ metal based catalysts, a ligand must often dissociate to allow access of the substate to the active site. The reverse process, in which the dissociated ligand rebinds to the metal center, can slow the overal rate. Phase transfer activation is a new method for catalyst activation based on two orthogonal phases: one phase is used to scavenge the dissociated ligand, while the other provides the locus for catalytic cycle. When applied to ruthenium based olefin metathesis, a faster reaction rate will be expected. A series of analogs of Grubbs' second generation catalyst with hydrophilic phosphines are synthesized, and those with Cy2PCH2CH2N(CH3)3Cl give a much faster ring closing metathesis under dichloromethane/aqueous or dichloromethane/aqueous HCl biphasic as opposed to dichloromethane monophasic conditions. This is attributed to rapid phase transfer of the dissociated ligand to aqueous phase, where it is protonated under acidic conditions.

ORGN 612

Palladium-catalyzed regiospecific reactions of N-acylbenzotriazoles with epoxides

Mirna El Khatib, [email protected], Mohamed Elagawany, Eka Todadze, Levan Khelashvili. Department of Chemistry, University of Florida, Gainesville, Florida 32611- 7200, United States

Halohydrin esters are important intermediates for the synthesis of a wide range of biologically active natural and synthetic products. The growing interest in such intermediates is associated with their importance in organic synthesis.

The reaction of N-acylbenzotriazoles with substituted epoxides, in the presence of catalyst, gave pseudohalohydrin esters, instead of the expected 1,4-benzoxazines. This new synthetic route proved to be an improved protocol for the regiospecific synthesis of pseudohalohydrin esters under solvent-free conditions.

ORGN 613

Regioselective synthesis of pyrazolo-1,2,4-triazoles

Davit Jishkariani, [email protected], Charles Dennis Hall. Chemistry, University of Florida, Gainesville, Florida 32611, United States

Growing attention directed to the synthesis of pyrazoloazines and pyrazoloazoles is associated with their industrial applications as hair and photographic dyes and other photosensitive materials.

The current route is designed to study the one-pot Cu(I)-catalyzed synthesis of pyrazolo-1,2,4-triazoles and similar heterocyclic systems. The desired pyrazolo-1,2,4- triazoles were generated by the reaction of triazolium salts with aromatic terminal alkynes in the presence of catalyst.

The results in terms of experimental conditions, substrate scope study and the regiochemistry of the reaction will be discussed.

ORGN 614

Ligand-accelerated catalysis in Pd(II)-mediated C–H functionalization Keary M Engle, [email protected], Dong-Hui Wang, Peter S. Thuy-Boun, Jin-Quan Yu. Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, United States

A lingering problem in the area of Pd(II)-catalyzed C–H functionalization is the dearth of suitable ligands to lower the activation energy for C–H cleavage. In our studies of aerobic Pd(II)-catalyzed C–H olefination reactions of phenylacetic acids, we have discovered dramatic rate increases when mono-N-protected amino acids are used as ligands. In light of these findings, systematic ligand tuning was undertaken, which has resulted in major improvements in substrate scope, reaction rate, and catalyst turnover. We present evidence from intermolecular competition studies and kinetic isotope effect experiments that implies that the observed rate increases are a result of acceleration in the C–H cleavage step. Furthermore, these studies suggest that the origin of this phenomenon is a change in the mechanism of C–H cleavage from electrophilic palladation to concerted metallation/deprotonation. Recent work has also demonstrated that amino acids ligands can enable efficient C–H functionalization with other substrates, including phenethyl alcohols and can accelerate other categorically distinct C–H functionalization reactions, including C–H/R–BX2 cross-coupling.

ORGN 615

Extending the scope of acylnitroso methodology

David Sandoval, [email protected], Javier Read de Alaniz. Chemistry and Biochemistry, University of California, Santa Barbara, Santa Barbara, CA 93106, United States

Reaction conditions developed in our group for a novel acynitroso ene reaction, have facilitated the extension of acynitroso methodology. This practical and operationally simple process utilizes a readily available metal catalyst, reagent grade solvent, and an environmentally benign oxidant, to afford a mild oxidation of hydroxamic acids and their subsequent trapping in the Diels-Alder, ene, and other reaction platforms. This presentation will discuss the development of this chemistry and highlight the unprecedented reactivity being explored in our lab.

ORGN 616

Controlled and chemoselective reductions of secondary and tertiary amides: Versatile applications of Hantzsch ester hydride and Et3SiH as reducing agents

Guillaume Pelletier, [email protected], William S. Bechara, Guillaume Barbe, André B. Charette. Chemistry, Universite de Montreal, Montreal, Quebec H3C 3J7, Canada

Finding mild, chemoselective, and general conditions for the reduction of amides is of great importance for pharmaceutical chemistry, as this could serve as a template for the direct formation of compounds possessing basic nitrogens. To address this problematic, the activation of secondary and tertiary amides to a more reactive intermediate can be performed with triflic anhydride, which was shown to react with weak hydride donors to result in a controlled reduction with high efficiency and chemoselectivity.

ORGN 617

In situ formation of N-trifluoroacetoxy succinimide (TFA-NHS): One-pot formation of N-maleoyl amino acid succinimidyl esters for the improved synthesis of a heterobifunctional linker

Nicholas M Leonard, [email protected], Jarmila Brunckova. Abbott Laboratories, Abbott Park, IL 60064, United States

A method for the in situ formation of N-trifluoroacetoxy succinimide (TFA-NHS) and its application in the formation of succinimidyl esters is presented. The developed method provides N-maleoyl amino acid succinimidyl esters from a variety of amino acids using a one-pot, high yielding protocol. Investigations supported the proposal of a revised reaction mechanism and the optimization of the reaction conditions. The refined process contributed to the improved synthesis of a heterobifunctional linker used in diagnostic immunoassays.

ORGN 618

Novel annulation strategies for the construction of polycylic scaffolds Dadasaheb V Patil, [email protected], Marchello A Cavitt, Paul Grzybowski, Stefan France. School of Chemistry & Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, United States

Highly substituted carbocyclic and heterocyclic molecules and their analogues are pharameceutically significant scaffolds, widely present in naturally occuring and synthetic biologically active molecules. Although classical synthetic approaches to such compounds have generally relied on linear substitution strategies, recently, convergent annulation methods have emerged as a powerful alternative strategy for the efficient construction of highly substituted cyclic compounds, particularly those with modified core and different substitution patterns. Herein, Lewis acid-catalyzed, highly efficient intramolecular cyclization strategies for the synthesis of functionalized polycycles are reported. The products were obtained in good to high yields(up to 99%). The scope of reactions will be discussed and a preliminary investigation of the reaction mechanism and stereochemical outcome of the cycliation will also be presented.

ORGN 619

Improved efficiency of flash chromatography through direct fluorometric monitoring

Megan Rushing1, [email protected], Christina Konecki2, Ashley De Lio2, Clifton J. Stepehsnon1, [email protected]. (1) Department of Chemistry, Loyola University New Orleans, New Orleans, LA 70118, United States (2) Department of Chemistry, Carthage College, Kenosha, WI 53140, United States

Flash chromatography has had wide utility in organic synthesis. Yet, despite its wide use flash chromatography can be problematic due to the large amounts of material and time required. In situ visual monitoring of flash chromatography would reduce the time and material needed to run a column, thus, making flash chromatography greener and more efficient. Herein, we will address the synthesis, testing, and optimization of an off/on fluorescent polymer that can serve as a silica gel doping agent. This xanthene dye based polymer becomes colored and fluorescent under basic conditions, and when this polymer is added to the stationary phase of a flash chromatography column, basic compounds can be monitored as they elute. The ability to directly monitor basic compounds on a flash chromatography column will afford a flash chromatography system that will save time and money.

ORGN 620

One-step in situ formation of trimethyl(trichloromethyl)silane: Application to the synthesis of a variety 2,2,2-trichloromethylcarbinols

Ricardo Lira1, [email protected], Kevin E. Henegar2. (1) Department of Neuroscience, Pfizer, Groton, Ct 06340, United States (2) Chemistry Research and Development, Pfizer, Groton, Ct 06340, United States 2,2,2-Trichloromethylcarbinols are useful synthetic intermediates with many applications in organic chemistry. Trichloromethylcarbinols are usually prepared from the corresponding aldehydes and ketones under a variety of conditions including TASF /F-, CHCl3/base, Cl3CCO2H, and Cl3C-TMS (trimethyl(trichloromethyl)silane) in the presence of a wide range of catalysts. Of the above protocols, CCl3-TMS remains the most attractive trichloromethyl source due to its mild reaction conditions. Here in we describe an improved, one-step in-situ formation of Cl3C-TMS and its application with a variety of aldehydes and ketones to the corresponding trichloromethylcarbinols.

ORGN 621

Calcium catalyzed cycloisomerization

Tobias Haven, [email protected], Meike Niggemann. Department of Organic Chemistry, RWTH Aachen, Aachen, NRW 52074, Germany

In the past decades, catalysts have been developed almost exclusively on the basis of transition metals. Nowadays, it is increasingly significant to create more sustainable alternatives, wherever it is possible. Calcium, among other alkaline earth metals, seems to be an ideal metal catalyst. It is essentially free of toxicity and the fifth most frequent element in the earth crust. Surprisingly, its catalytic potential remains hitherto almost unexplored. Our research focuses on the development of calcium catalyzed reactions.

We were the first to successfully apply calcium salts as highly efficient Lewis acidic catalysts in organic synthesis. In ongoing studies we now demonstrated the potential of our new calcium catalyst in cycloisomerization reactions. The first results in this research field traditionally dominated by transition metal catalysts are presented.

ORGN 622

Tin-free radical reactions under minimal solvent conditions for the synthesis of substituted chromones and coumarins

Jake Zimmerman, Madhuri Manpadi, Russell Spatney, [email protected]. Department of Chemistry and Biochemistry, Ohio Northern University, Ada, OH 45810, United States

Radical methodologies without the use of alkyltin reagents are increasingly important due to toxicity and difficulty in removing tin by-products from reaction mixtures. This poster highlights an alkyltin-free radical method developed using minimal solvent conditions. This free radical addition process allows for the preparation of a variety of substrates including substituted chromones and coumarins. The method is high yielding, conducted at ambient temperature, and in nearly all instances, classical purification techniques such as chromatography are not needed. It is also shown that the reactions are scalable, giving excellent yields and purities on up to one-gram scales.

ORGN 623

Stereoselective Reformatsky reaction using indium metal: Green chemical routes to oxindole natural products

Megan J Weyer, [email protected], Narayanaganesh Balasubramanian, Gregory R Cook. Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 58105-6050, United States

Over the past two decades, oxindole based alkaloids have become increasingly appealing targets for total synthesis. 3,3-Substituted oxindole systems are found at the core of numerous natural products, which posses significant medicinal value. Due to the presence of the quaternary center, they are interesting targets for total synthesis. The construction of these core motifs could be achieved using indium mediated Reformatsky reaction. The potential application of this methodology in making novel beta amino acids will also be discussed.

ORGN 624

Synthesis of L-1',2'-cis nucleoside analogs from acyclic N,OTMS-acetals

Starr Dostie1,2, [email protected], Michel Prevost1, Yvan Guindon1,2. (1) Bio- organic Chemistry Laboratory, Institut de Recherches Cliniques de Montreal, Montreal, Quebec H2W 1R7, Canada (2) Department of Chemistry, McGill University, Montreal, Quebec H3A 2K6, Canada

Effective treatments against cancer and viral infections involve the administration of "modified" nucleosides (nucleoside analogues; NA), which are a class of structurally well defined molecules that can act as antimetabolites. Despite the importance of the 1',2'-cis relative conformation of these NAs, their synthesis is still problematic. This project aims at developing a new generation of L-1',2'-cis NA using a novel approach for their synthesis from chiral acyclic N,OTMS-acetals. These acyclic acetals are formed from a diastereoselective nucleobase addition onto an acyclic polyalkoxyaldehyde derived from natural D-xylose. The acetals are cyclized through a C1'-C4' intramolecular SN2-like cyclization with inversion of configuration at the C4' stereocentre while conserving the C1' stereochemistry. Preliminary results suggest that this methodology has much potential in nucleoside synthesis.

ORGN 625

Highly enantioselective synthesis of 1,2,3-substituted cyclopropanes using α- iodozinc and α-chlorozinc carbenoids

Louis-Philippe B. Beaulieu, [email protected], Lucie E. Zimmer, André B. Charette. Department of Chemistry, Université de Montréal, Montreal, QC H3C 3J7, Canada

We investigated the enantioselective Simmons-Smith cyclopropanation using substituted zinc carbenoids and a dioxaborolane-derived chiral ligand to gain access to 1,2,3-trisubstituted cyclopropanes in enantioenriched form. The stereoselective iodocyclopropanation of allylic alcohols was achieved using iodoform as the carbenoid precursor and the resulting cyclopropanes were functionalized into a variety of 1,2,3- trisubstituted cyclopropanes. The homologous stereoselective chlorocyclopropanation reaction was carried out using chlorodiiodomethane as the zinc carbenoid precursor.

ORGN 626

Tandem semi-hydrogenation and isomerization of propargyl alcohols to unsaturated carbonyl analogs catalyzed by palladium nanoparticles

Young-Seok Shon, [email protected], Jordan A Koeppen, Diego Gavia, Elham Sadeghmoghaddam. Department of Chemistry and Biochemistry, California State University, Long Beach, Long Beach, CA 90840, United States This study shows that dodecanethiolate-capped Pd nanoparticles can catalyze the conversion of propargyl alcohols to their corresponding carbonyl analogues in the presence of hydrogen gas. The stable and soluble Pd nanoparticle catalysts are prepared using sodium S-dodecylthiolsulfate as a precursor to their stabilizing ligands. The transformation involves two steps, semi-hydrogenation of alkynes and subsequent isomerization of pi-bond. The reaction conditions such as temperature, amount of hydrogen gas, and the size and composition of Pd nanoparticles are controlled for the optimization. The catalytic reactions of several propargyl alcohols including 2-propyn-1- ol, 3-butyn-2-ol, 2-butyn-1-ol, and 3-phenyl-2-propyn-1-ol are studied for understanding the effects of substituent groups. Overall the reaction produces the corresponding carbonyl compounds in good yields showing high selectivity over complete hydrogenation of alkyne functional groups. More understanding towards the catalytic activity and selectivity of alkanethiolate-capped Pd nanoparticle catalysts will increase the future applications of these new semi-heterogeneous catalysts in organic synthesis.

ORGN 627

Non-resonant microwave applicator for continuous flow chemistry

Per Öhrngren1, Ashkan Fardost1, [email protected], Francesco Russo1, Jon-Sverre Schanche2, Magnus Fagrell2, Mats Larhed1. (1) Department of Organic Pharmaceutical Chemistry, Uppsala University, Uppsala, Sweden (2) WaveCraft AB, Uppsala, Sweden

Extremely rapid method development in small scale and direct scale-out without scale- up translation has been performed with a unique system utilizing a non-resonant microwave heating applicator purpose-built for continuous flow chemistry that heats an entire reactor vessel without pronounced hot and cold spots (Figure). The technology is demonstrated with classic organic reactions including heterocycle synthesis, widely used palladiumcatalyzed organic transformations, as well as the synthesis of a bioactive M. tuberculosis proteasome inhibitor.

ORGN 628

Ionic addition of thiols to alkynes

Catherine M Kingry, [email protected], David Son. Department of Chemistry, Southern Methodist University, Dallas, TX 75275, United States

This work examines the ionic addition of thiols to an array of acetylene compounds. The additions of simple thiols to mono- and disubstituted acetylene compounds are controlled by several factors, including ratios of thiol to acetylene, type of catalyst used, temperature, time of reaction, and type of solvent used. The goal of this work is the application of ionic thiol-alkyne addition for the synthesis of dendrimers and other functional branched molecules.

ORGN 629

Efficient synthesis of dendridic pre-cursors via the thiol-ene click reaction

Abby R Jennings, [email protected], David Y Son. Department of Chemistry, Southern Methodist University, Dallas, TX 75275, United States

The thiol-ene click reaction was utilized for the synthesis of dendritic molecules that contain latent reactive groups on the exterior of the molecule. The synthesis was designed with the expectation it would be much more efficient than other dendrimer syntheses. A key synthetic step is the ring opening of a cyclic dithiocarbonate to produce a thiol-terminated intermediate. Preliminary studies were performed using the anionic and free-radical thiol-ene click reactions with various cyclic dithiocarbonate and glycidyl derivatives.

ORGN 630

Substituent effects in the aza-Cope rearrangement—Mannich cyclization

Danielle St. Germaine, [email protected], Harriet A Lindsay. Department of Chemistry, Eastern Michigan University, Ypsilanti, MI 48197, United States Recently we have developed a catalytic version of the aza-Cope rearrangement— Mannich cyclization using boron trifluoride as a Lewis acid catalyst. In the course of exploring the scope and limitations of this reaction, we uncovered unexpected differences in reaction rate upon altering the iminium cation substituent. In an effort to more systematically probe the factors influencing the rate and diastereoselectivity of this reaction, we have designed a series of oxazolidines having aryl iminium cation substituents of varying electronic demand. Based on the aza-Cope—Mannich reactions of these substrates, insight into the rate determining step of this tandem reaction sequence will be reported.

ORGN 631

Synthesis of novel formyl-deuterated benzaldehydes via regio-selective deutero- formylation

Sobhana B Boga, [email protected], Abdul B Alhassan, Alan B Cooper. Department of Chemical Research, Merck Research Laboratories, Kenilworth, NJ 07033, United States

The deuterium kinetic isotope effect has long been exploited extensively by physical organic chemists for studying reaction mechanisms and medicinal chemists for studying metabolism of deuterated versions of drugs respectively. Benzaldehydes are important building blocks in synthetic organic chemistry that have wide applications for the synthesis of natural products and pharmaceutical drugs. Herein we report a general synthetic methodology for the synthesis of highly functionalized deuterated benzaldehydes in 100 % isotopic purity via regio-selective deutero-formylation. Regio- selective deprotonation of 1,3- disubstituted benzene 1 with LDA at -78 oC and treatment with d7-DMF led to the synthesis of 2-deutero-1, 3-disubstituted benzaldehydes 2 in moderate to good yields. The synthetic methodology described represents a simple yet versatile route to functionalized formyl-deuterated benzaldehydes.

ORGN 632

Selective hydrolysis of nitriles to amides: Nafion-ruthenium, an efficient catalyst G. K. Surya Prakash, Munoz B. Socrates, Attila Papp, [email protected], Kamil Masood, Thomas Mathew, George A. Olah.Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, CA 90089, United States

Application of environmentally friendly Lewis acid catalysts in organic synthesis has become crucial in satisfying the growing demand for clean synthetic processes. In continuation of our efforts in the area, perfluoroalkaneresinsulfonate of ruthenium (Nafion-Ru) was prepared by simple metal ion exchange procedure and its catalytic activity was explored in the hydrolysis of nitriles. The catalyst was found to be very efficient and selective towards the formation of the corresponding amides in high yields. A series of aromatic and heteroaromatic nitriles was selectively converted into their amides using water as the solvent. The catalyst was found to be reusable for at least six cycles.

ORGN 633

Mild and efficient reduction of amine N-oxides

Hari P Kokatla, [email protected], Paul F Thomson, Suyeal Bae, Mahesh K Lakshman. Department of Chemistry, The City College, City University of New York, New York, NY 10031, United States

Amine N-oxides are frequently encountered in the course of organic synthesis, and N- oxidation of amines also serves as a nitrogen protecting group. Commonly, after completion of requisite chemical transformations, reduction of the N-oxide is necessary. Although a number of N-O bond reductions are known, few are simple. We describe a simple, mild, and environmentally benign method for N-oxide reduction. Examples range from the N-oxides of alkyl amines, pyridines, and quinolines, to more complex systems such as nicotine and a nucleoside.

ORGN 634

Simple regiospecific deuteration of 1,2,3-triazoles

Hari K Akula, [email protected], Mahesh K Lakshman. Department of Chemistry, Graduate Center and The City College of New York, CUNY, New York, NY 10016, United States Deuterated compounds are gaining importance as pharmaceuticals. The concept underpinning this is the greater difficulty in cleaving a carbon-deuterium bond than carbon-hydrogen. Metabolic cleavage of C-H bonds in a drug can decrease its efficacy and may lead to undesired side effects. These can be circumvented by replacing H with D. Recent studies show deuterated analogues of several drugs to be superior to their undeuterated versions. We have developed a facile, regioselective deuteration of 1,2,3- triazoles.

ORGN 635

Samarium-mediated elimination/isomerization of allylic benzoates

Connor L Roberts, [email protected], Erasmus O Volz, Gregory W O'Neil. Chemistry, Western Washington University, Bellingham, WA 98225, United States

Allylic benzoyl esters undergo an elimination/isomerization process when treated with samarium diiodide to generate selectively non-conjugated diene products.

ORGN 636

Friedel-Crafts alkylation of arenes with vinyl amides and enamides: Direct synthesis of arylamides

G. K. Surya Prakash, Farzaneh Paknia, [email protected], Thomas Mathew, George A. Olah.Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, CA 90089, United States

Friedel-Crafts alkylation of aromatics with vinyl amides and enamides has been studied in strong acids such as trifluoromethanesulfonic acid. Depending on the nature of amides and pathway of addition, direct synthesis of the corresponding aryl amides has been achieved. The reaction of α,β-unsaturated amides such as acrylamide (1 ) occured through conjugate addition, whereas, the reaction of enamides such as N-vinyl acetamide (2 ) went through Markovnikov-type addition. The observed reactivity of these amides towards arenes can be attributed to protosolvation and the possible formation of dicationic intermediates in the superacidic medium.

ORGN 637

Diastereoselective nucleophilic addition to α-fluoroimines mediated by organosilanes

Roy M. Malamakal, [email protected], Matt Avila, [email protected], Todd A. Davis. Chemistry, Idaho State University, Pocatello, Idaho 83209, United States

The synthesis of fluorine containing organics has been of high interest in recent years, especially in the area of pharmaceutical sciences. It has been seen that the stereoselective introduction of a single fluorine atom can dramatically increase the biological activity of a drug; one such case was seen with the mono-fluorination of the HIV-1 protease inhibitor indinavir, where the introduction of a fluorine atom increased the biological activity of the drug up to 60 times. The presence of fluorine in molecules influences the metabolic stability, lipophilicity, and acidity of its corresponding organic, and also increases its affinity to biological receptors. Although there are many benefits to generate fluorinated organics, methods that generate high stereoselectivity are limited. Current methods involve the use of large, expensive organocatalysts to direct the stereoselectivity of the reaction. Our method proposes to direct the stereochemistry by use of the substrate interaction with organosilanes. This poster will focus on method development for the diastereoselective Strecker addition (TMSCN) to α-fluoroimines as potential precursors for the synthesis of fluorinated amino acids. Yields for the cyano additions ranged from 51-98%; diastereoselective ratios were substrate dependent, and varied between 49:1 syn/anti to 1:12 syn/anti.

ORGN 638

Development of two complementary syntheses for a privileged CGRP receptor antagonist substructure

David K. Leahy1, Lopa V. Desai1, [email protected], Rajendra P. Deshpande1, Antony V. Mariadass2, Sundaramurthy Rangaswamy2, Santhosh K. Rajagopal2, Lakshmi Madhavan2, Shashidhar Illendula2. (1) Chemical Development, Bristol-Myers Squibb Company, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States (2) Biocon Park, Jigni Link Road, Syngene International Ltd., Bangalore, India

1-(Piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one is a widely prevalent substructure found in >1000 CGRP receptor antagonists. Two complimentary and scalable syntheses of 1-(Piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one will be described. One route involves a chemoselective reductive amination of 1,2-diaminopyridine. A strong acid effect is observed in controlling selectivity and output for this reaction. The second route exploits a Pd-catalyzed amination reaction. Overamination is addressed by exploring ammonia surrogates, weak bases and ligand to metal ratios. Both the routes developed will exhibit wide utility in CGRP receptor antagonists synthesis.

ORGN 639

Formation of 1,3-dihydroisobenzofurans by intramolecular cyclization reactions

Alex Sens, [email protected], Hannah Ogden, Hee Jeong Ahn, Seth J. Friese. Department of Chemistry, Salisbury University, Salisbury, MD 21801, United States

An alternate approach for the synthesis of 1,3-dihydroisobenzofurans has been explored by the addition of nucleophiles to an activated α-keto ester (1 ). This addition results in an intramolecular cyclization with the ortho benzyllic bromide, which rapidly yields the desired 1,3-dihydroisobenzofuran substructure 2 in high yields (>95%). We are examining this cyclization reaction to determine its scope and limitation. Specifically, the reactivity with various nucleophiles and the characterization of these cyclization reactions will be presented.

ORGN 640

Development of intramolecular aza-[4+3] cycloaddition reactions and their applications in target-directed synthesis

John A. Eickhoff, [email protected], Arjun Acharya, [email protected], Christopher S. Jeffrey. Chemistry, University of Nevada Reno, Reno, NV 89557, United States Efforts to expand the scope and utility of the aza-[4+3] cycloaddition reaction of aza- allylic cations and dienes have led our group to explore its intramolecular variation. In these examples the alpha-halo amide and diene are tethered together and undergo an efficient cycloaddition reaction under basic conditions to provide polycyclic heterocyclic products. Details of the development, optimization and application in target-directed synthesis will be presented.

ORGN 641

Gold-(I) catalyzed hydrofunctionalization of allenes

Loruhama M Delgado1, [email protected], Kristina Butler2, Ross Widenhoefer2. (1) Department of Chemistry, University of Puerto Rico, San Juan, PR 00931-3346, United States (2) Department of Chemistry, Duke University, Raleigh, Durham, North Carolina, United States

New ways to synthetize allylic ethers are of high interest because of their versatility as substrates, however methods for their synthesis are limited due to the basicity of the alkoxide group. There are also several problems concerning the regio- and enantiomeric selectivity of the products. Our research focuses on the development of new methods to circumvent issues regarding the enantioselectivity of the resulting products. Here we present the Gold-(1) catalyzed hydrofunctionalization of 1-phenyl- 1,2-butadiene.

Our studies showed that, when using an alcohol as a nucleophile, no enantiomeric excess was obtained. It was discovered that this was due to the reversible nature of the reaction. To bypass this problem a cyclic urea and benzyl carbamate were explored as nucleophiles, but these reactions were also impeded due to the added steric hindrance. Although our attempts to develop an enantioselective hydroalkoxylation procedure were unsuccessful, we continue to work toward an understanding of hydrofunctionalization processes.

ORGN 642

Development of diaza-[4+3] cycloaddition reactions and their applications in target-directed synthesis

Devendar Anumandla, [email protected], Carson R Christopher, [email protected], Christopher S Jeffrey. Department of Chemistry, University of Nevada, Reno, Reno, Nevada 89557, United States

We have recently found that N-chloro urea substrates can be used to generate diaza- allylic cations and that these reactive intermediates undergo a diaza-[4+3] cycloaddition reaction with diene reactants and provide 7-membered urea products. Details of the development, optimization, and application in target-directed synthesis will be presented. ORGN 643

Application of microwave methods to the synthesis and alkylation of aldehyde derived enamines

Lizeth Perez, [email protected], Hannah M Pham, Paul T Buonora. Chemistry and Biochemistry, California State University - Long Beach, Long Beach, CA 90840, United States

Stork type enamine reactions have proved to be an efficient means for synthesizing alkylated aldehydes. Challenges in the synthesis include the generation of the requisite enamine, long reaction times and low yields for the alkylations, particularly in the case of low molecular weight aldehydes. As these alkylation reactions are typically run in polar solvent, we have investigated the use of microwave heating to both reduce the reaction time and improve yield. Both stepwise synthesis and isolation of the enamine followed by alkylation with a variety of alkylating agents, and tandem enamine synthesis followed by alkylation have been investigated. The results indicate that with a variety of aldehydes and alkylating agents, shortened reaction times, with yields at least comparable to traditional thermal methods, can be achieved using microwave heating.

ORGN 644

New methods to generate complex peptidomimetics

Kenneth V. Lawson, [email protected], Tristan E. Rose, Patrick G. Harran. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, United States

Modulating protein – protein interactions has significant therapeutic potential. Arguably there is no group of 'small' molecules better suited to target protein interfaces than peptides. However, peptides are known to have poor pharmacological properties. We are developing methods to restrict the conformational mobility of peptides and related heteropolymers while simultaneously altering their properties. Our experiments run as processes, wherein a conserved, lipophilic reagent is activated in stages to form composite products with unprotected polyamides in parallel. Here we describe our newest 'processing' reagents, and methods to directly imbed those molecules into peptide structure, forming novel polycyclic ring systems. The intent is for products to retain molecular recognition elements of the biopolymer, yet display that functionality as part of stable, cyclic structures having defined shapes and enhanced membrane permeability. This project has the potential to create unique small molecule collections from which new biologically active chemotypes can be discovered.

ORGN 645

Dimerization of alkynyl hemi-ketals to form novel spiro-ketals Jaideep Saha, Chris Lorenc, Bikash Surana, Mark W Peczuh, [email protected]. Department of Chemistry, University of Connecticut, Storrs, CT 06269-3060, United States

Efficient synthetic methods that avoid multistep processes have become a prevalent objective to modern organic reaction development. We have discovered a novel isomerization of alkynyl hemi-ketals using phosphine catalysts that yields cyclic enones as its product. The enone products from the new reaction are isomeric to products we had prepared using triethylamine as the isomerization catalyst. Specifically, the enones prepared in the phosphine mediated isomerization contain an exocyclic alkene in contrast to the oxepinones from the triethylamine mediated reaction. The enones from the phosphine isomerization, based on their structure, can undergo subsequent reactions. Most notably, the enones undergo a rapid [4+2] cycloaddition in situ that gives spiro-ketal products in a one-pot process. The tandem isomerization-cycloaddition process allowed access to a diverse collection of spiro-ketals from relatively simple starting materials. The new reaction should find application in the rapid preparation of natural product like molecules.

ORGN 646

Polyisobutylene-supported N-heterocyclic carbenes as recyclable and reusable catalysts

Yun-Chin Yang, [email protected], Yanfei Yang, Christopher E Hobbs, David E Bergbreiter. Department of Chemistry, Texas A&M University, College Station, TX 77842, United States

N-Heterocyclic carbenes (NHC) are useful both as ligands and organocatalysts. A variety of strategies to recycle NHC-ligated catalysts have been developed both by our group and others. However, problems remain in recycling NHCs not complexed to transition metals because of their air and moisture sensitivity. This report will describe work in our group that uses polyisobutylene (PIB) as a phase anchor to recycle NHCs. Two approaches will be discussed. The first emphasizes using PIB-modified aryl groups of N-substituents on the NHCs. The second strategy uses PIB on ancillary groups of known aryl isothiocyanate-NHC adducts whose use as latent NHC catalysts was recently reported. In either case, PIB was used as a heptane-phase selective support to insure hydrocarbon phase selective solubility of the NHC catalysts after a reaction. The activity of PIB-bound NHCs in both cyclization and polymerization reactions will be discussed using phenyl isocyanate trimerization and lactide polymerization as examples.

ORGN 647

Cyclic hydroboration of acyclic dienes: Accessing complex polypropionate subunits Matthew E Calder, [email protected], Kathlyn Parker. Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, United States

Polyketide natural products are desirable targets due to their interesting biological and pharmacological properties. Many polyketides contain synthetically challenging propionate subunits, which are comprised of alternating methyl and hydroxyl stereogenic centers. Stereoselective syntheses of acyclic propionate compounds with remote stereocenters (1<2) via asymmetric induction are rare and remain a difficult endeavor. Cyclic hydroboration has been shown to be an effective method for generating relatively simple acyclic compounds containing remote stereogenic centers in a single step. We look to further expand this methodology to include structurally complex acyclic dienes to achieve polypropionates containing stereotetrad and stereopentad subunits with high stereoselectivity and yields. Preliminary results show good diastereoselectivity on complex model dienes. Optimization and application of this methodology towards the synthesis of polyketide natural products will be discussed.

ORGN 648

Electrofilic organocatalytic alkynylation reaction using hypevalent iodine compounds

Jan Veselý, Martin Kamlar, [email protected]. Department of Organic Chemistry, Charles University, Prague, Czech Republic

Hypervalent iodine compounds attract in the last decade considerable attention in many areas of organic synthesis especially due to plenty reactions that can be performed employing them and their non-toxicity, selectivity and mild reaction conditions.

For example Dess-Martin periodinane (DMP) and 2-iodobenzoic acid (IBX) mediated oxidation of alcohols to aldehydes under mild conditions. Hypervalent iodine compounds can be useful in formation of C-C bond. In the last two year were published several papers using these compounds for alkynylation and arylation.

In context of our previous work of 1-(fluoro(nitro)methylsulfonyl)benzene addition to α,β- unsaturated aldehydes we turned our attention to the enantioselective electrophilic alkynylation of fluorinated derivatives of (phenyl)sulfonyl)methane using hypervalent iodine compounds. This methodology can be used for preparation of interesting building-blocks for pharmaceutical industry etc.

ORGN 649

Catalytic diazidation of olefins

Stepan Chuprakov, [email protected], K. Barry Sharpless, Valery V. Fokin. Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, United States A first catalytic method for diazidation of olefins has been developed. The new protocol avoids superstoichiometric amounts of Mn(III) acetate and provides very general, selective, experimentally simple and scalable route to vicinal diazides. Synthetic utility of the latter has been illustrated through several synthetically useful transformations.

ORGN 650

Preparation of medium sized cyclic 2-alkynones by fragmentation of α-diazo carbonyl compounds

Nikolay P Tsvetkov, [email protected], Ali Bayir, Matthias Brewer. Department of Chemistry, The University of Vermont, Burlington, Vermont 05405, United States

There are few methods available for the preparation of medium sized cyclic 2- alkynones. We have recently discovered that γ-oxy-β-hydroxy-α-diazo carbonyl compounds undergo a fragmentation reaction when exposed to tin tetrachloride. To further expand the scope of this reaction, and to apply it toward the synthesis of medium sized cyclic 2-alkynones, we have prepared bicyclic fragmentation precursors such as 2. In this case, the bond that fragments is the ring fusion bond and 9 to 12-membered cyclic 2-alkynones such 3 are formed. Synthetic routes to these bicyclic fragmentation precursors and the results of our fragmentation studies will be discussed.

ORGN 651

Stereospecific nickel-catalyzed cross-coupling reactions of benzylic ethers

Buck L. H. Taylor, [email protected], Michael R. Harris, Elizabeth C. Swift, Elizabeth R. Jarvo. Department of Chemistry, University of California, Irvine, Irvine, CA 92697, United States

A stereospecific nickel-catalyzed cross-coupling reaction is described. Aryl and alkyl Grignard reagents undergo cross-coupling with benzylic ethers to construct tertiary stereocenters from readily available secondary alcohol derivatives. The reaction proceeds with inversion of configuration and high enantiospecificity. Aryl and heteroaryl Grignard reagents can be used to form triarylmethanes in high optical purity. The cross- coupling reaction has been applied to the synthesis of enantioenriched medicinal targets. The scope of the reaction and mechanistic considerations will be presented.

ORGN 652

Exploration of siloles as intermediates in organic synthesis

Andrew C. Stevens, [email protected], Brian L. Pagenkopf. Department of Chemistry, The University of Western Ontario, London, Ontario N6A 5B7, Canada

Acyclic organosilanes have been heavily investigated and have proven to be an invaluable tool for synthetic organic chemists. Despite this success, silacycles have remained an underexplored motif with only occasional reports detailing the utility of these heterocycles. Siloles present an intriguing opportunity, as their carbocyclic analogs are well known to undergo Diels-Alder chemistry. Therefore it is somewhat surprising that there are scarce reports of Diels-Alder reactions of siloles in the literature, and no reports of the possible synthetic value of their Diels-Alder adducts. In order to evaluate this applicability as templating agents in organic chemistry, we have developed an efficient route for the synthesis of siloles bearing substituents that would facilitate functionalization of the C-Si bonds. Additionally, we have explored the Diels- Alder chemistry of the siloles and oxidatively cleaved the resulting bicyclic adducts to reveal a stereocontrolled synthesis of a cyclohex-2-ene-1,4-diol core that would otherwise prove difficult to obtain.

ORGN 653

Total synthesis of fellutamide B

Michael C. Pirrung, Y. Gangadhara Rao, Fa Zhang, [email protected]. of Chemistry, University of California, Riverside, Riverside, CA 92521, United States

Fellutamide B is a cytotoxic tripeptide and the most potent known inhibitor of the Mycobacterium tuberculosis proteasome. A solid-phase synthesis of fellutamide B is known, but peptide manufacture using solid-phase synthesis is not very green. We describe here the total synthesis of fellutamide B using new methodologies for solution- phase peptide synthesis. Key transformations included a hydrolytic kinetic resolution in the preparation of (R)-3-hydroxydodecanoic acid, and reagent-less peptide bond formations using simple activated acylating agents, a β-lactone and a cyanomethyl ester.

ORGN 654

Traceless bond construction through the [3,3] sigmatropic rearrangement of N- allylhydrazones

Kelly E. Lutz, [email protected], Regan Thomson. Department of Chemistry, Northwestern University, Evanston, IL 60208, United States

New synthetic methods based on the [3,3] sigmatropic rearrangement of N- allylhydrazones have been developed. Transformations include copper(II) chloride- promoted tandem carbon–carbon and carbon–chlorine bond formation, stereoselective synthesis of dienes, and Brønsted acid catalyzed carbon–carbon bond formation. Most recently hypervalent iodide species have also been shown to promote the rearrangement. When these oxidants are used in conjunction with an alcohol, the rearrangement was followed by nucleophilic addition, revealing a novel cascade ether synthesis, affording tandem carbon–carbon and carbon–oxygen bond formation. This methodology has recently been applied to the synthesis of a suite of aryltetralone lignans that possess anti-malarial activity, isolated from the Brazilian plant Holostylis reniformis. We have found that 8'-epi-aristoligone can be achieved in 8 steps with 17% yield from commercially available 3,4-dimethoxybenzaldehyde, employing the [3,3] sigmatropic rearrangement as a key bond-forming event. The enantioselective syntheses of several other lignans are currently being pursued.

ORGN 655

Formal oxidative arylation strategies: Synthesis of enantiopure biaryls

Leah Konkol, [email protected], Regan J. Thomson. Department of Chemistry, Northwestern University, Evanston, IL 60208, United States

Oxidative carbon–carbon bond forming reactions are powerful transformations, which when applied strategically for the construction of complex molecules, can provide concise and efficient syntheses. This research focuses on developing new methods for the formation of commonly occurring motifs in nature: namely that of 1,4-diketones and their potential to construct other classes of molecules such as linked quinones/phenols and benzofurans. By utilizing an enone aryl surrogate system, oxidative dimerization has led to a new method for biaryl synthesis. The enantioselective synthesis of various axially chiral biaryl compounds has been developed utilizing a templated chirality transfer approach in the formation of highly substituted single atropisomers. This methodology has been applied to the concise total synthesis of bismurrayquinone A.

ORGN 656

Synthesis and structure of 1-sulfonamido-2-(4'-nitrophenoxy)-5-methylbenzene

Michael H Silveira, [email protected], Edward Waters College, Jacksonville, FL 32209, United StatesForensic Science Program, Department of Sciences, Our Lady of the Lake College, Baton Rouge, LA 70808 70808, United States

The purpose of this paper is to report the synthesis and characterization of the previously unreported 1--sulfonamido-2-(4'-nitrophenoxy)-5-methylbenzene, a trisubstituted diphenyl ether derivative. 1H NMR (CF3COOH) d 2.50 (3 H, methyl5, s), 7.13 (2 H, H2', H6', d, J ~ 9.0 Hz), 7.27 (1 H, H4, d, J ~ 9.0 Hz), 7.60 (1 H, H3, d, J ~ 9.6 Hz), 7.95 (1 H, H6, s), 8.38 (2 H, H3', H5', J ~ 9 Hz). Diphenyl ethers are structural elements found in medicinally useful antibiotics such as vancomycin as well as in biological toxins in the environment such as dioxins. The reported compound serves as a useful advanced intermediate in the synthesis of these biologically active molecules. A multistep synthesis of this molecule has been designed by retrosynthetic analysis as part of an ongoing program aimed at a function-oriented, multi-step economical synthesis of vancomycin lead antibiotics.

ORGN 657

A greener route to N-arylation of sulfoximines using diaryliodonium salts

Buchi Reddy Vaddula, [email protected], John Leazer, Rajender S Varma.Sustainable Technology Division, National Risk Management Research Laboratory, U.S. Environmental Protection Agency, Cincinnati, Ohio 45268, United States

The C-N cross coupling reactions are crucial organic transformations that play a vital role in the construction of many important organic intermediates and biologically active compounds. A novel ultrasound-accelerated green route for the expeditious N-arylation of NH-sulfoximines is described that involves the use of benign diaryliodonium salts in aqueous polyethylene glycol-400 and CuBr as catalyst at room temperature. Iodoarene, which separates as a layer from the reaction mixture, can be reused for the synthesis of diaryiodonium salts thus minimizing the waste generation and improving the sustainability. The generality and the scope of the protocol were explored with different sulfoximines and diaryliodonium salts. The high yields of the products and simple work- up are the highlights of the protocol.

ORGN 658

Reprogramming the genetic code

Jason W. Chin, [email protected] Laboratory of Molecular Biology, Centre for Chemical & Synthetic Biology, Cambridge, United Kingdom

In the cell, DNA is copied to messenger RNA, and triplet codons (64) in the messenger RNA are decoded to synthesize polymers of the natural 20 amino acids. This process (DNA to RNA to protein) is the 'central dogma' of molecular biology.

Dr Chin's team is interested in re-writing the central dogma to create organisms that synthesize proteins containing building blocks beyond the 20 natural amino acids. In his talk he will discuss the invention and synthetic evolution of new components to address the major challenges of re-writing the central dogma, as well as the application of these approaches for investigating and synthetically controlling diverse biological processes in cells and animals.

ORGN 659

Small molecules: Structures, synthesis and functions

Andrew J. J. Phillips, [email protected]. Department of Chemistry, Yale University, New Haven, CT 06520-8107, United States

Recent studies in genomics and bioinformatics will be used as a starting point for the illustration of new paradigms for the discovery of functional small molecules. These foundational platforms have facilitated a new approach to the exploitation of the metabolic capabilities of microorganisms, and also the discovery of small molecules with important functions in cancer biology.

ORGN 660

Structure, function, and inhibition of human O-GlcNAc transferase Suzanne Walker, [email protected]. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, United States

Human O-GlcNAc transferase is an essential enzyme that catalyzes a unique post- translational modification called beta-O-GlcNAcylation, which modulates numerous kinase signaling pathways. We will describe published and unpublished structures of OGT that provide a view of the reaction trajectory as well as new insights into different modes of peptide substrate recognition. We will also describe the mechanism of action of a novel class of OGT inhibitors and their use to study OGT function.

ORGN 661

Award Address (Ronald Breslow Award for Achievement in Biomimetic Chemistry sponsored by the Ronald Breslow Award Endowment). Pro-fluorescent small molecules reveal allosteric mechanism of ligand-dependent EGFR activation

Alanna Schepartz, [email protected]. Department of Chemistry, Yale University, New Haven, CT 06520-8107, United States

Aberrant activation of the epidermal growth factor receptor (EGFR) is critical to the biology of many cancers. The molecular events that define how EGFR transmits an extracellular ligand-binding event through the membrane are not fully understood. This lecture will describe the application of a chemical tool, bipartite tetracysteine display, to study ligand-dependent EGFR activation in mammalian cells. Our findings provide new insight into how multi-domain membrane proteins decode and transmit distinct extracellular signals to the cell interior.

ORGN 662

Structure-Inducing molecular recognition of single-stranded oligonucleotides with synthetic nucleobase-pairing

Dennis Bong, [email protected]. Department of Chemistry, The Ohio State University, Columbus, Ohio 43210-1185, United States

We have designed a 21-residue α-peptide that simultaneously recognizes two decadeoxyoligothymidine (dT10) tracts to form triplexes with a peptide-DNA strand ratio of 1:2. The synthetic peptide sidechain-displays ten melamine rings, which provide a bifacial thymine-recognition interface along the length of the 21-residue peptide. Recognition is selective for thymine over other nucleobases and drives the formation of ternary peptide*[dT10]2 complexes as well as heterodimeric peptide*[dT10C10T10] hairpin structures with triplex stems. The use of this recognition strategy in different contexts will be described.

ORGN 663 Small molecule modulation of transient protein-protein interactions

Anna K Mapp, [email protected]. Chemistry, University of Michigan, Ann Arbor, MI 48109, United States

There are few methods suitable for the discovery and targeting of transient, moderate affinity protein-protein interactions in their native environment despite their prominent role in a host of cellular functions, including protein folding, signal transduction and transcriptional activation. To address this, we find that in vivo photocrosslinking using the unnatural amino acid p-benzoylphenylalanine can be used to capture and characterize the transient interactions of transcriptional activators in vivo. These data suggest the existence of conserved activator-binding motifs that should be highly targetable by small molecule inhibitors with applications in cancer biology and inflammation. Towards that end, we have identified through a combination of screening and design small-molecules that target the transiently-associated complexes of transcriptional activators and in doing so, down-regulate key genes associated with cancer stem cell self-renewal.

ORGN 664

Expanding the synthetic capabilities of the cell

Virginia W Cornish, [email protected]. Department of Chemistry, Columbia University, New York, NY 10027, United States

In vitro directed evolution allows biomolecules with new and useful properties to be engineered—mimicking natural evolution on an experimentally accessible time scale by creating large libraries of DNA mutants using PCR and then carrying out a high- throughput assay for variants with improved function. To provide a breakthrough in the complexity of libraries that can be readily searched experimentally, my laboratory is engineering S. cerevisiae so that both the mutagenesis and selection steps of directed evolution can be carried out entirely in vivo, under conditions of sexual reproduction. I will describe chemical complementation, which provides a selection for chemical transformations beyond those natural to the cell using themes and variations on the yeast two-hybrid assay. Furthermore I will present a heritable recombination system that allows mutations to be introduced and then crossed under conditions of sexual reproduction.

ORGN 665

Bioorthogonal noncovalent chemistry

Krishna Kumar, [email protected]. Department of Chemistry, Tufts University, Medford, MA 02155, United States The use of bioorthogonal covalent chemistry has gained widespread use in chemical biology. We have developed probes that have orthogonal noncovalent behavior with respect to other complex associating systems in biology. These materials have been used in the creation of self-assembling protein components in biological membranes, and in developing anti-microbial and anti-diabetic therapeutics. This lecture will describe our efforts at developing anti-metastatic agents and molecules for imaging metatstatic potential of tumors by 19F MRI before they are visible by other means. Some of the constructs developed are useful in delivering macromolecular cargo into living cells and provide the ability to display clustered sets of epitopes on cell surfaces.

ORGN 666

Activity-based proteomics: Applications for enzyme and inhibitor discovery

Benjamin F. Cravatt, [email protected]. Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, United States

Genome sequencing projects have revealed that eukaryotic and prokaryotic organisms universally possess a huge number of uncharacterized enzymes. The functional annotation of enzymatic pathways thus represents a grand challenge for researchers in the genome era. To address this problem, we have introduced chemical proteomic and metabolomic technologies that globally profile enzyme activities in complex biological systems. These methods include activity-based protein profiling (ABPP), which utilizes active site-directed chemical probes to determine the functional state of large numbers of enzymes in native proteomes. In this lecture, I will describe the integrated application of ABPP and complementary metabolomic methods to discover and functionally annotate enzyme activities in mammalian systems, including cancer and the nervous system. I will also present competitive ABPP platforms for developing selective inhibitors for poorly characterized enzymes and discuss ongoing challenges that face researchers interested in assigning protein function using chemoproteomic methods.

ORGN 667

In situ trihaloacetylation and bromomethylation of p-anisidine

Alonzo Gonzalez, Jose J Gutierrez, [email protected]. Chemistry, The University of Texas Pan American, Edinburg, Texas 78539, United States

Reported here is the bromomethylation of p-anisidine. The strong acidic conditions utilized in the reaction result in protonation of the amino group, deactivating the ring towards bromomethylation. To circumvent this, we protected the amino group using trifluoroacetic anhydride or trichloroacetic anhydride prior to the addition of the bromomethylating reagents. The corresponding monobromomethylated derivatives (2a , 2b ) were isolated in 50 % to 70 % yield for the trifluoroacetyl and trichloroacetyl groups, respectively. No bromomethylation was observed when anisidine was protected with acetic anhydride, suggesting that the acetyl group does not lower enough the basicity of the nitrogen to prevent protonation. The bromomethyl derivatives were converted into aromatic ethers (3a , 3b ) upon reaction with the corresponding alcohol using potassium carbonate as a base. Additionally, the bromomethyl derivatives were converted into phosphonate esters via the Arbuzov reaction (4a , 4b ). All products were characterized by 1H-NMR and 13C-NMR.

ORGN 668

Developments in the synthesis of a RGD-functionalized polysilole

Colleen N Scott, [email protected], Milind Bisen, Tamara Hill. Chemistry and Biochemistry, Southern Illinois University, Carbondale, IL 62901, United States

Polysiloles are fascinating to scientists, especially those in the field of electronics, because of their unique optical and electrical properties. However, the applications of polysiloles in devices have been limited due to the difficulty in their preparation. We have been interested in polysiloles for the same reasons as other scientists; however, we also aim to investigate their ability to function as biomaterials. In order to do this, we must develop reliable synthetic methods to synthesize and further functionalized these polymers. We are in the process of improving current methods and developing new methods to realize these valuable compounds. We will present our progress towards this endeavor; to develop reliable synthetic methods towards the synthesis of polysiloles, and to further functionalized them with a RGD peptide sequence.

ORGN 669

Oxidation of phenols as versatile methodology in building heterocycles

Maxim O Ratnikov, [email protected], Michael P Doyle. Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, United States

An efficient one-pot tandem sequence forming heterocycles is developed. The method consists of an efficient phenol oxidation with inexpensive T-HYDRO catalyzed by dirhodium caprolactamate followed by Brønsted acid promoted cyclization. Substrate scope includes uses of L-tyrosine ester and dipeptide derivatives. Application of chiral phosphoric acids for asymmetric cyclization is discussed. Previously unreported peroxide cleavage with TiCl4 enables a rapid synthesis of halleridone.

ORGN 670

Synthesis and polymerization of 3,4-difluorofuran

Justin Biffinger1, [email protected], Jeremy Pietron1, Syed Qadri2. (1) Department of Chemistry, US Naval Research Lab, Washington, DC 20375, United States (2) Department of Material Science and Technology, US Naval Research Lab, Washington, DC 20375, United States

This presentation will describe the first multi-gram one-step synthesis of 3,4- difluorofuran from 3,3,4,4-tetrafluorotetrahydrofuran. To date, NMR chemical shift data and physical properties have been theoretical (ab initio calculations and models) and not experimental. 3,4-Difluorofuran was synthesized using a double elimination mechanism with a sterically hindered alkoxide in a manner similar to published procedures for 3,4-difluoropyrrole. 1H-19F NMR shifts and coupling constants will be compared with experimentally derived chemical shifts from DFT calculations. The polymerization of 3,4-difluorofuran using oxidative chemical and electrochemical techniques will be described, And the conductive and physical properties of poly-3,4- difluorofuran in conjunction with initial characterization (TGA, XPS) of Co2+ metallopolyfurans will be reported.

ORGN 671

Triazolines photodecomposition in solid state

Denisse Atenea de Loera, [email protected], Miguel Garcia- Garibay.Departament of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, CA 90064, United States

Crystals help control the chemical behavior of reactive intermediates like nitrene, carbine and radicals. The rigid matrix prevents the movement and free diffusion of intermediates and therefore, the solid state reactivity is often more selective than in solution, giving higher region- and stereoselectivities. The photodecomposition of triazolines in solution occur in moderate yields due formation of byproducts.

In this work, we present the triazoline photodecomposition in the solid state. And the aziridine obtained is compared with the thermal decomposition product.

ORGN 672

Synthesis of novel nitroaromatic 1,3-disubstituted-1,3-dihydroisobenzofuran scaffolds

Otome E. Okoromoba, [email protected], Frederick A. Luzzio. Chemistry, University of Louisville, Louisville, Kentucky 40292, United States

The reaction of ortho-formyl cinnamates, ortho-formyl-α-benzalketones or ortho-formyl- chalcones with substituted α-nitrotoluenes or β-nitroethylbenzenes in the presence of 1,1,3,3-tetramethylguanidine (TMG) is an extension of our recently-reported tandem Henry/oxa-Michael route to 1,3-disubstituted-1,3-dihydroisobenzofurans. The employment of the aryl-substituted nitro compounds as reacting partners is an effective route to aromatic-substituted 1, 3-dihydroisobenzofurans thereby adding additional diversity to the 1,3-dihydroisobenzofuran scaffold. The reaction mechanism entails the TMG- mediated nitronate addition to the aryl formyl group followed by intramolecular alcoholate addition to the unsaturated component thereby affording the target benzoheterocyclic scaffold. While the use of TMG as a catalyst gives rise to chromatographically-inseparable diastereomers, the diastereoselectivity may be enhanced by employing substituent groups on the carbonyl substrates and/or by employing a catalytic amount of a chiral catalyst as opposed to TMG. The tandem Michael/oxa-Henry approach to 1, 3-disubstituted-1,3-dihydroisobenzofurans having appended aromatic groups, functional group modifications to the dihydroisobenzofuran core and elements of reaction stereocontrol will be presented.

ORGN 673

Porphyrin oligomers with enhanced π-conjugation: Synthesis and post- functionalization Aoife A Ryan, [email protected], Mathias O Senge. Department of Chemistry, Trinity College Dublin, Dublin, Ireland

Numerous optical applications of porphyrins in areas such as photodynamic therapy (PDT) and non-linear optics (NLO) necessitate that the dye absorbs far into the red region. Modifications to the porphyrin structure to accommodate this condition can be achieved by extending the conjugation of the porphyrin π-system, which will cause a bathochromic shift in the absorption spectrum. In our work, a series of symmetric and unsymmetric dimeric and oligomeric porphyrin β-β, meso-meso, β'-β' triply fused systems were synthesized. The unsymmetric dimers contain both hydrophilic and hydrophobic entities, which could enhance the amphiphilicity of the compound and hence assist accumulation in the target tissues for PDT. Further post-fusing chemical transformations, namely organolithium, cycloaddition and transition-metal catalyzed reactions, at the meso- and β- positions, enables the fine-tuning of such arrays with the aim of enhancing the bathochromic shift and their potential optical applications.

ORGN 674

Synthesis of novel transparent electro-optic chromophores

Joseph Dougherty, [email protected], B. Christopher Rinderspacher, Jan A Andzelm, Adam Rawlett. U.S. Army Research Laboratory, APG, MD 21005, United States

Several novel electro-optic (EO) D- π -A (EDG-[π-bridge]-EWG) chromophores based on the known Tolane template were synthesized using palladium coupling techniques between phenylacetylenes and aryl halides. The molecules were selected under guidance by an inverse molecular design targeting visually transparent Donor-Acceptor chromophores with high EO activity. Two challenges arise in the design of transparent EO chromophores: 1) planarity of the bridging π-system, 2) non-symmetric substitution on the π-bridge. A novel chromophore containing an intramolecular hydrogen bond was generated to enforce planarity of the π-bridge. The synthetic difficulty revolved around the placement of hydrogen bonding groups which needed to be installed without a large tradeoff involving D- π -A electronic effects. To address the second challenge, a class of compounds with varying naphthalene and anthracene π-bridges was also synthesized to generate novel non-symmetric chromophores from a precursor class of symmetric chromophores.

ORGN 675

Highly efficient intramolecular pyrolysis reactions in continuous flow under pressure and in vacuo

Richard Jones1, [email protected], Laszlo Lengyel1, Gellert Sipos1, Tibor Nagy1, Krisztina Konya2, Laszlo Kocsis1, Gyorgy Dorman1, Ferenc Darvas1. (1) ThalesNano Inc., Budapest, Hungary (2) Department of Chemistry, University of Debrecen, Debrecen, Hungary

Pyrolitic ring closure of ketene precursor intermediates (e.g. Gould Jacobs reaction) leads to a variety of substituted heterocyclic rings from aniline-type of aromatic substructures. With the application of “flash” chemistry such reactions were carried out in low boiling point solvents with very short residence times (0.45-4.5 min.) in excellent conversion and good to high yields [1]. Such reactions can also be performed in very high temperature (> 500 C) but under radically reduced pressure (< 0.1 mbar). This technique, called vacuum flash pyrolysis (VFP) in flow facilitates the ringclosure of rather unreactive species, however, such conditions often alter the regiochemistry. Additional ketene precursor compounds led to novel heterocylic ring systems under VFP. In summary, flow pyrolysis in high T/p and VFP holds the promise of reaching a novel chemical space, thus, rescuing the rather unproductive small-molecule based drug discovery.

[1] Lengyel L, Nagy Z T, Sipos G, Jones R, Dormán G, Ürge L and Darvas F Tetrahedron Lett (accepted for publication)

ORGN 676

Reductive alkylation of 2-hydroxyarylketones with malononitrile and borohydride

Robert E Sammelson, [email protected]. Department of Chemistry, Ball State University, Muncie, IN 47304, United States

Previously, we have optimized a new one-pot procedure for the reductive alkylation of various 2-hydroxybenzaldehydes (salicylaldehydes) where intramolecular cyclization occurs following the condensation step and several novel 4H-Chromenes were formed. In this research, we apply 2-hydroxyacetophenone with malononitrile and base followed by sodium borohydride and the intermediate and product steps of the reaction were optimized. Additional 2-hydroxyarylketones, prepared from phenols via esterification and Fries rearrangement, have been employed with additional optimization required. Current progress in our laboratory on this reaction and further reactions on the novel products will be discussed. Several of the chromenes have been submitted to the Open Innovation Drug Discovery (OIDD) with Eli Lilly & Company and their previous Phenotype Drug Discovery program.

ORGN 677

Skraup - Doebner - Von Miller quinoline synthesis: An alternative mechanistic pathway

Jean Fotie, [email protected]. Chemistry and Physics, Southeastern Louisiana University, Hammond, Louisiana 70402, United States The real mechanism of the Skraup – Doebner – Von Miller quinoline synthesis remains controversial and not well understood despite several mechanistic studies reported on the matter. A series of unexpected cycloalkenylated-dihydroquinoline derivatives have been obtained through the Skraup – Doebner – Von Miller quinoline synthesis. On the basis of these unexpected results and in agreement with some of the previously reported quinolines synthesis, an alternative mechanistic pathway is proposed for this variance of the reaction. We are discussing this newly proposed mechanistic pathway in this presentation.

ORGN 678

One size fits ball: Macrocyclic hosts for fullerenes with micromolar affinity

Emilio M Pérez1, [email protected], Helena Isla2, David Canevet1, María Gallego2, Alberto de Juan1, Nazario Martín1,2. (1) -, IMDEA Nanociencia, Madrid, - 28049, Spain (2) Department of Organic Chemistry, Universidad Complutense de Madrid, Madrid, - 28040, Spain

The search for molecular receptors for fullerenes that form complexes of high stability is a very active area of investigation. To date, the highest binding constants have been obtained utilizing metalloporphyrins as recognizing units. Here, we describe the synthesis of a collection of exTTF-based macrocyclic hosts and their binding abilities towards both C60 and C70 (JACS 2010 and 2011). Our macrocyclic receptors include two hosts capable of binding C70 with micromolar affinity, and one of the best hosts for C60 reported to date, with a log Ka = 7.5 (PhCN, r.t.). We also report insights into the thermodynamic nature of the association event, and its influence on the electronic properties of the host-guest systems. We have found that small variations in the structure of the host lead to very significant changes in affinity towards the fullerene guest, and in some cases even in the stoichiometry of the associates.

ORGN 679

Triarylamine units: A modular scaffold for light-triggered self-assembly and its use as metallic interconnects

Emilie Moulin, [email protected], Nicolas Giuseppone.SAMS Research Group- icFRC, Institut Charles Sadron - CNRS UPR 22, Strasbourg, France

Supramolecular self-assembly represents the key process for the spontaneous bottom- up construction of nanoarchitectures and, as such, is increasingly exploited for the development of functional, responsive, and self-healing (bio)materials with enhanced physical and chemical properties. To go one step further, and in order to build “smart” materials, it will be of first significance to couple environmental signaling events with the formation of self-assemblies that will be able, in turn, to transport this initial information in space and time. Here we will show that chemically-tailored triarylamine units, when exposed to simple visible light irradiation, produce cationic radicals that subsequently generate various hierarchical self-assembled structures, going from nanospheres to nanowires. We will also report on the direct self-assembly of such supramolecular organic nanowires in lateral electronic devices. Using a combination of light and electric field, these purely organic self-assemblies are able to precisely interconnect nanometer- sized metallic electrodes with a high efficiency.

ORGN 680

Controlling and switching the morphology of micellar nanoparticles with enzymes

Ti-Hsuan Ku, [email protected], Nathan Gianneschi. Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, United States

In biology, stimuli-responsive multisubunit assemblies are ubiquitous, and mimicking these systems via synthetic approaches is of increasing interest. Interfacing such synthetic materials with biological systems is particularly promising for a range of biomedical applications including targeted drug delivery and molecular diagnostics. Within this class of materials are particles capable of changing morphology in response to stimuli. Enzymes are attractive and unique stimuli with great potential in this regard, as they propagate an amplified response via catalytic reactions, can be highly substrate specific, and have expression patterns sometimes associated with disease states. Nanoscale assemblies of block copolymer amphiphiles are well-suited for the development of functional, stimuli-responsive systems because changes in the chemical or physical nature of the amphiphile can lead to formation, destruction, or morphological transformations. Here, the first example of enzymatic switches of micellar morphology will be demonstrated. Micelles were prepared from polymer-peptide block copolymer amphiphiles containing substrates for protein kinase A, protein phosphatase-1, and matrix metalloproteinases 2 and 9. Reversible switching of the morphology of these micelles through a phosphorylation-dephosphorylation cycle and peptide-sequence directed changes in morphology in response to proteolysis will be described. Furthermore, the exceptional uniformity of these polymer-peptide particles makes them amenable to cryo-TEM reconstruction techniques lending insight into their internal structure.

ORGN 681

Targeting the terminus to achieve site-selective molecular recognition of peptides and proteins

Adam R. Urbach, [email protected]. Department of Chemistry, Trinity University, San Antonio, TX 78212, United States

The design of artificial receptors that recognize target peptides and proteins with high fidelity stands as a major challenge in chemistry with wide-reaching implications for basic science and biotechnology. Proteins are particularly challenging targets for their (still) unpredictable correlation between amino acid sequence and folded structure. Moreover, approaches to peptide recognition have not translated to folded proteins. This presentation describes an approach to the site-specific recognition of peptides by the artificial receptor cucurbit[7]uril (Q7) that successfully translates to folded proteins by exploiting the unique properties of the polypeptide terminus. Natural aromatic residues at the terminal position are bind with equilibrium dissociation constant (Kd) values on the order of 1 micromolar. A simple modification of the sidechain of phenylalanine yields a Kd of 1 nanomolar, which is attractive as an affinity tag. The specificity for binding at the N-terminal position vs. other positions is high (up to 500- fold) and has enabled the development of a label-free assay for the quantitative kinetics, selectivity, and inhibition of thermolysin, a metalloendopeptidase that produces N- terminal phenylalanine-containing fragments upon proteolysis. The details of these recent studies will be discussed.

ORGN 682

Stereochemistry inside Cucurbit[8]uril: Biphenyls and chiral amines in a very special environment

Eric Masson, [email protected]. Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, United States

We present (1) the dethreading of an axle bearing two 15-crown-5 units and surrounded by Cucurbit[7]uril (CB[7]), promoted by metallic cations, (2) the design of a CB[7]- controlled chemiluminescent on/off switch, (3) the regio- and diastereoselective recognition of fluorine-substituted di- and tribenzyl ammonium cations by CB[8], (4) the effect of CB[8] on the torsional barrier of biphenyl units confined in its cavity, and the diastereoselectivity of the encapsulation when the biphenyl units are substituted with chiral sulfonium groups.

ORGN 683

Nanostructured solar cells from contorted donor molecules

Alon A. Gorodetsky1, [email protected], Chien-Yang Chiu2, Marshall Cox3, Colin Nuckolls2, Ioannis Kymissis3. (1) Department of Chemical Engineering and Materials Science, University of California - Irvine, Irvine, CA 92697, United States (2) Department of Chemistry, Columbia University, New York, NY 10027, United States (3) Department of Electrical Engineering, Columbia University, New York, NY 10027, United States

I will discuss our efforts toward efficient organic photovoltaics that take advantage of the complementary geometry of contorted donor molecules and spherical acceptor molecules. We have designed, synthesized, and characterized a new class of contorted coronene donor materials. Such molecules demonstrate numerous favorable features, including environmentally sensitive shape-shifting, templated assembly of robust organic/organic interfaces, and the formation of three-dimensional crystalline networks. These supramolecular self-assembly properties have enabled us to design and fabricate nanostructured bulk heterojunction devices with figures of merit that approach state-of-the-art values for small molecule organic photovoltaics. Overall, our findings may hold significant implications for inexpensive and efficient solar energy conversion technologies.

ORGN 684

Aziridine scaffolds for the detection and quantification of hydrogen-bonding interactions through transition-state stabilization

Cam Thuy Hoang1, [email protected], Luciana Giordano2, Michael Shipman1, James H. R. Tucker2, Tiffany R. Walsh1. (1) Department of Chemistry, University of Warwick, Coventry, West Midlands CV4 7AL, United Kingdom (2) School of Chemistry, University of Birmingham, Birmingham, West Midlands B15 2TT, United Kingdom

Accurately quantifying the strength, distance, and angular dependence of non covalent interactions is central to understanding numerous aspects of biology and medicine, as well as supramolecular and synthetic chemistry. Efforts in our laboratories are focused on exploiting molecular motion in the form of pyramidal inversion in aziridines for detecting and assessing the strength of specific weak interactions such as the H-bond. In this context, an intramolecular H-bond between a pyridine nitrogen and an amide NH formed in a transition state of an aziridine N-inversion process has been successfully characterized and quantified.[1] The strength of this individual H-bond was determined by N-inversion rates and activation parameters using variable-temperature NMR and also a chemical double mutant cycle.

[1] Giordano, L., Hoang, C. T., Shipman, M., Tucker, J. H. R., Walsh, T. R. Angew. Chem. Int. Ed. 2011 , 50, 741.

ORGN 685

Synthesis of encaged Verkade's superbases

Bastien Chatelet, [email protected], Alexandre Martinez, Jean-Pierre Dutasta. Department of chemistry, Ecole normale supérieure de Lyon, Lyon, F 69364, France Hemicryptophanes are host molecules with many applications as supramolecular catalysts. A very convenient and efficient modular approach has been developed which provides an easy way to access variable molecular cavity sizes and to change the functional groups in the linkers. Phosphorus was introduced in these hemicryptophanes leading to encaged azaphosphatranes. Proazaphosphatranes, known as Verkade's superbases, have been used as efficient basic or nucleophilic catalysts in a wide range of organic reactions. These species exhibit strong basicity (pKa~32). The basicity of these encaged superbases has been estimated and compared to classical Verkade's superbases.

ORGN 686

Cross-linking of C60-tagged polyphenylacetylene by molecular recognition

Takeharu Haino1, [email protected], Eri Hirai1, Yoshihisa Fujiwara2, Kouki Kashihara1. (1) Chemistry, Hiroshima University, Higashi-Hiroshima, Hiroshima 739- 8526, Japan (2) Mathematical and Life Sciences, Hiroshima University, Higashi- Hiroshima, Hiroshima 739-8526, Japan

Our group has been developing fullerene hosts based on a calix[5]arene. During the course of these studies, we found that covalently linked double-calix[5]arenes encapsulate fullerenes in their cavities to form 1:1 host-guest complexes. The molecular association between a C60 molecule and a double-calix[5]arene is strong enough to create a supramolecular polymeric array of [60]fullerenes. We set out to make use of this unique host-guest motif as a supramolecular cross-linkage between polymer chains.

In this presentation we report supramolecular cross-linking of a polyphenylacetylene by 1 C60-calix[5]arene-interaction. A polyphenylacetylene possessing C60 moieties has been cross-linked by a homoditopic tetrakiscalix[5]arene host via formation of a specific supramolecular complex. This noncovalent interaction leads to an increase of the molecular weight of the polymer and produces morphological changes upon addition of the host.

Reference

(1) Haino, T.; Hirai, E.; Fujiwara, Y.; Kashihara, K. Angew. Chem. Int. Ed. 2010 , 49, 7899–7903.

ORGN 687

Multi-component assembly studies for chemo and enantiodiscrimination of alpha- chiral primary amines

Pedro Metola, [email protected], Eric V Anslyn. Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, Tx 78712, United States

An alpha-chiral primary amine, enantiopure 1,1'-bi-2-naphthol (BINOL), and o- formylphenylboronic acid assemble efficiently and rapidly into chiral host-guest structures, inducing chirality in the system and causing distinct circular dichroism signals for each enantiomer of the amine. Using three different BINOLs to achieve an array of receptors, the CD signals resulting from several amines were processed using several chemometric tools to give satisfactory discrimination of the amines studied. PCA shows that the main contributor to the variance in the system is chirality and LDA was able to identify the different amines with a 100% confidence level, based on identity and chirality. For ee% determination using a calibration curve, the average total error was 5.8%. Competition experiments where BINOL analogues or amines for dynamic fingerprinting of mixtures are underway.

ORGN 688

Hydrophobic modulation of patchy thermosensitive self-assembled supramolecules

Luis Negron, [email protected], Jose M Rivera. Chemistry, University of Puerto Rico at Rio Piedras, San Juan/Rio Piedras, Puerto Rico 00931, Puerto Rico

The impact of the size, shape, and distribution of lipophilic regions on the surfaces of nanoscopic objects that are amphiphilic or patchy (such as proteins) are yet to be fully understood. We discovered a series of 8-aryl-2'-deoxyguanosine (8ArG) derivatives exhibit the LCST phenomenon in aqueous media. Thermoresponsive 8ArG derivatives self-assemble in discrete supramolecular hexadecamers that are composed of sixteen subunits held together by a combination of non-covalent forces. Self-assembly offers a complemented strategy with LCST for the development of hydrophobic patches by the modulation of the hydrophobic properties of these 8ArG derivatives. The synthetic strategy relies on the design of 8ArG isomeric derivatives by affecting the hydrophobic 3D structure of the resulting discrete supramolecular structures. We will show 1D/2D- NMR and other studies regarding the supramolecular structure and properties of these compounds. These results may impact the study of protein folding/assembly and may lead to the development of important technological applications.

ORGN 689

Synthetic approaches to papyracillic acids A, B, and C

Charles K. Zercher, [email protected], Jennifer Mazzone. Department of Chemistry, University of New Hampshire, Durham, NH 03824, United States

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The isolation of spiroketal papyracillic acid C from Microsphaeropsis sp., along with the previously identified papyracillic acids A and B, was reported in 2007. The cytotoxicity of papyracillic acid A is proposed to be due to its reactivity with nucleophiles, with the addition of the cysteine to the exocyclic alkene supporting the assertion that the spiroacetal of papyracillic acid A exists in equilibrium with open chain forms.

Inspection of the open chain form of a hemiacetal reveals a 1,4-dicarbonyl relationship that could arise from a chain extension reaction. Application of a tandem zinc carbenoid-mediated chain extension-acylation reaction provides an attractive synthetic route to these natural products. This method, in conjunction with a variation on the chain extension methodology that facilitates β-alkyl incorporation, offers a direct route to the racemic skeleton. In a parallel study, we have developed a strategy for the control of absolute stereochemistry at the β-carbon.

ORGN 690

Synthetic studies directed toward daphnicyclidin-type natural products

Travis B Dunn2, J Michael Ellis3, Kim Huard5, Christiane C Kofink4, James R Manning1, [email protected], Larry E Overman1. (1) Department of Chemistry, University of California, Irvine, Irvine, CA 92697, United States (2) Abbott Laboratories, North Chicago, IL 60064, United States (3) Merck & Co., Inc., Boston, MA 02115, United States (4) Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (5) Pfizer, Inc., New London, CT 06320, United States

Daphnipaxinin (3), the first known diamino daphnicyclidin-type alkaloid, isolated in 2004, contains several synthetically challenging structural features. These include a compact, hexacyclic core containing two fused seven-member rings, five stereogenic centers (one quaternary) and an unusual aminofulvene moiety. Studies directed toward the asymmetric total synthesis of this natural product are reported. Key steps in our approach include an aza-Cope-Mannich reaction of (Z)-trisubstituted olefin 1 to form the A and C rings along with the quaternary stereocenter, and a ring-closing metathesis reaction to form the D ring.

ORGN 691

Toward the total synthesis of radicicol

Jennifer R Lachs, [email protected], Anthony G M Barrett. Department of Chemistry, Imperial College London, London, United Kingdom

Recent research has shown radicicol (1) to be a potent and selective inhibitor of Hsp90, stimulating a renewed interest in this natural product.[1],[2] Using a new late-stage aromatisation strategy developed in our group, a concise and convergent total synthesis of radicicol (1) was envisaged. Formation of the 14-membered macrocycle will rely on a late-stage relay-RCM of precursor 2 using the Hoveyda-Grubbs 2nd generation catalyst. The key late-stage aromatisation sequence consisting of the thermal retro-Diels-Alder reaction of 3 followed by ketene trapping with 4 will be used to construct the aromatic resorcylate framework of 2. The known aromatic chlorination completes the synthesis.[3]

[1] Schulte, T. W.; Akinaga, S.; Soga, S.; Sullivan, W.; Stensgard, B.; Toft, D.; Neckers, L. M. Cell Stress Chaperones 1998, 3, 100.

[2] Sharma, S. V.; Agatsuma, T.; Nakano, H. Oncogene 1998, 16, 2639.

[3] Garbaccio, R. M.; Stachel, S. J.; Baeschlin, D. K.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 10903.

ORGN 692

Synthetic studies on the pluramycin natural products: Total synthesis of isokidamycin

B. Michael O'Keefe1, [email protected], Douglas M Mans2, David E Kaelin, Jr3, Stephen F Martin1. (1) Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, TX 78712, United States (2) Glaxo Smith Kline, King of Prussia, PA 19406, United States (3) Merk & Co., Inc., Rahway, NJ 07065, United States

We report the first total synthesis of the complex C-aryl glycoside isokidamycin, the epimer of the naturally-occuring pluramycin antibiotic kidamycin. Key features of the synthesis include the use of a silicon-tether as a disposable regiocontrol element in an intramolecular Diels—Alder reaction between a glycosyl furan and a highly substituted naphthyne to form the anthracene core, as well as an O → C-glycoside rearrangement to install the vancosamine amino glycoside.

ORGN 693

Model studies related to CP-molecules

Farzad Malihi, [email protected], Derrick L. J. Clive. Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada

Synthetic approaches to the anhydride subunit of CP-225,917 and CP-263,114 will be presented.

ORGN 694

Total synthesis of Ac2SGL and sulfolipid-1: Two 1,3-methyl branched sulfoglycolipids from mycobacterium tuberculosis

Danny Geerdink, [email protected], Adriaan J Minnaard. Department of Bio-Organic Chemistry, University of Groningen, Groningen, Groningen 9747 AG, The Netherlands

Tuberculosis (TB) has been one the most infectious and deadly diseases for decades and is nowadays responsible for the death of 1.7 M people annually. The thick hydrophobic cell wall of the microorganism responsible for TB, Mycobacterium tuberculosis (M.tb), is the main reason for its persistence, creating an impermeable barrier for antibiotics.

Two interesting constituents of this cell wall and only present in M.tb are acyl2sulfoglycolipid (Ac2SGL) and sulfolipid-1 (SL-1). Ac2SGL was recognized to function as an antigen, able to activate T-cells which in turn can release interferon-γ, kill mycobacteria in vitro and recognize M.tb infected antigen presenting cells. The exact role of SL-1 is not yet known, although there are reports which associate it with the virulence of TB. To elucidate their exact structure and function we report the first complete synthesis of both.

The branched fatty acids acylated at varying positions of the trehalose core were synthesized by means of an iterative protocol. This protocol relies on the highly selective copper-catalyzed 1,4-addition of Grignard reagents to alpha,beta-unsaturated thioesters. Regioselective acylation of the acids was obtained by a protection/deprotection sequence. To minimize the purification of highly polar intermediates the synthesis was planned in such a way that all protecting groups could be removed in a single final step. In the presentation we will discuss the strategy used and highlight the crucial steps in our synthesis.

ORGN 695

Development of an efficient Pd catalyzed process for Axitinib (AG-013736)

Jay K Srirangam, [email protected], Shu Yu, Rob Singer, Erik Flahive, Neal Sach, Qingping Tian, Srin Babu, James Saenz. Chemical R&D, Pfizer Global R&D, San Diego, CA 92121, United StatesChemical R&D, Pfizer Global R&D, San Diego, CA, United StatesChemical R&D, Pfizer Global R&D, Groton, CT, United StatesChemical R&D, Pfizer blobal R&D, San Diego, CA, United StatesChemical R&D, Pfizer Global R&D, San Diego, CA, United StatesChemical R&D, Pfizer Global R&D, San Diego, CA, United StatesChemical R&D, Pfizer Global R&D, San /Diego, CA, United StatesChemical R&D, Pfizer Global R&D, San Diego, CA, United States

Axitinib is a VEGF inhibitor in advanced clinical trials for cancer. We have recently filed the NDA for advanced renal cell carcinoma. The original synthesis of this compound involved 11 steps from 6-nitroindazole with an overall yield of ~2%. Efforts to overcome the bottlenecks and development of a scalable process for exploratory development will be discussed. This will be followed by our efforts in the development of a three step process utilizing efficient Pd cross couplings. Finally, the development of a commercial process for the manufacture of Axitinib will be presented. Interesting results from our efforts in controlling the crystal form as well as the Pd content of the final API will also be discussed.

ORGN 696

Chemical reactivity and biological significance of bicyclic lactone analogs derived from rearranged spongian diterpenes

Nathan E Genung1, [email protected], Martin J Schnermann1, Stephen M Canham1, Breanne D. W. Karanikolas2, Christine Sütterlin2, Larry E Overman1. (1) Department of Chemistry, University of California, Irvine, Irvine, CA 92697-2025, United States (2) Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697-2025, United States

The chemical synthesis of bicyclic lactone analogs related to the oxygenated fragments found in several spongian diterpenes has been achieved. Structure activity relationship studies have identified bridged and fused bicyclic lactone analogs that initiate a unique pericentriolar localized Golgi fragmentation phenotype similar to that exhibited by the spongian diterpene macfarlandin E. These studies indicate that acetoxy-substitution adjacent to the lactone moiety is a key structural feature responsible for inducing the observed phenotype. The chemical reactivity of simplified bicyclic lactone fragments has also been investigated. Reaction of both the substituted dioxabicyclo[3.2.1]octanone and dioxabicyclo[3.3.0]octanone ring systems with a primary amine leads to pyrrole products. Exposure of hen egg white lysozyme to the bicyclic lactone analogs under biologically relevant conditions affords pyrrole conjugates.

ORGN 697

Construction of the carbon skeleton of Salvinorin A via an intramolecular Diels- Alder/Tsuji allylation (IMDA/TA) sequence

Sean C Butler1, [email protected], Craig J Forsyth2. (1) Department of Chemistry, The University of Texas at Tyler, Tyler, Texas 75799, United States (2) Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, United States

Salvinorin A (1 ), a very unique diterpenoid isolated from the sage Salvia divinorum, is the only known non-nitrogenous psychedelic compound as well as being a very potent κ-opioid receptor agonist. Efforts toward the total synthesis including the construction of the full carbon skeleton (2 ) will be discussed. Particular emphasis will be placed on the two integral steps involved in the assembly of the decalin core: (i) a stereoconvergent intramolecular Diels–Alder cycloaddition; and (ii) a stereospecific Tsuji allylation.

ORGN 698

Total synthesis of echinopines A and B

Jean-Alexandre Richard1, [email protected], Philippe A. Peixoto1, Hanfeng Ding1, Chih-Chung Tseng1, Rene Severin1, K. C. Nicolaou2, David Y.-K. Chen3. (1) Organic chemistry @ Helios, Institute of Chemical and Engineering Sciences, Singapore, Singapore 138667, Singapore (2) Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, United States (3) Department of Chemistry, Seoul National University, Seoul, Republic of Korea

Echinopine A and B are sesquiterpenes isolated in 2008 from the roots of Echinops spinosus, a common North African plant. An unprecedented structure featuring a [3,5,5,7] tetracyclic system has been proposed. These targets constitute a challenge for a total synthesis that could confirm their intriguing structure and investigate their biological activity. The first total synthesis of has been reported in 2009, confirming the accuracy of the unusual structure. Our concomitant investigations led to one formal and two total syntheses.

ORGN 699

Progress toward the total synthesis of a novel Huperzine alkaloid with AChE inhibitory properties

Anthony J. Ostlund, [email protected], Gregory R. Cook. Department of Chemisty and Biochemistry, North Dakota State University, Fargo, North Dakota 58108, United States

Alkaloids from the Lycopodium (Huperzine) club moss family have generated many natural products with beneficial pharmacological effects towards central nervous system diseases, most notably Alzheimer's disease (AD) and Parkinson's disease. Many of these alkaloids are Acetylcholesterase inhibitors (AChEi) and represent attractive targets for both total synthesis and pharmacological development. Recently, a novel Huperzine alkaloid was discovered possessing a highly unorthodox “cage-like” pyran linkage. This molecule is synthetically challenging and structurally complex, which allows for a unique total synthesis of this type of alkaloid. The studies related to this synthesis are ongoing, but currently include creation the core scaffold by Horner- Wadsworth-Emmons olefination and Suzuki-Miyaura cross coupling. Also, setting of the major stereochemistry found in the natural product is accomplished by a chiral Lewis Acid-catalyzed ynamide Diels-Alder reaction, followed by an intramolecular allylation- cyclization sequence to set the bridge-like structures. Synthetic strategies toward the completion of the natural product will also be discussed.

ORGN 700

New total synthesis of Dehydrorabelomycin and C-aryl glycoside derivatives thereof Heemal Dhanjee, [email protected], Judy Salandanan, Thomas Minehan. Department of Chemistry and Biochemistry, California State University-Northridge, Northridge, California 91330, United States

The Dehydrorabelomycin chromophore is present in many DNA-binding natural products which possess potent antibiotic and antitumor properties. In an effort to explore the preparation of natural product analogues with increased biological activity, we have devised a quick method for the synthesis of this chromophore compound. This presentation will highlight critical steps leading to dehydrorabelomycin that involve key C-C bond formations through a Fries rearrangement and a Lewis acid promoted intramolecular cyclization. Our attempts at preparing C-Aryl glycoside derivatives of this chromophore will also be detailed.

ORGN 701

Base-free preparation of arylphosphonates

Robert A Stockland, [email protected], Marcia E Richard. Chemistry, Bucknell University, Lewisburg, PA 17837, United States

The generation of arylphosphonates is an important reaction due to the myriad of applications these compounds have in organic, medicinal, and agricultural chemistry. The synthetic methodology for the preparation of arylphosphonates normally involves a base-assisted coupling reaction between an aryl halide and a hydrogen phosphonate using a palladium or copper complex as the catalyst. The development of a base-free procedure for this coupling reaction is of interest to the synthetic community due to the range of substrates that contain base-sensitive functional groups. This presentation will highlight our recent efforts towards the design of such a reaction.

ORGN 702

Copper-catalyzed synthesis of alkylboronate esters

Hazmi Tajuddin1, [email protected], Chu-Ting Yang2, Zhen-Qi Zhang2, Chen-Cheng Wu2, Jun Liang2, Jing-Hui Liu2, Yao Fu2, Maria Czyzewska1, Lei Liu2, Todd B Marder1, Patrick G Steel1. (1) Department of Chemistry, Durham University, Durham, United Kingdom (2) Department of Chemistry, Tsinghua University, Beijing 100084, China An unprecedented Cu-catalyzed cross-coupling reaction of unactivated alkyl halides and pseudo-halides with diboron reagents will be described.

This reaction can be used to prepare both primary and secondary alkylboronic esters with diverse structures and functional groups, many of which would be difficult to access by other means. Mechanistic insights into the reaction pathway will also be presented.

ORGN 703

Unnatural amino acid synthesis By C-H bond functionalization methodology

Ly Dieu Tran, [email protected], Olafs Daugulis. Chemistry Department, University of Houston, Houston, Texas 77204, United States

The auxiliary-assisted, palladium-catalyzed functionalization of acid derivatives was used to modify β-positions of amino acids. Efficient methods were developed for acetoxylation, arylation, and alkylation of amino acid C-H bonds. Good functional group tolerance was observed. Moreover, the auxiliary can be removed in one step to generate the modified amino acids in high yield and with minimal erosion of enantiomeric excess.

ORGN 704

Preparation of N-alkyl amides using transition metal catalysis

Qun Xu, [email protected], Donald Watson. Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, United States

A transition metal-mediated method for the preparation of N-alkyl amides will be presented. This novel method allows for the construction of highly substituted N-alkyl amides under mild reaction conditions. Substrate scope, functional group compatibility, and a possible reaction mechanism will be discussed.

ORGN 705

Synthesis of new water soluble phosphine ligands for application in environmentally benign syntheses Jane N Moore, [email protected], Kevin H Shaughnessy, Emma J Catt, Alfred Hamilton. Chemistry, University of Alabama, Tuscaloosa, Alabama 35405, United States

Over the last decade, palladium catalyzed coupling reactions have become increasingly utilized in organic synthesis for the formation of carbon-carbon or carbon-heteroatom bonds. New approaches are being pursued to minimize the use of traditional organic solvents, develop recyclable catalysts, and to limit the overall production of environmentally harmful waste material. One way that this can be achieved is through the synthesis of water soluble phosphine ligands by the addition of anionic groups for catalysis in water or biphasic systems. Our design of these water soluble ligands is based on the need for steric bulk and electron richness to promote the catalytic cycle. The design also utilizes the flexible coordinating ability of a benzyl moiety which may contain additional electron donating substituents. Once we have synthesized these ligands, we will be studying their activity in palladium-catalyzed coupling reactions. Further studies will help to elucidate the role of the different groups on the ligand in promoting catalysis.

ORGN 706

Recent advances in metal-catalyzed amination using Pd-NHC complexes: The structure and role of the base

Ka Hou Hoi1, Selçuk Çalimsiz1, Robert D. J. Froese2, Alan C. Hopkinson1, Michael G. Organ1, [email protected]. (1) Department of Chemistry, York University, Toronto, ON M3J 1P3, Canada (2) The Dow Chemical Company, Midland, Michigan 48674, United States

Through a detailed analysis of the physical/structural properties of Pd-NHC complexes, which includes NMR spectroscopy, rate studies, and calculation, a high-performing catalyst has been developed that very effectively cross-couples amines and sulfides to aryl chlorides using mild reaction conditions. In this presentation, the evolution of this catalyst, Pd-PEPPSI-IPent, will be discussed and a wide sampling of examples will be presented demonstrating the general utility and high reactivity of this NHC-derived catalyst. In particular, the role and structure of the base will be evaluated, which in general has been overlooked. This has led to the design and synthesis of a new base specifically for amination that shows excellent kinetics with a variety of NHC- and phosphane-based catalysts when compared with commonly used carbonate bases. Importantly, this base complete high functional group compatibility, unlike potassium or sodium -tert-butoxide, which are also commonly used and have very high reactivity.

ORGN 707

From allylic alcohols to α-haloketones: Ir-catalyzed tandem isomerzation/halogenation reactions Nanna Ahlsten, [email protected], Antonio Bermejo, Agnieszka Bartoszewicz, Santosh Agrawal, Belén Martín-Matute. Department of Organic Chemistry, Stockholm University, Stockholm, Sweden

Electrophilic α-halogenation of carbonyl compounds is a useful method for aliphatic C−X (X = halogen) bond formation. However, in the case of unsymmetrical aliphatic ketones, highly regioselective enolate formation is a challenge. In an alternative strategy, transition metal-catalysed redox isomerization of allylic alcohols (1 ) can be used to generate enol(ate)s. In the presence of electrophilic reagents, these couple to form α– functionalized carbonyl compounds. Here, we present an iridium-catalyzed tandem isomerization / electrophilic halogenation of allylic alcohols (Scheme 1). This convenient and operationally simple approach provides access to various aliphatic α-halo ketones (2 ) in a fully regiocontrolled manner.

Scheme 1 . Ir-catalyzed isomerization/halogenation of allylic alcohols.

ORGN 708

Rh-catalyzed intermolecular hydroacylation of unactivated alkenes with salicylaldehydes: Mechanistic studies and application to natural product synthesis

Max von Delius, [email protected], Christine M Le, Vy M Dong. Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada

Despite its great potential for the synthesis of valuable ketone products, the intermolecular hydroacylation of olefins with a broad scope of the alkene component is an unsolved problem. Here we present a method that promotes the hydroacylation of an exceptionally wide range of unactivated, terminal alkenes with salicyladehyde derivatives. Good to excellent yields, as well as high regioselectivities (linear products) were obtained and catalyst loadings as low as 2% [Rh] could be employed. Key for the observed reactivity and selectivities is a bulky, chiral phosphoramidite ligand whose mechanistic role was investigated by in situ 31P NMR spectroscopy and x-ray crystallography. Further mechanistic studies based on 2H-labeling and the 12C/13C kinetic isotope effect led to a detailed mechanistic proposal. The applicability of the catalytic method was demonstrated by the total synthesis of several recently isolated natural products. ORGN 709

Recent advances in transition metal-assisted radical reactions

Gagik Melikyan, [email protected], Erin Voorhees, Bianca Rivas, Vahe Darabidian, Deborah Meron, McKinzie Garrison. Department of Chemistry and Biochemistry, California State University Northridge, Northridge, CA 91330, United States

The novel methods for generation of alpha-alkoxy, alpha-alkyl, alpha-alkenyl, and alpha-alkadienyl cobalt-complexed propargyl cations and radicals were developed. The experimental protocols include treatment of propargyl derivatives with triflic anhydride, trifluoroacetic anhydride, or tetrafluoroboric acid, followed by an in situ reduction of intermediate cationoid species with cobaltocene, or zinc. The applicability of reaction conditions to intramolecular reactions, affording bis-alkynylated cycloalkanes (C5&C6) and bis-alkoxylated 1,5-cycloalkadiynes was demonstrated. The impact of gamma- substituent (1,3-steric induction) and a phosphine-/phosphite-modified metal core upon the stereoselectivity of the radical C-C bond formation will be discussed, along with multinuclear NMR analysis of bis-propargyl cations and computational data for the requisite cationic and radical species. The relevance of intramolecular reactions to the development of dormant, non-toxic anticancer drugs will also be presented.

ORGN 710

Nickel-catalyzed multicomponent coupling: A new approach to synthesize 1,4- difunctionalized compounds

Sanjeewa K Rodrigo, [email protected], Hairong Guan. Department of Chemistry, University of Cincinnati, Cincinnati, Ohio 45221, United States

A new catalytic system for the synthesis of 1,4-difunctionalized compounds has been developed. The method involves Ni(COD)2 with an N-heterocyclic carbene ligand as the catalyst and triethylsilane as the reducing agent to couple a propiolate ester and an aldehyde to give the target product.

ORGN 711

New strategy fot the synthesis of highly substituted alkenes via copper-catalysed difunctionalization of alkynes

Marcos G. Suero, [email protected], Elliott Bayle, Beatrice S. LeFanu Collins, Matthew J Gaunt. Department of Chemistry, University of Cambridge, Cambridge, Cambridgeshire CB2 1EW, United Kingdom

The expeditious, regio- and stereoselective synthesis of tri- and tetrasubstituted olefins has provided a challenge for synthetic organic chemists for years. Although these systems can be obtained, for instance by the McMurry reaction or Wittig olefination, the generality as well as the regio- and stereoselectivity of these procedures are major problems. Hydro- and carbometallation of alkynes are the most widely used methods for the formation of these unsaturated systems. However, these approaches do not generally employ readily available starting materials, sometimes lack regio- and stereoselectivity, and are fairly limited in scope. Herein, we present a simple and efficient synthesis of both tri- and tetrasubstituted olefins by a copper-catalyzed difuntionalization of alkynes with iodonium salts. The alkene products display highly versatile functionality that will likely find broad application in chemical synthesis.

ORGN 712

Intramolecular aryne-ene reaction: Synthetic and mechaistic studies

David A Candito, [email protected], Dennis Dobrovolsky, Mark Lautens. Department of Chemistry, University of Toronto, Toronto, Ontario M5S3H6, Canada

Although the chemistry of arynes is well developed some challenges still remain. The ene reaction of arynes has not gained widespread use in synthesis due to poor yields and selectivity. A general, high yielding and selective intramolecular aryne-ene reaction is described providing various benzofused carbo- and heterocycles. The scope of the reaction will be presented along with mechanistic data derived from a combined theoretical and experimental approach. Furthermore, the application of this methodology to the synthesis of (±)-Crinine will be discussed.

ORGN 713

Catalytic Claisen rearrangements of O-allyl kojates Jenifer N. Nalbandian, [email protected], Michael C. Pirrung.Dept. of Chemistry, University of California, Riverside, Riverside, CA 92521, United States

The classical Claisen rearrangement requires harsh conditions, such as long reaction times or high temperatures, which limits the substrates that can be used. This necessitates the identification of catalysts for the reaction. Due to the structural similarity of O-allyl kojates to (allyloxy)acrylates, among the best substrates for the catalytic Claisen, we have used various catalysts with these novel reactants, including Brønsted-Lowry and Lewis acids as well as hydrogen-bonding and transition metal catalysts. These conditions tolerate many substituted allyl kojates.

ORGN 714

SNAAPTM isopropyl sulfonimidate alkylating agents for acids, alcohols, and phenols

Tom J. Maricich, [email protected], Jessica L. Burton, Christine N. Bradford, Brian Kammourieh, Andrew Sykahua. Department of Chemistry and Biochemistry, California State University, Long Beach, Long Beach, CA 90840, United States

We have developed a special alkylating agent that is very simple to synthesize and react. Stable, crystalline N-1-adamantyl-O-isopropyl-p-nitrobenzenesulfonimidate has been prepared by O-alkylation of N-1-adamantyl-p-nitrobenzenesulfonamide with 2- iodopropane and silver oxide. This sulfonimidate rapidly converts acids to isopropyl esters, while catalysis with tetrafluoroboric acid dimethyl ether complex converts alcohols and phenols to isopropyl ethers in minutes at RT. SNAAPTM is an acronym for Substitution, Nucleophilic of Acids, Alcohols and Phenols. This procedure permits the synthesis of ethers with a secondary alkyl group, without the use of strong bases [Williamson reaction] and the competing E2 elimination process.

ORGN 715 Regioselective synthesis of meta-aminohydroxy benzenes and pyridines

Marisa G Weaver, [email protected], Stephen K Jackson, Thomas R. R. Pettus. Department of Chemistry & Biochemistry, University of California Santa Barbara, Santa Barbara, CA 93106, United States

A new method for formation of meta-aminohydroxy benzenes (m-AHB) and pyridines (m-AHP) in four steps from 1,3-diketones is presented. Products derived from these scaffolds can exhibit antifungal properties, act as ATP binding modulators or exhibit cytotoxicity. Other known methods for introducing electron deficient amino functionality into a ring system are difficult. However, this novel methodology provides access to these cores in a facile manner. The scope and range will be discussed.

ORGN 716

Organoboron reagents as mild nucleophiles in copper catalyzed reactions

Aaron M. Whittaker, [email protected], Richard P Rucker, Gojko Lalic. Department of Chemistry, University of Washington, Seattle, Wa 98195, United States

Copper is commonly employed as a catalyst to deliver hard nucleophiles from transmetallating partners such as Grignards, organolithium, and organozinc reagents. The use of readily available organoboron reagents as novel transmetallating partners in copper-catalyzed reactions is discussed. These reactions include an allylic substitution reaction with unprecedented regioselectivities and moderate enantioselectivities, an electrophilic amination reaction to provide hindered aniline derivatives, and a highly regioselective anti-Markovnikov hydroamination of terminal alkenes. ORGN 717

New strategies for the synthesis of all-carbon quaternary stereocenters in sterically hindered environments via hetero-[3,3] sigmatropic rearrangements

Ryan E Michael, [email protected], Tarek Sammakia. Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309-0215, United States

The stereoselective synthesis of all-carbon quaternary centers continues to be a daunting challenge in organic chemistry. Especially difficult is the synthesis of quaternary carbons that bear additional proximal steric hindrance. [3,3] Sigmatropic rearrangements are a powerful tool for the stereo-controlled synthesis of these hindered systems. Topics discussed will include the design and implementation of new hetero- [3,3] sigmatropic rearrangements and the application of these methods for the stereocontrolled synthesis of all carbon quaternary stereocenters in sterically congested environments.

ORGN 718

Synthesis of fused heterocycles and carbocycles through rhodium-catalyzed alkyne arylation and cyclization

Jane Panteleev, [email protected], Lei Zhang, Mark Lautens. Department of Chemistry, University of Toronto, Toronto, Ontario M5S3H6, Canada

The design of more efficient methodologies in heterocycle synthesis is of paramount importance as a result of increasing demand for fine chemical production with minimal environmental impact. The Lautens group's work on alkyne and alkene functionalization through the rhodium-catalyzed arylation reaction has led to the development of several concise syntheses of polycyclic compounds. A synthesis of dihydroquinolines through a two-metal/two-ligand catalytic system is disclosed, including the optimization and exploration of the scope as well as the challenges of combining two transition metal- mediated processes into a tandem reaction. Additionally, mechanistic investigations of the intricate metal-ligand interactions and their effects on the overall reactivity of the catalyst system are discussed. Application of this reactivity to other heterocycles, such as dibenzoxipins and dibenzazepins is also touched upon.

ORGN 719 Novel access to methyl substituted polyketides structural units

Eric Stefan, [email protected], Richard E Taylor. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States

The combination of our interest in the cyanobacteria-derived polyketides and the development of the ether transfer methodology has inspired us to explore new methodologies for the production of unique methyl substituted polyketide structural units. The extension of the ether-transfer methodology enabled the stereoselective formation of tertiary ethers and was applied to the synthesis of the C9-C19 fragment of Lyngbyaloside C. In addition, modification to ether transfer substrates and activating conditions were investigated in an effort to promote intramolecular 1,5-hydride transfer.

ORGN 720

Epoxide approach for the synthesis of the C14-C25 polypropionate fragment of bafilomycin A1

Elizabeth M Valentín Nevárez, Marlenne Mulero, José A Prieto, [email protected]. Department of Chemistry, University of Puerto Rico, San Juan, PR 00931, Puerto Rico

Bafilomycin A1 is a prominent member of the plecomacrolide family of natural products, which possess interesting biological activity. Our synthetic efforts towards the convergent synthesis of the bafilomycin A1 polypropionate chain encompasses a three- step, reiterative methodology that consists of epoxide ring opening with an alkynyl organoalane reagent, reduction of the alkyne to form a homoallylic alcohol, and their stereoselective epoxidation to produce stereodefined 3,4-epoxy alcohols. These epoxides were used for the construction of configurationally defined stereotriads and stereotetrads in six to eight steps. These precursors were then coupled using dithiane chemistry to produced the C14–C25 polypropionate fragment of bafilomycin A1. This work was supported by NIH RISE (1R25-GM-61151-01A1) and NIH SCORE (2S06GM- 08102-29)

ORGN 721

Formal cycloadditions of alkoxy-susbtituted donor-acceptor cyclopropanes and cyclobutanes

Andrew C. Stevens, [email protected], Brian L. Pagenkopf. Department of Chemistry, The University of Western Ontario, London, Ontario N6A 5B7, Canada Cyclopropanes have long been exploited as building blocks for the synthesis of highly substituted heterocycles. We have shown that with the addition of an appended alkoxy substituent these strained carbocycles have enhanced reactivity that facilitates reactions with nitriles and indoles to expand the products accessible from cyclopropane cycloadditions. Additionally, we have been recently exploring similar cycloaddition reactions with cyclobutanes, which have received relatively sparse attention despite possessing a similar degree of bond strain. We have discovered that under Lewis acid catalysis alkoxy-activated cyclobutanes undergo facile reactions with imines, aldehydes, and nitrones to form unique structural motifs.

ORGN 722

How to make an amide bond from just about anything

Clare-Liana Allen, [email protected], Jonathan MJ Williams. Department of Chemistry, University of Bath, Bath, Somerset BA2 7AY, United Kingdom

The amide bond is one of the most important linkages in contemporary chemistry, being one of the most prolific moieties in pharmaceutical molecules and natural products. This research has explored novel, efficient reactions to form amides with the principles of green chemistry in mind and aims to address the current lack of atom efficient and cost effective synthesis options for making amides.

C. L. Allen et al., Tetrahedron Lett., 2011, 52, 4252; Chem. Soc. Rev., 2011, 40, 3405; Org. Lett., 2010, 12, 5096; Tetrahedron Lett., 2010, 51, 2724; Tetrahedron Lett., 2009, 50, 4262.

ORGN 723 Pd-Catalyzed regioselective synthesis of catechols from phenols via traceless silanol-directed C–H oxygenation

Chunhui Huang, [email protected], Nugzar Ghavtadze, Buddhadeb Chattopadhyay, Vladimir Gevorgyan. Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, United States

A silanol-directed, Pd-catalyzed synthesis of catechols from phenols via C-H oxygenation is disclosed. This method is highly regioselective and general, as it allows for oxygenation of not only electron-rich- and electron-neutral- but also electron- deficient phenols. The scope will be presented and detailed mechanism of this reaction will be discussed.

ORGN 724

Copper catalyzed cross coupling interrupted by an opportunistic Smiles rearrangement: An efficient domino approach to dibenzoxazepinones

Matthew O Kitching, [email protected], Timothy E Hurst, Victor Snieckus. Department of Chemistry, Queen's University, Kingston, Ontario K7L 3N6, Canada

The use of 2-iodobenzamides (1 ) and 2-bromophenols (2 ) in a one-pot copper catalyzed process affording tricyclic dibenzoxazepinones (3 ) is reported. The highly convergent nature of this transformation allows diversity to be incorporated late stage in the synthesis of these ring systems. The scope of the reaction with regard to steric and electronic effects is discussed, as are experiments to support the mechanism of this process. The extension of this work to include sulphonamides in an analogous process is also dicsussed.

ORGN 725

Reverse Cope cyclisations: Synthesis of novel heterocyclic nitrones and exploration of their synthetic utility

Lucy R Peacock1, [email protected], Steven D Bull1, Dominique Amans2. (1) Department of Chemistry, University of Bath, Bath, Avon BA2 7AY, United Kingdom (2) Department of Epinova, GlaxoSmithKline, Stevenage, Herts SG1 2NY, United Kingdom Nitrones are a highly versatile synthon and commonly synthesised via metal-catalysed amine oxidation. The use of reverse-Cope cyclisations1 as a metal free strategy for nitrone synthesis has not previously been reported. We now describe the development of this methodology and report results demonstrating the synthetic utility of these novel nitrones.

Currently, asymmetric conditions for the reduction to amine (a potential substrate for novel β-amino acid foldamers) are being explored.

1. N. J. Cooper, D. W. Knight, Tetrahedron, 2004 , 60, 243-269.

ORGN 726

Pyridine synthesis: A modular, catalytic approach

Mary E Gunn1, [email protected], Stephen Marsden1, Steven Wailes2. (1) Department of Chemistry, University of Leeds, Leeds, United Kingdom (2) Jealott's Hill International Research Centre, Syngenta, United Kingdom Substituted pyridines occur widely in nature and have high biological activity leading to their prevalence in both the agrochemical and pharmaceutical industries. The aza-Diels- Alder reaction of 2-azabutadienes has provided an alternative pathway to pyridines avoiding the use of multiple electron-withdrawing groups and limited substitution patterns that many classical methods suffer from. However, the requirement for organic azides and generation of stoichiometric phosphine oxide waste in the preparation of 2- azabutadienes via aza-Wittig reaction has prevented its wider uptake. We recently described a organocatalytic azide-free aza-Wittig reaction utilising a phosphine oxide catalyst and isocyanate precursors. This has now been extended to the intermolecular aza-Wittig reaction using vinyl isocyanates to give 2-azabutadienes and dienophiles added to give substituted pyridines in a one-pot fashion.

ORGN 727

Modular reaction pairing approach to the diversity-oriented synthesis of fused- and bridged-polycyclic sultams

Joanna K Loh, [email protected], Thiwanka B Samarakoon, Alan Rolfe, Sun Young Yoon, Paul R Hanson. Department of Chemistry, University of Kansas, Lawrence, Kansas 66045, United States

A reaction pairing strategy focused on the utilization of a collection of reactions (sulfonylation, SNAr addition and Mitsunobu alkylation) to generate skeletally diverse benzofused sultams is reported. The pairing of sulfonylation and SNAr reactions rapidly generates tricyclic, bridged benzofused sultams. The addition of the Mitsunobu reaction in a sulfonylation–Mitsunobu–SNAr sequence allows access to benzo-oxathiazocine- 1,1-dioxides, while a simple change in combination to sulfonylation–SNAr–Mitsunobu affords structurally distinct tricyclic, bridged benzofused sultams. With these scaffolds in hand, two 40-member libraries were efficiently prepared via a microwave-assisted intermolecular SNAr diversification reaction.

ORGN 728

Network detection of novel one-pot reactions of quinoline derivatives

Nosheen A. Gothard, [email protected], Chris M. Gothard, Siowling Soh. Department of Chemistry, Northwestern University, Evanston, IL 60208, United States

In search for simpler, more efficient and economical ways to make useful organic compounds, chemists have been inspired to find conditions that combine a series of reactions in a single reaction vessel (i.e. one-pot synthesis). We have established a computational method using network theory and topology (Nature Chemistry 2009, 31), to algorithmically detect novel tandem reaction sequences with high step economy. Here, we present the synthesis of C2- and C4-substituted quinoline derivatives using one-pot protocols guided by our network and synthetic knowledge.

ORGN 729

Synthesis and application of rhodamine B and fluorescein dyes for early corrosion sensing

Andre A. Williams1, [email protected], Joseph Labukas2, Joshua A. Orlicki1, John A Escarsega2, Brian Placzankis2. (1) Macromolecular Science & Technology Branch, Army Research Laboratory, Aberdeen Proving Ground, Maryland 21005, United States (2) Coatings, Corrosion, & Engineered Polymers Branch, Army Research Laboratory, Aberdeen Proving Ground, Maryland 21005, United States

Rhodamine B and fluorescein were chemically modified with ketones and aldehydes to control the steric environment and electron density surrounding the binding site in an attempt to impart selectivity for specific metals. Solution phase studies evaluated dye binding to iron (III), which is formed in the corrosion process, relative to other metal ions such as iron (II), aluminum (III), chromium (III), and zinc (II). Evaluation using ultraviolet- visible spectroscopy and fluorescence measurements revealed significant environment effects as the solvation solvent was changed. These dyes were then integrated into epoxy coating formulations to determine the ability of these dyes to detect and report the early onset of metal corrosion, and to ascertain the impact of the solid state on dye- metal binding interactions. The detection limit was evaluated by determining the effectiveness of the fluorescence in response to variations in coating thicknesses.

ORGN 730

Pyridine N-oxide, nitropyridines, and nitropyridine N-oxides

Cyril Parkanyi1, [email protected], Zuzana Zajickova2, Omar R. Martinez1, Marwan Dakkouri3. (1) Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, Florida 33431-0991, United States (2) Department of Physical Sciences, Barry University, Miami Shores, Florida 33161-6695, United States (3) Abteilung fur Elektrochemie, Universitat Ulm, Ulm, Germany

Pyridine can be characterized as a π-deficient, six-membered ring, 6π-electron aromatic heterocycle, π-isoelectronic with benzene. In pyridine N-oxide, four of the possible resonance structures contributing to the resonance hybrid have a negatively charged oxygen atom and the dipolar forms are important. In addition to the N→O bond, the three nitropyridine N-oxides contain a strongly electron-withdrawing nitro group. We have studied the physical properties (electronic absorption spectra, geometries, ground- and excited-state dipole moments) and chemical reactivity (catalytic hydrogenation, chemical reduction, deoxygenation, substitution reactions, and acid-base reactions) of pyridine N-oxide, 2-, 3-, and 4-nitropyridine, and 2-, 3-, and 4-nitropyridine N-oxide. The experimental information will be compared with the results of quantum chemical calculations (ab initio, PPP, HyperChem).

ORGN 731

Synthesis and characterization of luminescent conjugated organoborane macrocycles

Pangkuan Chen, [email protected], Frieder Jäkle. Department of Chemistry, Rutgers University-Newark, Newark, New Jersey 07102, United StatesDepartment of Chemistry, Rutgers University-Newark, Newark, New Jersey 07102, United States

Macrocycles continue to attract considerable attention because of their broad applications in the area of host-guest chemistry, in supramolecular chemistry, and in catalytic engineering.1 Fully conjugated macrocycles represent chain end-free π- systems, which can be advantageous in comparison to the respective linear oligomers. They often exhibit significant ring strain, and therefore dramatic ring size-dependent changes in the optical and electrochemical properties.2

Boron-containing electron-deficient macrocycles could be of great potential significance due to the expected unusual linear and nonlinear optical properties and potential applications as electron-transport materials, emitters in OLEDs, etc.3 Of interest is also that tricoordinate organoborane compounds can serve as selective chemosensors for the recognition of samll anions. All these properties stem from the electron-deficient nature of boron and from conjugation of the empty pπ orbital with π orbitals of attached π-conjugated moieties.4

Recently, we have developed a selective and versatile route to fluoreneborane oligomers that are structurally well-controlled and defined in conjugation length.5 We describe herein the preparation and photophysical and electrochemical investigation of the first highly Lewis acidic bora-cyclophanes. Comparisons will be made to related aza- cyclophanes reported by Tanaka,6 which provide important insights into how the electronic structure correlates with the nature of the bridging atoms. 1. D. Ramaiah, P. P. Neelakandan, A. K. Nair, R. R. Avirah, Chem. Soc. Rev. 2010 , 39, 4158.

2. T. Iwamoto, S. Yamago, et al, J. Am. Chem. Soc. 2011 , 133, 8354.

3. a) F. Jäkle, Coord. Chem. Rev. 2006, 250, 1107; Chem. Rev. 2010 , 110, 3985; b) N. Matsumi, Y. Chujo, Polym. J. 2008 , 40, 77.

4. C. D. Entwistle, T. B. Marder, Chem. Mater. 2004 , 16, 4574.

5. P. Chen, R. A. Lalancette, F. Jäkle, J. Am. Chem. Soc. 2011 , 133, 8802.

6. A. Ito, K. Tanaka, et al, Angew. Chem. Int. Ed. 2010 , 49, 8205.

ORGN 732

Inverse electron demand hetero-Diels-Alder reaction of o-quinones

Jinsong Zhang, [email protected]. Department of Chemistry and Biochemistry, California State University, Chico, Chico, CA 95929, United States

The inverse electron demand hetero-Diels-Alder reaction of o-quinones and various dienophiles is studied experimentally and computationally. The reaction can be applied to natural product and organic synthesis in making 1,4-benzodioxane-based compounds. In order to achieve regioselectivity, approaches including modifying structures of dienophiles and o-quinones and using metal catalysts will be presented.

ORGN 733

Atropdiastereoselective C-arylation process for the generation of novel tricyclic sultams

Kyu Ok Jeon1,2, [email protected], Paul R. Hanson1,2. (1) Department of Chemistry, University of Kansas, Lawrence, KS 66045, United States (2) The Center for Chemical Methodologies and Library Development at the University of Kansas (KU-CMLD), Lawrence, KS 66047, United States

The development of new methods to access diverse sultams based on central α-halo benzenesulfonamide and vinyl sulfonamide building blocks is reported. These molecules are inspired by a number of biologically active sulfonamides and sultams reported in the literature. A strategy termed “Click, Click, Click, Cyclize” is reported for the generation of an array of benzofused tricyclic sultams. In this process, an atropdiastereselective C-arylation reaction is utilized for the generation of 7- and 8- membered tricyclic sultams. Screening of these libraries within the MLPCN will provide insight into their potential bioactivity.

ORGN 734

Syntheses of highly fluorinated naphthalene derivatives: Comparison of the Bergman cyclization approach with a fluorothiophene route

Markus Etzkorn1, Timothy B. Callahan1, Tiffany B. Meyers1, [email protected], Michael Gerken2. (1) Department of Chemistry, The University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States (2) Department of Chemistry and Biochemistry, University of Lethbridge, Lethbridge, Alberta T1K 3M4, Canada

In our efforts to synthesize large fluorinated polyarene scaffolds we require tera- and hexafluoronaphthalene derivatives as building blocks. These compounds are not readily available and we developed two approaches to these important intermediates:

(1) A series of fluorinated benzofused enediynes, obtained through Sonogashira cross- coupling, was subjected to Bergman cyclization, furnishing a variety of di- and tetrafluorinated naphthalene derivatives. We will present selected structures of starting materials and cyclized products to discuss their molecular structures and packing arrangements.

(2) A second route relies on the Diels-Alder reaction of fluorinated thiophenes with tetrafluorobenzye. We will present our results on the synthesis of novel fluorinated 3,4- disubstituted thiophene derivatives and their cycloaddition to tetrafluorobenzyne, providing access to tetra- and hexafluoronaphthalene derivatives.

ORGN 735

Emerging rules in hydrogen-bond and coordination-driven self-assembly to direct solid-state reactivity: Quantitative photocycloaddition of conformationally- frustrated olefins

Elizabeth Elacqua, [email protected], Joseph C. Sumrak, Paul T. Jurgens, Bradley Loren, Ryan H. Groeneman, Poonam Kaushik, Dejan-Kresimir Bucar, Leonard R. MacGillivray. Department of Chemistry, University of Iowa, Iowa City, IA 52245, United States

Supramolecular chemistry focuses on the design of molecular architectures by relying on the complementary recognition and assembly of well-defined subunits. Molecular recognition stems from biology, wherein systems must balance a panoply of intermolecular interactions to achieve targeted properties. In an effort to mimic Nature, chemists employ noncovalent interactions to direct self-assembly. Specifically, small molecule 'templates' have been designed to influence the packing of olefins, so as to facilitate a [2+2] photocycloaddition. To expand the applicability of our approach, we pursued the photoreaction of trisubstitued olefins. Trisubstituted olefins are known building blocks of natural products, and are well-studied in the context of biosynthesis, wherein subtle changes in molecular structure can affect properties.

In this contribution, we will present a series of trisubstituted olefins that prefer twisted geometries and discuss the impact of the methyl group on solid-state reactivity. We will discuss the difficulties encountered in achieving reactive assemblies with sterically- congested systems.

ORGN 736

Organic nanocrystals of pharmaceutical cocrystals and a host-guest system

John R. G. Sander1, [email protected], Dejan-Krešimir Bučar1, Rodger F. Henry2, Jonas Baltrusaitis3, Geoff G. Z. Zhang4, Leonard R. MacGillivray1. (1) Department of Chemistry, The University of Iowa, Iowa City, Iowa 52242-1294, United States (2) Structural Chemistry, Global Pharmaceutical R&D, Abbott Laboratories, Abbott Park, Illinois 60064, United States (3) Central Microscopy Research Facility, The University of Iowa, Iowa City, Iowa 52242-1294, United States (4) Materials Science, Global Pharmaceutical R&D, Abbott Laboratories, Abbott Park, Illinois 60064, United States

The size-dependent properties related to nanocrystals make such solids of great interest. Whereas inorganic nanocrystals have experienced immense utility, nanocrystals comprised of purely organic components have remained relatively unexplored despite unique physicochemical properties (i.e. molecular recognition). In recent years cocrystals (i.e. multi-component molecular crystals) have garnered interest in the field of Pharmaceutics owing to an ability to improve the physicochemical properties of pharmaceutical agents (PAs) through noncovalent means. Coupling the benefits of pharmaceutical cocrystals and nanocrystals can be expected to further improve PA properties. With this in mind, we turned to a sonochemical approach that employed multiple-solvents and surfactant to achieve nano-cocrystals of caffeine 2,4- dihydroxybenzoic acid monohydrate, (caff)·(dhba)·(H2O), with an average crystal size of 136.4 nm ± 65.05. The utility of the sonochemical approach was further realized with additional pharmaceutical cocrystals and the host-guest system C- methylcalix[4]resorcinarene (CMCR). Sonochemistry not only yielded CMCR nanocrystals but afforded hollow crystals.

ORGN 737

Luminescence sensing of Fe(III) and Cu(II) through redox active 1,8-disubstituted anthraquinone macrocycles Mariah M Hoffman, [email protected], Prem N Basa, Andrew G Sykes. Department of Chemistry, University of South Dakota, Vermillion, SD 57069, United States

Regional concentration imbalances of Fe(III) and Cu(II) have been linked to neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, but the relationship between the ions and the diseases is not fully understood. Here we employed the concept of 'fluorophore-spacer-receptor' to selectively respond to Fe3+ and Cu2+ by mimicking naturally available siderophores. A series of 1,8-disubstituted anthraquinone polyamide tripodal macrocycles are designed as receptor systems and dansyl, rhodamine and anthracene as fluorophore reporters. A simple synthetic procedure of ester hydrolysis starting from 1,8-diester anthraquinone and TREN derivatives in toluene/methanol effected product formation. Synthesis was confirmed through 1H and 13C NMR and single crystal XRD. The dansyl and rhodamine derivatives showed fluorescence turn-on (OFF-ON) response to Fe3+ and Cu2+ among sixteen tested transition, alkali and alkaline earth cations. Metal ion selectivity, binding stoichiometry and redox chemistry will be discussed in detail.

ORGN 738

NMR reveals variable degrees of order inside the cavity of pyrogallolarene hexamers

Byron W Purse1, [email protected], Jennifer C Chapin1, Miroslav Kvasnica2, Hannah M La Belle-Hamer1. (1) Department of Chemistry and Biochemistry, University of Denver, Denver, CO 80208, United States (2) Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic

Pyrogallolarene self-assembles in non-polar organic solvents to form hexamers of octahedral symmetry. Recently, our group has shown that the versatility of these capsules can be dramatically extended by inducing the self-assembly using a procedure of melting and cooling mixtures of pyrogallolarene and a desired guest under solvent- free conditions. This approach provides efficient encapsulation of many guest molecules and, remarkably, often provides kinetically trapped complexes that are indefinitely stable at room temperature and that do not form when solvent is present. Using these assembly conditions, we have carried out detailed studies on the interactions between host and guest, and have found that these interactions are strongly dependent on the guest's size, shape, and functional groups. The results reveal that an increasingly good fit of host and guest reduces the rate of guest tumbling, slows guest exchange from the capsules, and even increases the communication between host and guest.

ORGN 739

Molecules to materials: The design of mercury-containing gelators

Kelsey N. King, [email protected], Anne J. McNeil. Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, United States

Molecular gels are formed by the self-assembly of small molecules into a material that exhibits solid-like behavior, but is largely comprised of liquid. Details as to what causes a molecule to form a gel and the mechanism of gelation remain elusive. Furthermore, there is no reliable method to identify gelators from nongelators without extensive screening. This talk will therefore describe our efforts to towards predicting new gelators from their crystal structures. We recently discovered a novel stimuli-responsive gelator by examining crystal structures of mercury complexes containing 1D mercury-π intermolecular interactions. Subsequent modification of the ligand scaffold led to the discovery of both gelators and nongelators. We then determined the enthalpy and entropy of dissolution for all of these compounds to identify possible structure-gelation trends. This information should provide valuable insight into the differences between gelators and non-gelators and eventually aid in the design of new gelators.

ORGN 740

Fluorescence sensing of imine derivatives of anthraquinone macrocycles

Andrew G Sykes, [email protected], Prem N Basa, Mariappan Kadarkaraisamy, Arundhati Bhowmick, Mariah M Schulz. Department of Chemistry, University of South Dakota, Vermillion, SD 57069, United States

A one pot synthetic procedure using Ti(IV)/DABCO as the catalyst, results in the site- selective imination of one extraannular carbonyl group within an anthraquinone macrocycle. When aromatic diamines are employed, diimines result and the 1,3-diimine derivative showed selective fluorescence 'turn on' only in the presence of Ba(II) ion. Through spectroscopic titrations and Jobs plot data, the imine derivatives require the association of two Ba(II) ions in order for luminescence to occur. Reaction of hydrazines with anthraquinone macrocycles produces exclusively intraannular hydrazones however, which is contrary to what has previously been reported in the literature. Hydrazones formed from hydrazine, phenyl hydrazine and nitro-substituted phenyl hydrazines all react with only the internal carbonyl group and have been structurally characterized by single-crystal X-ray diffraction. We also explore the reduction chemistry of these new imines, involving selective reduction of the extraannular Schiff bases and the hydrazones with the application to new luminescence sensor design.

ORGN 741

Developement of new nanostructures from phenylacetylene macrocycles

Jean-Francois Morin, [email protected]. Chemistry, Université Laval, Quebec, Quebec G1V 0A6, Canada

The preparation of well-defined, shape persistent and stable organic nanostructures is recognized as one the most important milestones for the development of nanoscience. Among other assemblies, phenylacetylene macrocycles (PAMs) are particularly interesting for the construction of supramolecular and covalently linked organic nanotubes with definite dimensions since their diameter can be adjusted through the careful design of macrocycles used as building blocks. Here we present the synthesis and characterization of new assemblies of PAMs based on the 1,3-butadiyne motif for further construction of semi-conducting nanotubes. The assembly of those materials has been studied using various techniques, including UV-visible, DSC and NMR to determine the precise structure of these supramolecular nanotubes. Intermolecular topochemical polymerization of the 1,3-butadiyne units has been attempted on these PAMs under different conditions, leading to rigid and stable semi-conducting nanotubes with poly(diacetylene)-based wall.

ORGN 742

Developing new, modular components for the self-assembly of functional donor- acceptor columnar liquid crystalline materials

Joseph J Reczek, [email protected]. Department of Chemistry and Biochemistry, Denison University, Granville, OH 43023, United States

Combining electron-rich with electron-poor aromatic molecules can lead to the formation of face-to-face assembled Donor-Acceptor Columnar Liquid Crystals (DACLCs). These sparsely studied materials exhibit fascinating properties, including light absorption, and charge mobility, distinct from their component molecules. Described here is work to expand upon the scope of available components for DACLC formation, including synthesis of expanded aromatic thiophenes and aromatic poly-imides. The bulk characteristics of new DACLC materials from these components were studied in modular fashion, including absorption characteristics and structure as related to DFT energy calculations of the component molecules. The results provide an increased variability in known classes, property tunability, and structure-property relationships for self-assembled DACLC materials. ORGN 743

Nanoparticle monolayers as selective, supramolecular catalysts

Kevin P. Browne, [email protected], Chris M. Gothard, Baudilio Tejerina, Bartosz A. Grzybowski. Department of Chemistry, Northwestern University, Evanston, IL 60201, United States

A self-assembled monolayer on a nanoparticle acts as a supramolecular environment for performing selective catalysis, here for ionic substrates.

ORGN 744

Self assembly of terpyridine based supramolecules

Anthony Schultz1, [email protected], Xiaopeng Li1, Rajarshi Sarkar1, Chrys Wesdemiotis1,2, Charles N Moorefield2, George R Newkome1,2. (1) Department of Chemistry, University of Akron, Akron, OH 44325, United States (2) Department of Polymer Science, University of Akron, Akron, OH 44325, United States

In recent years several bisterpyridine ligands have been utilized for the assembly of a plethora of supramolecules, utilizing the complex. Although a variety metal ions have been implemented in this chemistry, typically transition metals ions, such as RuII, OsII, FeII, ZnII, and CdII are used. The lability of the CdII complexes has proven invaluable in the synthesis of simple polygons. In particular, novel metallotriangles will be addressed. Bisterpyridine ligands have been synthesized by a variety of simple known organic transformations. Recent commercial availability of 4-formylphenylboronic acid has paved the way for several novel ligands to be synthesized, based off a central benzene core, with anywhere from 1-6 terpyridine moieties attached. Increasing the complexity of the terpyridine ligands has been shown to give higher ordered structures in high yields. The physical properties of these snowflake structures have been studied, as well as their assembly into even higher ordered nanoarchitectures, via a variety of intermolecular interactions, such as van der Waal and ionic. These novel assemblies will be discussed; also the synthesis and structural characterization will also be considered.

ORGN 745

Selective recognition of neurotransmitters by chiral phosphonatocavitand hosts

Jean-Pierre Dutasta, [email protected], Bastien Mettra, Jean-Christophe Mulatier, Jérôme Vachon, Steven Harthong.Laboratoire de Chimie, Ecole Normale Supérieure de Lyon, Lyon, France

Phosphonatocavitands are remarkable ligands for polar guests and have been particularly involved in the recognition of ammonium guests. It has been possible to introduce chirality by desymmetrization of the molecular cavity giving access to inherently chiral hosts. Inherently chiral phosphonatocavitands with various bridging moieties at their wide rim were thus synthesized. Optical resolution by chiral HPLC affords enantiopure compounds, which form inclusion complexes with chiral ammonium neurotransmitters, some presenting enantioselectivity towards the right or left-handed host enantiomers. On the other hand, we will also report on the selective recognition of choline vs. acetylcholine neurotransmitters, both playing a fundamental role in the neuronal processes. The molecular structures of different hosts and their complexes will be presented and discussed on the basis of NMR experiments, mass spectrometry, and X-ray data.

ORGN 746

Synthetic studies on the archazolid natural products

Gregory W O'Neil, [email protected]. Chemistry, Western Washington University, Bellingham, WA 98225, United States

The archazolids are a family of natural products that display potent growth inhibitory activity against a number of human cancer cell lines based on selective VATPase inhibition. A synthesis of the entirety of the archazolid framework has been completed along with the development of convenient Arabidopsis-based VATPase assays.

ORGN 747

Tandem radical cyclization for the synthesis of bisabosqual A

Christopher W am Ende, [email protected], Zhou Zhou, Kathlyn A Parker. Department of Chemistry, Stony Brook University, Stony Brook, New York 11794, United States

The Bisabosquals are natural products that display broad spectrum antifungal activity and inhibit squalene synthase. We have developed a mild, tin-free, 5-exo 6-exo tandem radical cyclization method for construction of the cis, cis-fused bisabosqual tetracyclic ring system. This key transformation creates two rings and sets three stereogenic centers, one of which is quaternary. Optimization and application of this chemistry to the total synthesis of Bisabosqual A will be presented.

ORGN 748

Total synthesis of (–)-N-methylwelwitindolinone C isothiocyanate

Alexander D. Huters, [email protected], Neil K. Garg. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, United States

N-methylwelwitindolinone C isothiocyanate is a complex alkaloid that was first isolated from the cyanobacterium Hapalosiphon welwitschii in 1994. The unique structure and promising biological activity of this natural product has prompted our laboratory to pursue its total synthesis. In this presentation, the completed total synthesis of N- methylwelwitindolinone C isothiocyanate will be described. Our approach relies on the use of an indolyne cyclization to form the [4.3.1]-bicyclic framework of the natural product. The approach also utilizes a late-stage nitrene insertion to install the bridgehead nitrogen.

ORGN 749

Discovery and total synthesis of laetirobin

James La Clair2, [email protected], Martin J Lear1, Oliver Simon1, Bastien Reux1. (1) Department of Chemistry, National University of Singapore, Singapore, Singapore (2) Department of Chemical Biology, Xenobe Research Institute, San Diego, CA 92163- 1052, United States

Laetirobin, isolated from a parasitic fungus host-plant relationship, was synthesized in six practical steps with an overall yield of 12% from commercially available 2,4- dihydroxyacetophenone. Because the product is a pseudosymmetric tetramer of benzo[b]furans, each step of the synthesis was designed to involve tandem operations. Highlights include: 1) the double Sonogashira reaction of a bis(alkyne), 2) the practical copper(I)-mediated formation of a bis(benzo[b]furan), and 3) the biomimetic [4+2] dimerization and unexpected cationic [5+2] annulation of gem-diaryl alkene precursors. Preliminary structure-activity relationship data between the isomeric [4+2] and [5+2] tetramers revealed only the natural product to possess promising anticancer potential. Specifically, laetirobin is capable of blocking tumor cell division (mitosis) and invoking programmed cell death (apoptosis).

ORGN 750

Total synthesis and structure elucidation of FD-895 and a general route towards the pladienolides polyketides Reymundo A Villa, [email protected], Alexander L. Mandel, Brian D. Jones, James J. La Clair, Michael D. Burkart. Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, United States

Since their discovery in 2004, the pladienolides underwent rapid development and entry into clinical trials. Structurally based on a motif first discovered in FD-895, a related polyketide isolated in 1994 from an isolate of Streptomyces hygroscopicus, the potent activity and novel target (the spliceosome) of the pladienolides offered strong potential supporting the clinical trials. While clinical trials were recently suspended, interest in this unique family of spliceosome inhibitors continues. Our studies have focused on generating second-generation clinical candidates by developing a detailed understanding of the pharmacology of this family of natural products. We now describe the total synthesis of a related natural product FD-895 and several structurally related analogs and reflect on the current initiative to translate FD-895 into the clinic for use against metastatic bone cancer.

ORGN 751

Studies towards the total synthesis of the spirohexenolides

Justin C Hammons, [email protected], Brian D Jones, James J La Clair, Michael D Burkart. Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, United States

The spirohexenolide natural products belong to a class of structurally unique spirotetronates isolated from a strain of Streptomyces platensis in 2008. The compounds show unique cytotoxic activity in the NCI-60 cell line screening analysis while maintaining low cytotoxicity in mice. The total synthesis of the spirohexenolides is examined through a two component strategy involving Stille coupling of the spirotetronate to the pyran ring followed by an intramolecular Julia-Kocienski olefination to close the macrocycle. This strategy is described towards the progress of the total synthesis of (±)-spirohexenolide B.

ORGN 752

Application of the intramolecular vinylogous aldol reaction to the synthesis of (+)- peloruside A

Jeffrey A Gazaille, [email protected], Joseph A Abramite, Tarek Sammakia. Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, Colorado 80301, United States

The use of the intramolecular vinylogous aldol reaction for the preparation of an advanced intermediate for the synthesis of peloruside A is described. The reaction was applied and proceeds in high yield and good levels of diastereoselectivity. Application of the Achmatowicz reaction to this intermediate provided the corresponding pyranone, a late stage intermediate well positioned for conversion to the natural product.

ORGN 753

Total synthesis of flinderoles A-C by diastereoselective intramolecular Friedel- Crafts cyclizations of N-acyl indoles

Dadasaheb V Patil, [email protected], Stefan France. School of Chemistry & Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, United States

A simple and efficient total synthesis of (±)-flinderoles A-C, members of a new class of antimalarial bisindole alkaloids isolated from plant of the Flindersia genus. Key steps include: Lewis acid catalyzed intramolecular Friedel-Crafts alkylation that establishes pyrrolo[1,2-a]indole core with isobutenyl functionality and Pd-catalyzed cross-coupling reaction.

ORGN 754

Total synthesis of loline alkaloids

Guoqing Wei, [email protected], Theodore Cohen. Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States

A highly enantioselective synthesis of loline alkaloids in 11 steps will be presented. Key features include a highly anti-selective Mannich reaction of a chiral imine with a cyclic alpha-aminoester followed by oxidative coupling leading to the formation of a fused bicyclic system with a nitrogen atom at the bridgehead.

ORGN 755

Total syntheses of ent-heliespirones A & C Wenju Bai, [email protected], Thomas R. R. Pettus. Department of Chemistry & Biochemistry, University of California Santa Barbara, Santa Barbara, CA 93106 - 9510, United States

Stereodivergent total syntheses of ent-heliespirone A and C were both completed in eleven pots and ~24% combined overall yield (A+C). These syntheses employed an identical inverse demand Diels-Alder reaction between a surrogate for an extendedly conjugated γ-δ unsaturated ortho-quinone methide and L-lactic acid derived exo-cyclic enol ether. Novel reactions of special note include a diastereoselective reduction of a chroman spiroketal by combination of borontrifluoride etherate and triethyl silane, along with oxidative rupture of a chroman etherial ring into the corresponding p-quinone by argentic oxide (AgO). In addition, an unusual intramolecular etherification of a 3° alcohol caused by cerium ammonium nitrate was observed.

ORGN 756

Enantiocontrolled synthesis of the 25-membered lactone core of amphidinolide C

Derek A Fischer, [email protected], David R Williams, Ramkrishna De, Micheal Fultz, Angel Morales-Ramos, David Rodriguez-Reyes. Department of Chemistry, Indiana University, Bloomington, IN 47405, United States

We have developed a convergent enantiocontrolled route to the macrolactone core (1 ) of amphidinolide C from five readily accessed fragments. The C1–C9 fragment features a substrate directed SE' addition, providing the necessary stereotriad with a pendant vinylstannane positioned for subsequent cross-coupling chemistry. An acyl anion equivalent initiates a 5-exo-tet cascade utilizing the nonracemic bis-epoxide for formation of the chiral 2,5-trans-disubstituted THF system of the C10–C24 component. The discussion will present the development of key reactions leading to 1 .

ORGN 757

Application of the phosphine catalyzed (3+2) annulation: Total synthesis of ibophyllidine

Ian P Andrews, [email protected] of chemistry and biochemistry, university of california, los angeles, los angeles, california 90024, United States

The total synthesis of the alkaloid natural product ibophyllidine is described. Utilizing the phosphine catalyzed (3+2) annulation of sulfonyl imine 1 and electron deficient allene 2 to forge the substituted pyrroline 3. T he d-ring of ibophyllidine was established in good yield and with exquisite diastereoselectivity. Hydrogenation of the resultant (3+2) adduct 3 yields an all syn, trisubstituted prrolidine ring bearing three of the four stereocenters of ibophyllidine in only two steps from imine 1 and allene 2 . The E-ring is formed by an intramolecular alkylation at C-3 of the indole ring with the final C-ring resulting from an intramolecular aza-Baylis-Hillman reaction. Future efforts include using a P-chiral phosphine catalyst in an effort towards an enantioselective total synthesis and synthesis of related alkaloids including deethylibophyllidine.

ORGN 758

Mechanistic insights into CuAAC using well-defined copper(I)-acetylides

Brady T Worrell, [email protected], Jamal A Malik, Valery V Fokin. Department of Chemistry, The Scripps Research Institute, San Diego, California 92117, United States

Rigorous examination of reactions of organic azides with well-defined copper(I)- acetylides stabilized by an NHC ligand unequivocally established the intermediacy of dinuclear copper complexes within the CuAAC. The roles of two copper centers were delineated using isotopically enriched copper(63) catalysts, demonstrating their equivalency during the course of the reaction and the true step-wise nature of the C–N bond-forming events. New elementary steps within the CuAAC were identified expanding the reach of catalytic cycloadditions.

ORGN 759

Intramolecular catalytic asymmetric transformations of diazo sulfonylamidines: An unexpexted formal reduction of sulfur(VI) to sulfur(IV)

Nicklas Selander, [email protected], Valery V. Fokin. Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, United States

A variety of diazo sulfonylamidines (1) was prepared by the cycloaddition of sulfonyl azides and ynamines. In the presence of chiral rhodium(II) carboxylates, an unexpected intramolecular transfer of an oxygen atom from sulfur to carbon was observed. This formal reduction of sulfur occured rapidly under mild reaction conditions, to obtain enantioenriched sulfinylamidines (2) in excellent yield and with high enantioselectivity.

ORGN 760

New insights into the Negishi cross-coupling reaction: The role of salt additives

Ka Hou Hoi, Selçuk Çalimsiz, Lucas McCann, Michael Organ, [email protected]. Department of Chemistry, York University, Toronto, ON M3J 1P3, Canada

Through the combination of synthetic studies, NMR spectroscopy, and mass spectrometry, a new theory for the structure of the active transmetallating species in the Negishi reaction has emerged. Through careful titration and solvent studies, the effect that salt additives, such as LiBr, has on the Schlenk equilibrium has been studied in detail. The precise role of polar solvent on this equilibrium is also presented and how the solvent facilitates the formation of the critical higher-order transmetallating zincate, which we suggest is critical for the reaction to proceed. This higher order zincate now has been successfully prepared and subjected to the Negishi reaction with surprising results.

ORGN 761

Metal-catalyzed sulfination using Pd-NHC complexes: The importance of catalyst activation

Mahmoud Sayah, Michael G. Organ, [email protected]. Department of Chemistry, York University, Toronto, ON M3J 1P3, Canada The role of catalyst bulk in NHC-Pd complexes has been assessed in the metal- catalysed sulfination reaction. The most bulky PEPPSI complex yet reported, IPent, has shown dramatic rate enhancements over not only less hinder NHC complexes, (e.g., IPr), but also highly active phosphane catalysts (e.g., JosiPhos). The mechanism of catalyst activation has been studied and the byproducts of activation isolated and identified. In stark contrast to other cross coupling reactions, precatalyst activation is especially important in this sulfination reaction. Mechanistic aspects will be discussed and utility demonstrated.

ORGN 762

WITHDRAWN

ORGN 763

Synthesizing organic electronic materials by palladium-catalyzed direct arylation polymerization

Calvin Wiley1, Shiloh Stone1, Andrey Rudenko2,3,4, Keenan Woods1, Allyson Dorsey1, Robert Springer1, Erin Cyffka1, Lindsay Lawrence1, Barry C Thompson2,3,4, John F Tannaci1, [email protected]. (1) Department of Chemistry, California Lutheran University, Thousand Oaks, CA 91360, United States (2) Department of Chemistry, University of Southern California, Los Angeles, CA 90089, United States (3) Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, CA 90089, United States (4) Center for Energy Nanoscience, University of Southern California, Los Angeles, CA 90089, United States

Recently, direct arylation has emerged as a novel methodology that is on the verge of large-scale application. By eliminating pre-functionalization of one of the coupling partners, direct arylation offers a “greener” route to installing carbon-carbon bonds, and it is being actively investigated by medicinal chemists. However, despite the benefits in terms of atom economy and minimal organometallic waste, direct arylation has not been incorporated into the standard toolkit for constructing organic electronic materials. To address this deficiency, we studied small-molecule model systems to develop palladium-catalyzed direct arylation polymerization conditions, which were then applied to the synthesis of regioregular poly(3-hexylthiophene). Polymerization conditions were optimized by monitoring both molecular weight and regioregularity using gel permeation chromatography and NMR spectroscopy, respectively. Ongoing research regarding the substrate scope for palladium-catalyzed direct arylation polymerizations will also be presented.

ORGN 764

Asymmetric synthesis of functionalized cyclopropane via Co(II)-based metalloradical catalysis Xue Xu, [email protected], Xin Cui, Shifa Zhu, Peter Zhang. Department of Chemistry, University of South Florida, Tampa, FL 33620, United States

The metalloradical catalysts [Co(D2-Por*)] have been shown to be highly effective for asymmetric intermolecular cyclopropanation of a broad scope of substrates with different classes of carbene sources, particularly including acceptor/acceptor-substituted diazo reagents, with this catalyst system, we could synthesize highly functionalized cyclopropanes in excellent diastereoselectivity and enantioselectivity.

ORGN 765

Debunking myths about cobalt-complexed propargyl cations and radicals

Gagik Melikyan, [email protected], Louis Carlson, Bianca Rivas, Erin Voorhees. Department of Chemistry and Biochemistry, California State University Northridge, Northridge, CA 91330, United States

In the course of systematic studies on cobalt-complexed reactive intermediates, we proved the following myths false concerning propargyl cations and radicals: (1) organometallic cations are thermally labile species that can be used only at ambient, or lower temperature; (2) organometallic radicals are unruly, and stereoselectivity of the C- C bond formation cannot be effectively controlled; (3) 1,5-cyclodecadiynes cannot be assembled by intramolecular radical reactions in a selective manner; (4) meso-1,5- cyclodecadiynes are thermodynamically unstable and cannot be stereoselectively synthesized by intramolecular cyclization reactions; (5) synthesis of propargyl cations can only be accomplished under acidic conditions that are incompatible with acid- sensitive functional groups; and (6) propargyl radicals are kinetically independent species with the diastereoselectivity of the C-C bond formation being independent from the nature of a reducing agent. Along with the reaction scope and its synthetic potential, the novel mechanistic tools for stereodirecting both inter- and intramolecular processes will be presented.

ORGN 766

Selective reductions of various functional groups with HInCl2

Jaime Z Saavedra, [email protected], Panathada Bayrasy, Angel Resendez, Bakthan Singaram. Department of Chemistry and Biochemistry, UC Santa Cruz, Santa Cruz, CA 95064, United States

The in situ generation of dichloroindium hydride (HInCl2) via the reduction of InCl3 with various hydride sources in different solvents was explored. HInCl2 generated from InCl3/ NaBH4 also produced various borane complexes which were identified as BH3- tetrahydrofuran (THF), BH3-dimethyl sulfide (DMS), BH3-tetramethylethylenediamine (TMEDA), and BH3- N-methyl-2-pyrrolidone (NMP). Diisobutylaluminum hydride (DIBAL- H) and dimethyl lithium aminoborohydride (MeLAB) were also used to produce HInCl2 which along with NaBH4 allowed for the selective and/or partial reduction of multi- functionalized compounds containing carbonyls, nitriles, and halogens.

ORGN 767

Non precious metal complexes of 1,2,4-triazoles as versatile catalysts for atom transfer reactions and redox processes

Ashesh S Belapure1, [email protected], Chinmay N Dabke1, Ramez Elgammal1, Gabriel Goenaga2, Alex Papandrew2, Tom Zawodzinski2, Shane Foister1. (1) Department of Chemistry, University of Tennessee, Knoxville, TN 37996, United States (2) Chemical and Biomolecular Engineering Department, University of Tennessee-Knoxville, University of Tennessee, Knoxville, TN 37996, United States

We have observed that metal complexes of 1,2,4-Triazoles catalyze various chemical transformations such as aziridination, hydrocarbon oxidation and oxygen reduction reaction (ORR).

We have found that Ni(II) complexes of 1,2,4-Triazoles catalyze the direct aziridination of various alkenes with aryl azides under relatively mild conditions with moderate to good yields over a wide substrate scope. This transformation has a high atom economy and eliminates the need to use exotic activation groups or sequences of reactions to synthesize aziridines.

When complexed with Cu(II), triazoles show remarkable potential for catalysis of hydrocarbon oxidation. Cyclohexane and methane are both converted to their respective alcohols at room temperature in aqueous media while maintaining high turnover rate. Allowing direct apllication to the efficient production of alternate fuels and feedstocks.

Perhaps not surprisingly, similar 1,2,4-Triazoles complexes show great promise as catalysts for ORR. This process works under very mild conditions over a wide pH range with both adsorbed and covalently anchored triazole ligands

In fact we have found triazole complexes immobilized on carbon surfaces are as efficient catalysts as their homogenous counterparts for all the processes discussed here.

ORGN 768

Ligand electronic effects on Ni-catalyzed chain-growth polymerizations

Se Ryeon Lee, [email protected], Anne J McNeil. Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States

Organic π-conjugated polymers are promising materials for current technologies, such as light-emitting diodes and solar cells, due to their tunable properties, solution processability, and low cost. Since 2004, several chain-growth methods for synthesizing π-conjugated polymers using nickel catalysts have been reported. However, the current methods result in relatively broad molecular weight distributions. This indicates the presence of competitive reactions and hence, uncontrolled chain-growth. Our work focuses on developing new catalysts that will improve the polymerization by stabilizing the proposed key intermediate – a nickel-polymer π-complex. We synthesized a series of ligands with different electronic properties and have investigated their use in the polymerization of 4-bromo-2,5-bis(hexyloxy)phenylmagnesium chloride. We discovered that the electron-rich catalyst had the slowest overall rate for both initiation and propagation and led to narrower molecular weight distributions of resulting polymers. These results suggest that electron-rich ligands stabilize the nickel-polymer π-complex and promote chain-growth polymerization.

ORGN 769

Chemical constituents of the Burmese python (python molurus bivittatus) sexual attractiveness pheromone

Allison J Balloon1,2, [email protected], Jeff M. Goff1,2, Chris Carmichael1,2, Skip Snow3. (1) Department of Natural Sciences, Malone University, Canton, OH 44709, United States (2) The Herbert W. Hoover Foundation, Canton, OH 44702, United States (3) The Everglades National Park, Homestead, FL 33034, United States

In recent years the population of the invasive Burmese python (Python molurus bivittatus) has threatened several endangered species and the balance of the ecosystem in the Everglades National Park. By extracting, identifying, and synthesizing the sexual attractant pheromone, we will explore its use as a lure and population control for invasive species management. The objective of this project was to separate and characterize the structure of the female pheromone that stimulates male courtship and trailing behavior. Chemical separation was accomplished after extraction of neutral skin lipids from the female shed skin in hexanes. Preparative flash chromatography and semi-preparative HPLC were used to further separate specific lipid classes. Using Y- maze, tongue flick density, and vector analysis the suspected pheromone fraction was shown to elicit natural courtship behaviors with statistical significance over the remaining skin lipid fractions and controls. This demonstrates that an intrinsic chemical in the shed skin lipids successfully elicits male sexual attraction behavior. Isothermal GC-FID analysis of the pheromone fraction shows that the compound peaks elute during regularly spaced intervals in a staggered pattern suggesting the presence of both saturated and mono-unsaturated long chain (C25-C38) fatty acid derivatives. Preliminary spectroscopic methods and previous research in similar snake species suggest that the pheromone consists of aliphatic and olefinic methyl ketones differing in carbon chain length and double bond location. This will be confirmed using H1, C13, and 2-D NMR methods.

ORGN 770

Synthesis of zolpidemphenyl-4-carboxylic acid drug metabolite

Martha Lixin Liu, [email protected], Uma Sreenivasan, Huahua Jian, Josh Cooper. Cerilliant, Round Rock, Texas 78664, United States

Zolpidem phenyl-4-carboxylic acid is a major metabolite of Zolpidem, also known as Ambien or Stilnox, a prescription medication used for the short-term treatment of insomnia, and some brain disorders. Metabolites of zolpidem are useful markers in clinical monitoring of therapeutic drugs and forensic investigations. Well characterized and high purity metabolites are required for quantitative applications in these fields. The aim of this work was to synthesize & optimize the processes for zolpidemphenyl-4- carboxylic acid through six steps. Synthesis of zolpidem phenyl-4-carboxylic acid started with the cyclization of α–bromo-4-(carboethoxy)acetophenone and 2-amino-5- methylpiridine to form an imidazopyridine. This was followed by introduction of the side chain as a tert-butyl acetate group, acid-hydrolysis, amide formation and finally base hydrolysis. Analysis & characterization of zolpidem phenyl-4-carboxylic acid was accomplished via HPLC, Mass Spectra, 1H and 2D-COSY NMR. Stability of the product in the low concentration was investigated.

ORGN 771

Design and synthesis of new selenium antioxidants

Jin Jin, [email protected], Shaozhong Zhang, Ahmad F Qarah, Dinesh R Gangaram, Deeraj R Gari. Department of Chemistry, Western Illinois University, Macomb, IL 61455, United States Selenium antioxidants are one of the important types of antioxidants. All antioxidants have a chemical element referred to as a “redox” potential, which is the measurement of their ability to be oxidized. Experiment evidence has shown that incorporation of silicon atom or Si-Si bond at the beta position of Se atom in organoselenium compounds will enhance the activities of these compounds by lowering the redox potential. This is due to the beta-silicon effect or beta-disilanyl effect. Here we report the design and synthesis of a series of new organoselenium antioxidants with incorporation of silicon atom at the beta position. These new compounds are proposed to have lower redox potentials and therefore show more potent antioxidant activity compared to the currently available selenium antioxidants. Their antioxidant ability will be evaluated by testing their redox potentials and different antioxidant capacity assays such as hydroxyl radical scavenging assay, ferric-reducing antioxidant power assay, etc.

ORGN 772

Rational design of DNA aptamer sensors for adenosine and 8-oxoguanine

Jagruti Rana, [email protected], Jyoti Roy, Mayurbhai Patel, Haidong Huang. Department of Chemistry and Environmental Science, New Jersey Institute of Technology, Newark, New Jersey 07102, United States

Abasic site-containing DNA duplex can be used as a universal structural motif to design receptors and sensors for aromatic compounds. The nucleotide opposite the abasic site automatically provides a hydrogen bonding interaction site. Additional interactions can be added by introducing triplex formation oligonucleotide or chemically modifying the abasic site. An adenosine receptor and an 8-oxoguanine receptor were designed based on this strategy. Fluorescent nucleotides were incorporated to the binding site as reporter groups. The resulting adenosine sensor can detect adenosine in the concentration range between 50 nM and 2 μM in the presence of guanosine, uridine, cytidine, AMP, and ATP. The 8-oxoguanine sensor can detect 8-oxoguanine in the concentration range between 0.2 and 5 μM in the presence of guanine, adenine, and thymine. Both examples demonstrated the importance of major groove binding groups to the selectivity of duplex DNA receptors.

ORGN 773

Total synthesis and biological activity of the lantibiotic epilancin 15X and analogs

Patrick J Knerr, [email protected], Wilfred A van der Donk. Department of Chemistry, University of Illinois, Urbana-Champaign, Urbana, IL 61801, United States

The lantibiotics are a family of polycyclic ribosomal natural products with promising antimicrobial activities that originate from posttranslational installation of thioether- containing residues lanthionine and methyllanthionine. Chemical synthesis provides a means to access these compounds and analogues for structure-activity relationship and engineering studies. Here, a solid-phase approach using orthogonally-protected (methyl)lanthionine building blocks enabled the total synthesis of the lantibiotic epilancin 15X. Several analogues were also produced and evaluated to probe the currently unknown mode-of-action of this potent compound.

ORGN 774

Multivalent glycomimetics generated from shikimic acid scaffolds as probes for DC-SIGN and other C-type lectins

Joseph C. Grim1, [email protected], Lynne R. Prost2, Laura L. Kiessling1,2. (1) Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706-1322, United States (2) Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706-1544, United States

C-type lectins (CTLs) are a class of calcium-dependent carbohydrate binding proteins critical to many immunological processes. One CTL of particular interest, dendritic cell- specific ICAM-3-grabbing non-integrin (DC-SIGN), is co-opted by many pathogens for proliferation, but the mechanisms of these phenomena are poorly understood. Compounds that mimic pathogenic carbohydrate epitopes aid in understanding CTL function. Previously, we have generated D-mannose glycomimetics for DC-SIGN utilizing (-)-shikimic acid as a scaffold. We have generalized this strategy by developing a divergent synthesis of shikimic acid epimers that serve as scaffolds to mimic L-fucose, D-galactose, and D-glucose. As with all carbohydrate ligands, a multivalent display of glycomimetics enhances affinity and specificity. Protein- and polymer-based multivalent displays of mannose glycomimetics were found to engage DC-SIGN and elicit signaling and receptor-mediated internalization demonstrating the glycomimetics indeed mimic their carbohydrate analogues. These selective multivalent probes will provide insight into the importance of ligand architecture in CTL recognition and signaling.

ORGN 775

Activity-based imaging probe for the integral membrane hydrolase KIAA1363

Jae Won Chang, [email protected], Raymond E Moellering, Benjamin F Cravatt. Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, United States

The integral membrane serine hydrolase KIAA1363 is elevated in aggressive cancer cells where it plays a role in pro-tumorigenic lipid metabolism. To more thoroughly understand the function of KIAA1363 in cancer and other biological processes, new tools are required to characterize the activity and cellular distribution of this enzyme in living systems. Here, we describe the synthesis and biological application of a small- molecule imaging probe, JW576, that selectively targets KIAA1363 in cells and animals. We use JW576 to determine that KIAA1363 is predominantly localized to intracellular membrane compartments in cancer cells that include, but are not restricted to the endoplasmic reticulum. We also show that JW576 can be used to measure the cellular half-life of KIAA1363 activity and for profiling this enzyme in peripheral mouse tissues in vivo.

ORGN 776

Photoactive protocells from acyclic reactants in a one-flask process

Ana R. M. Soares, [email protected], Masahiko Taniguchi, Vanampally Chandrashaker, Jonathan S. Lindsey. Department of Chemistry, North Carolina State University, Raleigh, NC 27695, United States

Combinatorial reactions of two α-aminoketones and two diones in water (pH 7, 60 °C) with accompanying photooxidation afford a series of porphyrins distinguished by four classes of polarity: hydrophilic, indeterminate, amphiphilic, and hydrophobic. The reaction in the presence of lipid vesicles leads upon polarity-based self-sorting to porphyrin-containing vesicles that are photoactive, as demonstrated by the Krasnovsky reaction (a photosynthetic-like process). The spontaneous formation of photoactive protocells from acyclic reactants provides a model for the origin of proto-photosynthesis.

ORGN 777

Fluorinated galactofuranose donors as mechanistic probes of the carbohydrate polymerase GlfT2

Christopher D Brown1,3, [email protected], Laura L Kiessling1,2. (1) Department of Chemistry, Univeristy of Wisconsin-Madison, Madison, WI 53706, United States (2) Department of Biochemistry, Univeristy of Wisconsin-Madison, Madison, WI 53706, United States (3) School of Medicine and Public Health, Univeristy of Wisconsin- Madison, Madison, WI 53706, United States

Carbohydrate polymerization is integral to cell wall biosynthesis in pathogenic organisms such as Mycobacterium tuberculosis (Mtb). A critical portion of the Mtb cell wall termed the galactan, a linear chain of galactofuranose (Galf) residues, is assembled largely through the polymerizing activity of the galactofuranosyltransferase, GlfT2. GlfT2 generates a linkage pattern wherein adjacent galactose monomers are joined with alternating β-(1,5) and β-(1,6) regiochemistry. The importance of the alternating linkage pattern on polymer length has not been explored, nor has any scrutiny of GlfT2's sequence specificity been performed. Synthetic fluorinated anaolgs of UDP-Galf were found to be useful substrates for determining the regiochemical fidelity of the polymerase. Incorporation of a fluorinated residue into a polymerizing chain blocked subsequent elaboration of the alternating pattern. As such, the degree of polymerization using fluorinated donors could be used as a measure of the enzyme's patterning integrity.

ORGN 778

Synthesis and antitumor activities of ferrocenyl derivatives of Paclitaxel

Damian Plażuk1, [email protected], Blazej Rychlik2, Anna Wieczorek1, Andrzej Blauz2. (1) Department of Organic Chemistry, University of Lodz, Faculty of Chemistry, Lodz, Tamka 12 91-403, Poland (2) Department of Molecular Biophysics, University of Lodz, Faculty of Biology and Earth Sciences, Institute of Biophysics, Lodz, Banacha 12/16 91-231, Poland

In recent years, considerable growth of interest of organometallic chemistry in terms of their use in medicinal science, such as anticancer or antineoplastic drugs is observed. The main area of interest is focused on compounds containing metallocene fragment (eg. ferrocenyl group) and a biologically active moiety.

Paclitaxel is one of the widely used anticancer drugs that inhibit tubulin depolymerization. Herein we present the first example of synthesis and anticancer activities study of ferrocenyl taxol analogues. Synthesized new ferrocenyl compounds exhibit antitumor activity against SW620 cells at the level of 0.3-0.5 uM (1.74 uM Pacitaxel).

ORGN 779

Synthesis and self-assembly of semi-fluorinated polymeric micelles for delivery of hydrophobic drugs

Aaron McCoy1, [email protected], Jun-Pil Jee2, Sandro Mecozzi1,2. (1) Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, United States (2) School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705, United States

Micelle-based drug delivery systems made from amphiphilic block copolymers have proven to be an attractive method of delivering poorly soluble drugs. PEG-DSPE micelles have been successfully used for the solubilization of several hydrophobic drugs but generally lack sustained stability in blood. Our novel PEG-Fluorocarbon- Phospholipid containing polymers were designed to increase micelle stability and improve time-release properties of drug-loaded micelles. Particle size analysis, encapsulation properties, and in vitro release profile of the micelles with Amphotericin B were investigated. Förster Resonance Energy Transfer was utilized to analyze particle stability in human serum. The fluorocarbon placed between hydrophilic and hydrophobic block enhanced thermodynamic stability of micelles and contributed to the sustained release of encapsulated drug. Furthermore, we have synthesized block copolymers with a hydrophilic PEG block and substituted polyaspartamides as the hydrophobic and fluorophilic blocks to study the effect of size and location of the fluorous block on micelle stability and drug delivery.

ORGN 780

Rational design and development of a fluorogenic azido-fluorescein for cellular imaging

Peyton Shieh1, [email protected], Matthew J. Hangauer1, Carolyn R. Bertozzi1,2,3. (1) Department of Chemistry, University of California, Berkeley, CA 94720, United States (2) Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, United States (3) Howard Hughes Medical Institute, Berkeley, CA 94720, United States

The reaction of azides and alkynes to form triazoles, promoted by either Cu(I) catalysis or strain-promoted alkyne activation, has found widespread use in cellular imaging. Much of this success lies on the utility of both the azide and alkyne as reporter groups, given their small size and inertness to biological functional groups. One limitation, however, is the low signal over background when labeling these reporter groups intracellularly or in vivo, which is problematic in studying biological systems where high sensitivity is necessary. This issue can be resolved by the use of fluorogenic/turn-on probes. While a variety of blue-fluorescent fluorogenic azides have been developed, more red-shifted fluorogenic azides remain elusive. Here, we report the development of green-fluorescent azido-fluoresceins which become fluorescent upon triazole formation.

ORGN 781

Novel, rigid, highly-fluorinated dendrimer core for use in 19F MRI

Evan H Darrow1, [email protected], Marly De Gracia1, Curtis E Moore2, Arnold L Rheingold2, Douglas B Grotjahn1, Erik C Weiner3. (1) Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182-1030, United States (2) Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093-0358, United States (3) Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, United States

Fluorine MRI is an attractive imaging method, because 19F has a 100% natural abundance, there is a negligible amount of background signal due to lack of detectable fluorine in the body, and 19F has the same spin and high intrinsic sensitivity similar to that of 1H, allowing the possibility of using conventional MRI scanners to obtain 19F MRI images. Challenges include the need for high concentrations of fluorine atoms with similar chemical shifts, the poor water solubility of fluorocarbons, and the possible toxicity when using fluorocarbon-containing tracers. Our goal is to synthesize highly- fluorinated, symmetric dendrimer-based 19F MRI tracers with fluorocarbon groups recessed within the core and multiple peripheral hydrophilic carboxylic acid groups, mitigating possible toxicity, and increasing water solubility. Here we report the synthesis of several variants on a rigid triazole-linked dendrimer core, each containing 36 equivalent fluorine atoms per molecule, and showing water solubility at physiological pH.

ORGN 782

Studying the chemical ecology of Piper: Towards a concise synthesis of Piper imides

Trang T Nguyen, [email protected], Christopher S Jeffrey. Department of Chemistry, University of Nevada, Reno, Reno, Nevada 89557, United States

Over the past ten years natural products from the Genus Piper family, Piper imides, have been extensively studied due to their potent biological activity. In addition, recent studies show that these Piper imides induce cancer apoptosis. Due to these recent discoveries it is necessary to develop methods for the synthesis, isolation and rapid characterization of these natural products. To examine these biological activities we will synthesize a series of N-acylated imide derivatives. This will allow us to further understand their coevolution of the plant itself with their secondary metabolites with the addition to study their cytotoxicity in cancer cells. We will prepare a series of imides using hydrocinnamoyl chloride, both non-substituted and substituted, with N-acylation of substituted pyridines or piperidinone derivatives to achieve the N-acylated imide moiety. The syntheses of these natural products, isolatable from the Genus Piper family, will provide valuable knowledge and insight towards their biological activity in both nature and medicine.

ORGN 783

Understanding oscillatory calcium signaling via a photochromic reversible calcium cage Adwoa Sasu, [email protected], Irvin Coria, James Huang, Alison McCurdy. Department of Biochemistry and Chemistry, California State University Los Angeles, Los Angeles, Ca 90032, United States

Calcium acts as a second messenger in cells. The basis of oscillatory signals is known, yet how they affect the cell on a molecular level is not understood. Calcium signaling is often oscillatory, such as in the role it plays in triggering the enzyme calmodulin- dependent protein kinase II. A proposed method to study this phenomenon is the use of a reversible cage for calcium based on a photochromic scaffold. A previously published photochromic compound is currently under modification to improve the binding affinity and selectivity towards calcium. Various modifications are being tested, which include increasing the chelate effect. The synthesis and characterization of model open and closed forms will be presented and binding studies are currently underway.

ORGN 784

Multifunctional PET tracer based on a pendant-armed cross-bridged tetraazamacrocycle scaffold

Marie-Caline Z. Abadjian1, [email protected], Riccardo Ferdani2, Douglas B. Grotjahn1, Carolyn J. Anderson2, Erik C. Wiener3. (1) Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182, United States (2) Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15219, United States (3) Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213, United States

Positron emission tomography (PET) is a widely used technique that generates 3-D images of the body functions via a positron-emitting radionuclide (tracer). We report synthesizing an azide-bearing multi-functional tracer using a coupled cross-bridged tetraazamacrocycle which is a chelator for 64Cu, a positron source. Using click chemistry, two peptides could be coupled to each chelate using one clickable alkynyl amino acid. Such a functionalized cross-bridge tetraazamacrocycle with two identical azide-bearing side arms provides several advantages with respect to applications. This tracer would increase the avidity of the agent and potentially allow attachment to more than one clickable amino acid.

ORGN 785

Zinc based metal organic framework: Synthesis, characterization and applications

Oluwaseun Falola1, [email protected], Jason Matthews1, Little Reginald2. (1) Chemistry, Howard University, Washington, DC 20059, United States (2) Chemical Engineering, Howard University, Washington, DC 20059, United States The increasing need for more efficient materials suitable for toxic gas separation from flue streams of power plants in order to alleviate global warming has resulted in the development of metal organic frameworks. Novel zinc based metal organic frameworks has been synthesized based on beta-enaminoester as organic linker. These materials show gas adsorption ability for Oxygen, Nitrogen and Carbon Dioxide.

ORGN 786

Synthesis and incorporation of 6-seleno-2'-deoxyguanosine triphosphate into DNA by DNA polymerase

Manindar Kaur, [email protected], Julianne Caton Williams, Jozef Salon, Bo Zhang, Zhen Huang. Department of Chemistry, Georgia State University, Atlanta, GA 30303, United States

Functionalized nucleotides are instrumental in modern nucleic acid biochemistry. Nucleoside triphosphates (dNTPs and NTPs) are involved in various biological processes like neurotransmission, replication, transcription and translation. Various functional group modifications have helped researchers to have an in-depth understanding of nucleic acid structures and functions. Selenium modification of these nucleotides can provide further insight into nucleic acid flexibility, nucleobase pairing/stacking, and duplex recognition/stability. Herein, we report the first chemical synthesis of 6-Se-2'-deoxy-guanosine-5'-triphosphate (6-SedGTP) via a “new synthetic methodology” developed in Prof. Huang's laboratory. In this strategy, 2-chloro-4H- 1,3,2-benzodioxaphosphorin-4-one and tri-n-butylammonium pyrophosphate are used to form a triphosphate intermediate which reacts with the nucleoside to form P2, P3- dioxo-P1-5'-nucleosidylcyclotriphosphite. The product 6-SedGTP being yellow in color offers potential applications as deoxyribonucleic acid (DNA) visualization probe. This Se-modified triphosphate is efficiently recognized by DNA polymerase. The synthetic Se-DNA is highly nuclease-resistant compared to the native. These findings indicate that the modified Se-DNAs have a great potential for nucleic acid based diagnosis and therapeutics.

ORGN 787

NMR study on the tautomerism of anti-HIV nucleoside analogs

Katherine J Silvestre1, [email protected], Deyu Li1,2, Jeffrey H Simpson1, John M Essigmann1,2. (1) Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States (2) Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States

DNA nucleoside analogs, KP-1212 and 5-hydroxy-2'-deoxycytidine, are drug candidates for the treatment of HIV/AIDS via lethal mutagenesis (viral decay acceleration) mechanism. KP-1212 is currently in Phase II clinical trials because it can induce a significant increase in viral mutation frequency and make the virus unable to synthesize functional proteins. The mechanism of action believed to be responsible for lethal mutagenesis is tautomerization of the nucleoside analog, which allows the nucleoside to base-pair with more than one complementary base. NMR spectroscopy can be used to identify the tautomeric forms of these nucleosides and the ratios of these tautomers. 1D 1H, 13C, 2D homonuclear (1H-1H COSY, NOESY), heteronuclear (1H-13C HSQC, HMBC), and variable temperature experiments are used to assign chemical shifts and characterize enol-keto and amino-imino tautomers of these nucleosides. By evaluating the tautomerization of multiple nucleoside analogs, we rationalize the molecular mechanism of lethal mutagenesis as a novel drug design principle.

ORGN 788

Ergot alkaloid analogs: Engineering a library-optimized route

Matthew Parker1, [email protected], Scott Burley1, [email protected], Alex Colla1, David Eccker1, Clara Croux1, Fred Lakner2, Vicki Lam2, Mikael Bergdahl1, [email protected]. (1) Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182, United States (2) ChemDiv, Inc., San Diego, CA 92121, United States

Ergot alkaloids possess perhaps a greater diversity of bioactivity than any other class of natural products. They and their semisynthetic derivatives are exceptionally active as dopamine and serotonin receptor agonists and antagonists, having found utility in treating Parkinson's disease and migraines. We have engineered an efficient library- optimized route to underrepresented ergolines with diversity in the 'A' (phenyl) ring. In addition, the route allows for the incorporation of conjugated unsaturated systems for tuning of the natural fluorescence wavelengths of ergolines to yield a set of biological probes with fluorescent properties. A highly functionalized pyridine derivative is the key to the efficiency of the route, allowing for introduction of 'A'-ring molecular diversity as late as possible in the synthetic route. Utilizing this derivative, a functionalized ergoline skeletal framework has been synthesized via a key intramolecular Heck cyclization in seven steps from readily available starting materials.

ORGN 789

Synthesis of selenium modified cytidine nucleoside and nucleic acid for DNA structural determination and functional study

Wen Zhang, [email protected], Jia Sheng, Abdalla E. Hassan, Zhen Huang. Department of Chemistry, Georgia State University, Atlanta, GA 30303, United States

Methylation of cytidine in vivo is an important epigenetic event relating to gene expression regulation. We report here for the first time the synthesis of a novel 5-methyl deoxycytidine analog and its phosphoramidite modified with selenium at the 5-position (SeC) and the SeC incorporation into DNA via solid-phase synthesis. Our UV-melting study indicates that the Se-derivatization does not disrupt the native DNA duplex stability. Consistent with the thermostability result, our X-ray crystal structure study reveals that SeC forms the Watson-Crick base pair with guanosine virtually identical to the native pair, and the Se-moiety causes no structural perturbation. Moreover, the Se- derivatization generates a novel strategy to study the function and mechanism of cytidine related protein, such as DNA methyltransferase, which provides a useful biochemical and structural tool to investigate the DNA cytidine 5-methylation in vivo.

ORGN 790

Extraction and isolation of cyclopamine from Veratrum californicum

Rynne Ambrose1,2, [email protected], Dr. Owen McDougal1. (1) Chemistry and Biochemistry, Boise State University, Boise, ID 83709, United States (2) Chemistry, Salem College, Winston Salem, North Carolina 27108, United States

Veratrum californicum is a plant native to the western United States that initially received negative publicity as the origin of birth defects in sheep throughout mountainous grazing lands in Idaho. Upon rigorous investigation, it was discovered that V. californicum produces a potent anti-cancer agent; cyclopamine. Cyclopamine is a steroid alkaloid that inhibits the hedgehog mechanism, which is integral to cell growth and maturation. Cyclopemia, a craniofacial defect, is commonly observed in newborn infants when the hedgehog mechanism is inhibited by cyclopamine during gestation. In- vivo and in-vitro studies of certain cancer cell lines have shown decreased tumor growth through inhibition of the hedgehog mechanism. Pancreatic, breast, prostate and colorectal cancer cell lines have shown diminished cell proliferation when treated with cyclopamine. The purpose of this study was to extract, isolate and characterize cyclopamine from V. californicum. Initial extractions of V. californicum plant material yielded 0.14%, 0.26%,and 0.19% of combined alkaloid extract. The alkaloid solid showed a consistent infrared spectrum to cyclopamine. Future work to be accomplished includes a final purification and characterization by HPLC, NMR spectroscopy, and mass spectrometry.

ORGN 791

Tandem Achmatowicz-Knoevenagel protocol: Diastereoselective synthesis and anticancer evaluation of cyclopenta[b]pyrane derivatives

Mohammad Hrab Semreen1, [email protected], Taleb Hassan Al-Tel1, Wolfgang H Voelter3. (1) pharmacy practice/Medicinal chemistry unit, University of sharjah, sharjah, sharjah 27272, United Arab Emirates (2) pharmacy practice/medicinal chemistry unit, University of sharjah, sharjah, sharjah 27272, United Arab Emirates (3) Interfakultares Institut fur Biochemie, Eberhard-Karls-Universitat Tuebing, Tuebingen, Tuebingen 72076, Germany Synthesis of cyclopenta[b]pyrane derivatives via Achmatowicz oxidative cyclization of furanols followed by intramolecular Knoevenagel condensation of the β-ketoester arm is examined. The extent of diastereoselectivity was dependent on the nature of the chiral atom within the tethering carbon of the pyrenone ring. In some cases, this process proceeds with a high degree of stereoselectivity after protection of the anomeric hydroxyl group. Furthermore, the cytotoxic activity of pyrazolone derivatives thereof was studied against HCT116 (human colorectal cancer cells), SK–N-SH (human Caucasian bone arrow neuroblastoma) cells and the non-tumorigenic cells (MCF10A). To understand the structure activity relationships of the newly synthesized motifs, two traditional medicinal chemistry strategies namely, ring expansion and contraction, were followed (Scheme 1). 1 These studies indicated that tetrahydropyrano[3,2-b]pyrrol-2(1H)-one derivatives are more selective for breast cancer cell line compared to other cell lines under investigations. Furthermore, it was found that hexahydropyrano[3,2-c][1,2]diazepin- 3(4H)-one derivatives are potent anticancer agents compared to tetrahydropyrano[3,2- b]pyrrol-2(1H)-one analogs.

Scheme 1. Strategies used to understand the SAR of the new scaffolds.

Al-Tel, T.H; Semreen, M.H; Voelter, W., Organic & Biomolecular Chemistry, 2010, 8, 5375–5382

ORGN 792

Catalytic hydrogenation and hydroboration of model and biologically active (nucleoside) alkene with borane

Joanna Niziol, [email protected], Tomasz Ruman, [email protected]. Department of Chemistry, Rzeszow University of Technology, Rzeszow, Poland

The olefin hydrogenation is extremely important chemical modification used in organic synthesis both on the small and industrial scale. This work describes unusual activity found in applied catalytic system that is very similar to the one reported by Miyaura group. Mentioned group reported mainly hydroboration processes taking place in reaction mixture. Our experimental data suggest that the main reaction in applied catalytic systems is hydrogenation of cycloalkene to cycloalkane (Figure 1).

The experimental data obtained for model olefin allowed synthesis of few unique boron derivatives of anti-HIV agent stavudine and thymidine. The hydroboration of stavudine yielded 2',3'-dihydrostavudine under conditions applied. The hydroboration process was found to be present only in oxygen-free system which resulted in the formation of four unique pinacolborano-analogues of thymidine containing boron at 2'- and 3'-positions.

ORGN 793

Synthesis of new phenol compounds from isoeugenol: Investigation of antioxidant properties

Esra Findik, [email protected]. Department of Chemistry, University of Gaziosmanpasa, TOKAT, Turkey

We are attempting to develop the novel phenolic synthetic antioxidants aimed at retarding the effects of free radicals and oxidants. The phenolic compounds were synthesized by Friedel-Crafts alkylation of isoeugenol, phenol, pyrocatechol and resorcinol and their structures were determined by spectroscopic methods. Antioxidant and radical scavenging activities of synthesized compounds were determined by using various in vitro assays such as 1,1-diphenyl-2-picrylhydrazyl free radicals (DPPH.), 2,2- azino-bis(3-ethylbenzothiazoline-6- sulfonic acid) radicals (ABTS˙+), and superoxide - anion radicals (O2 ) scavenging, ferric reducing antioxidant power (FRAP) and total antioxidant activity by ferric thiocyanate. The antioxidant activities of compounds were compared with standard antioxidants such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and trolox as positive controls.

The compounds 3 and 4, containing a catechol moiety, showed the highest activity in all assays. These results suggest that these new phenolic compounds are promising candidates to be used as alternative antioxidants to BHA and BHT.

ORGN 794

Synthesis of the novel benzothiazole compounds from 7-benzylidenebicyclo [3.2.0] hept-2-en-6-ones and 2-aminobenzenethiol

Esra Findik, [email protected]. Department of Chemistry, University of Gaziosmanpasa, TOKAT, Turkey

The direct synthesis of the 2-(2-styrylcyclopent-3-enyl)benzo-[d]thiazoles (6a-i ) is reported for the first time. The reaction of 7-benzylidenebicyclo [3.2.0] hept-2-en-6-ones (3a-i ) and 2-aminobenzenethiol (4 ) in the presence of p-TsOH as a catalyst resulted in the formation of novel 2-(2-styrylcyclopent-3-enyl)benzo[d]thiazoles in high yields.

7-benzylidenebicyclo-[3.2.0]hept-2-en-6-ones (3a-i ) were firstly synthesized from the condensation of cis-(1R,5S)-bicyclo[3.2.0]hept-2-en-6-one (1 ) with substituted benzaldehydes (2a-g ), thiophene-2-carbaldehyde (2g ) and furan-2-carbaldehyde (2h ). Then, the acid-catalyzed reaction of 7-benzylidenebicyclo[3.2.0]hept-2-en-6-ones (3a-i ) with 2-aminobenzenethiol (4 ) was examined. The reaction of 7- benzylidenebicyclo[3.2.0]hept-2-en-6-ones (1a-i ) with 2-aminobenzenethiol (4 ) in the presence of 10% mol p-TsOH in ethanol at reflux conditions resulted in the formation of the rearrangement products 6a-i , 2-(2-styrylcyclopent-3-enyl)benzo[d]thiazoles (6a-i ), instead of expected 1,5-benzothiazepines (5a-I ). The products 6a-i was isolated in high yields (in the range of 93%-98%). Also, we suggest the mechanism explaining the rearrangement products (6a-i ).

ORGN 795

Synthesis of ±-threo-Ritalinic acid-D10 hydrochloride and deuterium placement determination by qNMR

Elizabeth Marek, [email protected], Huahua Jian, Uma Sreenivasan, Isil Dilek. Cerilliant, Round Rock, TX 78665, United States

Ritalinic acid is a major metabolite of and synthetic precursor to methylphenidate (Ritalin®) and may be monitored clinically and forensically. ±-threo-Ritalinic acid-D10 HCl was synthesized as an analytical reference standard and as a precursor to deuterated ±-threo-methylphenidate in seven steps with a purity of 99% and an isotopic purity ratio of D0/D10 = 0%. The presence of significant amounts of the D9-D7 isomers prompted extensive structure elucidation using 1D and 2D NMR. Additionally, qNMR was used to determine exactly what percentage of hydrogen, and therefore deuterium, is present on each carbon in the molecule. These results suggest that the Pt/C catalyst used in the synthesis also facilitated the exchange of aromatic hydrogens to deuterium creating the undesirable deuterium distribution. This study highlights chemical interactions that factor into the design of stable labeled internal standards for LCMS applications.

ORGN 796

Four component reactions for the synthesis of adenine-like and hypoxanthine- like pyrrolo[2,3-d]pyrimidines

Liliya V. Frolova1, [email protected], Isaiah Otero2, Alexander Kornienko3, Igor V. Magedov4. (1) Chemistry, New Mexico Institute of Mining and Technology, Socorro, NM 87801, United States (2) Chemistry, New Mexico Institute of Mining and Technology, Socorro, NM 87801, United States (3) Chemistry, New Mexico Institute of Mining and Technology, Socorro, NM 87801, United States (4) Chemistry, New Mexico Institute of Mining and Technology, Socorro, NM 87801, United States

Privileged medicinal scaffolds based on the structures of adenine-like and hypoxanthine-like pyrrolo[2,3-d]pyrimidines were prepared via one-pot four component reactions of structurally diverse aldehydes, N-(methanesulfonamido)acetophenones and malononitrile (cyanoacetamide). In preparation of the adenine-like compounds the forth component was formamide, whereas for the synthesis hypoxanthine-like compounds ethyl orthoformate was used. Both procedures are high yielding and lead to the preparation of libraries of diversely substituted medicinally relevant pyrrolo[2,3- d]pyrimidine scaffolds. Investigation of the reaction scope reveals that various aliphatic, aromatic and heteroaromatic moieties can be utilized in both the aldehyde and sulfonamidomethylaryl(hetaryl) ketone components.

ORGN 797

Efficient and scalable synthesis of 4-O-methylhonokiol

Hyeju Jo1, [email protected], Min Ho Choi1, Young Ae Cho2, Da Young Kim1, Sri Hari Galla1, Jae-Hwan Kwak1, Heesoon Lee1, Young-Shin Kwak2, Jae-Kyung Jung1. (1) Chungbuk National University, College of Pharmacy and Medical Research Center (MRC), CBITRC, Cheongju, Republic of Korea (2) Korea Research Institute of Bioscience and Biotechnology, Ochang, Republic of Korea

Pharmacological properties of biphenyl-neolignans, such as honokiol, magnolol, and obovatol, from Magnolia species have been reported to include anti-inflammatory, anti- allergic, anti-bacterial, and anti-depressant activities. In addition to these biphenyl- neolignans, 4-O-methylhonokiol was isolated from Magnolia species and exhibits various biological activities. Interestingly, 4-O-methylhonokiol has the higher anti- inflammatory activity than honokiol and its analogs. Moreover, 4-O-methylhonokiol was recently found to exhibit neurotropic and memory improving activity.

The structural feature of 4-O-methylhonokiol is the unsymmetrical 5,3'-diallyl-biphenyl, which differs from honokiol by the methoxy group at its C4 position. In spite of its interesting biological activities, only one pioneering total synthesis of 4-O- methylhonokiol has been reported by Denton group. Because of that, we interested to develop a new and scalable synthesis of 4-O-methylhonokiol and its analogs. Therefore, we attempted to develop an efficient and shorter method for the total synthesis of 4-O-methylhonokiol featuring a Suzuki-Miyaura cross-coupling as the key step.

ORGN 798

Structure-activity relationship study of quinine analogs with modifications at the vinyl moiety Theresa Dinio1, [email protected], Andrew McGinniss1, Alexander P Gorka2, Paul D Roepe2, Jeremy B Morgan1. (1) Department of Chemistry and Biochemistry, University of North Carolina, Wilmington, Wilmington, NC 28403, United States (2) Department of Chemistry, Georgetown University, Washington, DC 20057, United States

Plasmodium falciparum, the deadliest form of the malarial parasite, has developed resistance against nearly all man-made anti-malarials within the past century. However, quinine, the first malaria treatment, remains efficacious worldwide. Using the Heck reaction, we have developed a structure-activity relationship study around vinyl modifications on quinine that may help to understand the resistance mechanism employed by the parasite. Several Cinchona alkaloid derivatives have shown high anti- plasmodial activity in QN-resistant and QN-sensitive strains with lower IC50 values than quinine.

ORGN 799

Redox-gated self-immolative liposomal drug delivery systems

Suraj U Hettiarachchi, [email protected], Robin L McCarley. Chemistry, Louisiana State University, Baton Rouge, LA 70803, United States

Currently, much attention is being paid to the design of multi-agent drug delivery systems (DDS) and stimuli-responsive liposomes are at the forefront of many of these efforts. This work involves development of redox-triggered, self-immolative liposomal DDS based on phosphoethanolamine lipids possessing a head group composed of an aza-quinone-methide (AQM) core to which are attached a redox-active quinone trigger group and a reducing agent. Disconnection of the quinone head group and subsequent removal of the AQM core is achieved by chemical or enzymatic means resulting in release and therefore activation of the attached (cloaked) reducing agent. The free reducing agent is capable of stimulating neighboring quinone trigger groups on the liposome surface, thereby amplifying the initial reductive stimulus that eventually leads to disruption of the liposome. This unique feature of our system has great potential in applications wherein targeted stimuli levels exist at relatively low concentrations, such as in diseased tissues.

ORGN 800 Sultam thioureas: Synthesis and antiviral activity against West Nile virus

Diane N Le1, [email protected], Rachel M Feeny1, Joseph W Parks1, Mark G Epstein1, Joseph V Pagano1, Albert C Abbene1, Elaina B Graham1, Joanna R Farrell1, Jason R McGuire2, Robert W Zoellner2, Edward J Valente1, Eric Barklis3, Warren JL Wood1. (1) Department of Chemistry, University of Portland, Portland, OR 97203, United States (2) Department of Chemistry, Humboldt State University, Arcata, CA 95521, United States (3) Vollum Institute and Department of Molecular Microbiology and Immunology, Oregon Health & Sciences University, Portland, OR 97239, United States

West Nile virus (WNV) is a significant human pathogen and further work is needed to develop antiviral drugs. Four sultam thiourea compounds have been reported to inhibit WNV replication in cells and appear to be non-toxic, but few have been reported in the literature. The syntheses of 11 sultam thioureas, including nine new compounds, are described here. These compounds were synthesized from thioureas and using the synthetic procedure, sultam thioureas can be synthesized with alkyl/alkyl, aryl/alkyl, or aryl/aryl groups at the R1/R2 positions and with alkyl groups at the R4 and/or R5 positions. Sultam thioureas with different groups at the R1/R2 position have not been reported. In addition, the first X-ray crystal structures of sultam thioureas and the antiviral activity of these compounds against WNV are reported.

ORGN 801

Three bioactive decapeptide-functionalized rosette nanotubes (RNTs) for bone tissue engineering

Alaaeddin Alsbaiee, [email protected], Rahul Agrawal, Mounir El Bakkari, Hicham Fenniri. Department of Chemistry/National Institute for Nanotechnology, University of Alberta, Edmonton, Alberta T6G2M9, Canada

Titanium (Ti) implants are the most widely used materials to treat severe bone injuries. However, the deterioration of the implant/bone interface due to the low biocompatibility of Ti surface often leads to surgery revision. Rosette nanotubes (RNTs) are biologically- inspired nanomaterials obtained through the self-assembly of a hybrid guanine-cytosine base (GΛC motif). When coated on Ti surface, the RNTs were found to increase osteoblast adhesion and hydroxyapatite deposition on the surface. One of the unique advantages of RNTs is the ability to express a variety of bioactive molecules on their outer surface by synthetically conjugating the desired group to the GΛC motif. To further increase the bioactivity of RNTs, we herein present the synthesis, self-assembly, and preliminary biological studies of three GΛC motifs functionalized with three bioactive decapeptides derived from the knuckle region (bioactive area) of the natural bone morphogenic proteins-7 (BMP-7)

.

ORGN 802

Furin controlled intracellular assembly of nanoparticles for enhanced uptake of radionuclide in living cells

Gaolin Liang, [email protected], Qingqing Miao, Xiaoyu Bai, Bin Mei. Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China

Herein, we report a condensation system which could be controlled by furin, an important protease which is associated with early development of cancer. We designed Acetyl-Arg-Val-Arg-Arg-Cys(StBu)-Tyr(I-125)-CBT (1 ) for self-assembling radioactive nanoparticles (I125-NPs) in living cells. Its scrambled control Acetyl-Arg-Tyr(I-125)-Arg- Cys(StBu)-Arg-Val-CBT (1-scr ) which can not be cleaved by furin was also prepared for study in parallel. At 160 min after cell efflux, 17.9% of the radioactivity was retained in the cells incubated with 1 and 100 μM 1-cold while the percentages of other three groups are 4.4%, 3.7%, and 3.7% respectively. By means of intracellular assembly of radioactive nanoparticles, this provides us with a new method of furin detection or cancer early detection.

Figure 1 . (a) Chemical structures of four compounds for this study. (b) Time course of cellular efflux of 1 and 1-scr after the incubation with cells with/without co-incubation of 1-cold or 1-scr-cold at 100 μM for 30 min. (c) Radioactivity retained in cells after 160 minutes' efflux.

ORGN 803

Synthesis of caged phosphoramidites and their application in the photochemical activation of DNA function

Rajendra Uprety, [email protected], Colleen Connelly, James Hemphill, Jeane Govan, Alexander Deiters. Department of Chemistry, North Carolina State University, Raleigh, NC 27695, United States

Nature controls biological processes such as gene regulation and protein function with high spatio-temporal resolution. The study of gene regulation with spatial and temporal resolution is important to explore biological functions. Light, one of the most precise and least invasive control elements, can be used for the photo-regulation of caged oligonucleotides to understand various cellular processes in a spatially and temporally controlled manner. We report the synthesis of new caged phosphoramidites and employ these nucleotides in the photochemical control of DNA and RNA function. Applications of these caged oligonucleotides range from basic biological studies of gene expression to potential precursors for gene therapeutics.

ORGN 804

Synthesis of PF-04691502, a highly potent PI3K/mTOR dual inhibitor Jacqui Hoffman, [email protected], Simon Bailey, Hengmiao Cheng, Robert Kania, Lei Jai, Mitch Nambu, Sacha Ninkovich, Mason Pairish, Jay Srirangam, Xiaolong Wang, Phuong Le. Cancer Chemistry, Pfizer Worldwide Research and Development, La Jolla, California 92121, United States

The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays crucial roles in cell growth, proliferation and survival. Genomic aberrations in the PI3K pathway, such as mutational activation of PI3Ka or loss of function of tumor suppressor PTEN, have been closely linked to the development and progression of a wide range of cancers. Hence, inhibition of the key targets in the pathway, e.g. PI3K, AKT, mTOR, offers great potential for the treatment of cancer. High throughput screening identified 4- methylpyridopyrimidinones (MPP) as a series of interest for the inhibition of PI3K. Structure based drug design and physical chemical based optimization led to the discovery of 2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxypyridin-3-yl)- 4-methylpyrido[2,3-d]pyrimidin-7(8H)-one, PF-04691502, which is currently being evaluated in human clinical trials for the treatment of cancer. The synthesis of PF- 04691502 and its analogues will be presented.

ORGN 805

Synthesis and characterization of selective cell permeable fluorogenic cyanine dyes

Katherine Chong, [email protected], Nathaniel Shank, Gloria Silva, Bruce Armitage. Chemistry, Carnegie Mellon University, Pittsburgh, PA 15213, United States

Fluoromodules are complexes of non-covalently bound fluorogenic dyes and their fluorescence activating protein partners. Previously, fluorogenic unsymmetrical cyanine dyes were used to sort a diverse protein library to obtain protein partners and create a library of fluoromodules that span the visible spectrum. The dyes were designed for easy modification for favorable spectral properties and binding specificity. Non-specific interactions with nucleic acids are minimized through the incorporation of sterically bulky or negatively charged groups, which are electrostatically repelled by the anionic phosphate backbone of DNA and RNA. However, the addition of charged groups decreases the cell permeability of dyes. In the interest of cytoplasmic imaging studies, modifications to the dyes were explored in order to allow for cell permeability and subsequent cytoplastmic fluoromodule formation. Replacement of previously used sulfonate groups with hydrolyzable acetoxymethyl esters was found to allow for cell permeability while maintaining the protein binding-affinity and specificity of the dyes.

ORGN 806

Turn-on luminescent lanthanide probes for the detection of enzymes

Elias Pershagen, [email protected], Eszter Borbas. Department of Organic Chemistry, Institution for Chemistry, Stockholm, Sweden Lanthanide-based turn-on luminescent probes for the detection of various enzymes are presented. The probes are constructed from the same framework and are made analyte responsive by the choice of caging group. The uncaging reveals a coumarin antenna which is able to sensitize both Eu and Tb. By varying the lanthanide, multiplex detection of several enzymes is possible.

ORGN 807

Solid-state characterization and polymorphism of dehydro-aripiprazole

Tarek A Zeidan, [email protected], Jacob T Trotta, Renato A Chiarella, Mark A Oliveira, Julius F Remenar. Research & Development, Alkermes plc, Waltham, MA 02451, United States

Aripiprazole is an atypical antipsychotic approved for the treatment of schizophrenia and bipolar disorder. The drug's main active metabolite is dehydro-aripiprazole, which is formed by dehydrogenation of the lactam ring of aripiprazole in a metabolic process involving CYP 2D6. Dehydro-aripiprazole has affinity and activity at dopamine D2 and serotonin receptors, and thus the metabolite has a pharmacological profile comparable to that of the parent drug. To date there is no reported physical characterization of dehydro-aripiprazole in the literature. Crystal form diversity exploration elucidated five polymorphs of dehydro-aripiprazole as well as a solvate with methanol. Physico- chemical characterization data for these forms are compared with corresponding data for aripiprazole forms. Single-crystal structures of the dehydro-aripiprazole crystal forms demonstrate that despite structure similarity with aripiprazole, the crystal packings observed in the polymorphs of the active metabolite differ from those known for the drug.

ORGN 808

Synthesis of unnatural substrates for PikC oxidation studies: Exploring macrolide biosynthetic P450's as biocatalysts for sp3 C-H oxidation

Solymar Negretti1, [email protected], Karoline Chiou2, David H Sherman1,2,3, John Montgomery1,2. (1) Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, United States (2) Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, United States (3) Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, United States Macrolide biosynthetic P450 enzymes perform regio- and stereoselective oxidations of unactivated C-H bonds with ease, although the exploitation of this capability in organic synthesis remains underdeveloped. The PikC-catalyzed hydroxylation of YC-17 and narbomycin exemplifies such transformations, with oxidation occurring at positions distal from the desosamine directing group. An engineered, self-sufficient PikC (PikCD50N- RhFRED) has been employed for the moderately regioselective hydroxylation of non- natural desosamine-linked carbocyclic rings, illustrating its potential as a biocatalyst for C-H oxidation. Substrate scope has been extended to include macrocycles with non- sugar anchors, expanding the procedure's utility as a synthetic tool. The selectivity of the oxidations was evaluated as a function of both the aglycone, employing unnatural substrates with variable degrees of structural complexity within the macrolactone ring, and the anchoring group, with non-sugar anchoring group analogs of both YC-17 and narbomycin.

ORGN 809

Design and synthesis of fluorinated dendrimers as 19F MRI Imaging agents

Farhana Barmare1, [email protected], Douglas B Grotjahn1, Erik C Weiner2. (1) Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182-1030, United States (2) Department of Radiology, Department of Bioengineering, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, United States

Dendrimers are highly branched macromolecules consisting of a central core from which emanate regular repeating units. Fluorine-rich dendrimers can exhibit unique physiochemical and biological properties. The work here describes the design and synthesis of highly fluorinated dendrimers with three arms arranged in such a way that the fluorine atoms are embedded in the interior of the dendrimer as to reduce toxicity. Our goal is to employ the fluorinated dendrimers as imaging agents for 19F MRI guided drug therapy because of the potential properties such as a singlet 19F signal for multiple fluorine atoms, short T1, and good water solubility. The effects of using a fluorinated amino acid derivative in racemic and enantioenriched form on dendrimer spectra will be part of this presentation.

ORGN 810

Aryl azides in the traceless Staudinger ligation: Applications to prodrug synthesis

Thomas Price Kirby, [email protected], Tad H Koch. Department of Chemistry & Biochemistry, University of Colorado at Boulder, Boulder, Colorado 80309, United States

Here we report the use of aryl azides in the traceless Staudinger ligation for the installation of a Katzenellenbogen spacer derived from p-azidobenzyl alcohol, and its application in prodrug synthesis. Compounds incorporating the p-amidobenzyloxy carbonyl moiety have previously been assembled by step-wise acylation of the analine nitrogen and subsequent coupling via the mixed p-nitrophenyl carbonate to yield the prodrug. However, in cases where a final deprotection reaction is then required to generate the enzymatically active substrate, the sensitivity of the substrate to the deprotection conditions may preclude efficient synthesis. We demonstrate that p- azidobenzyloxy carbamates allow for chemoselective amidative-installation of the Katzenellenbogen spacer via a Staudinger ligation, thereby obviating the need for a final deprotection reaction. Given the prominent use of the self-immolative spacer in prodrug design, we feel this transformation provides a valuable alternative route to delicate therapeutics such as prodrugs of the anthracycline doxazolidine.

ORGN 811

Rational design and synthesis of potential inhibitors of tryptophan biosynthesis enzymes

Christopher J. Oulton, [email protected], Samuel C. Gilmore, Andrew C. Allen, Dorothy J. Kampf, Matthew J. Gage, Cindy C. Browder. Department of Chemistry and Biochemistry, Northern Arizona University, Flagstaff, Arizona 86011, United States

Tryptophan is an essential amino acid that has a vital role in the metabolism of bacteria. Since tryptophan is not biosynthesized by humans, tryptophan is a potential new antimicrobial target. This is of special importance considering the increasing incidence of bacterial antibiotic resistance. Our research has focused on designing inhibitors for indole-3-glycerol-phosphate synthase (IGPs), a key enzyme in bacterial biosynthesis of tryptophan. Utilizing the known structure and mechanism of action of the enzyme, we have designed a library of synthetic compounds and fragments that are predicted to have good enzyme-substrate recognition and compromise enzyme activity. A preliminary fragment library has been prepared and screened for activity against IGPs by a high-throughput enzymatic assay. The results have established the basis of design of our second-generation library of potential inhibitors. Efforts towards the synthesis of this library and accompanying results from in silico, in vitro, and in vivo screens will be presented.

ORGN 812

Reactive group-functionalized fluorescent silsesquioxane nanoparticles for E-coli treatment in water: Synthesis, characterization, and particle morphology

John Ferguson1, [email protected], Leslie Wilson2, Hemali Rathnayake2. (1) Department of Chemistry, Western Kentucky University, Bowling Green, KY 42101, United States (2) Department of Chemistry, Western Kentucky University, Bowling Green, KY 42101, United States Nanoscale particles derived from silicon, such as silica and siloxane are important examples of nanomaterials that can be applied in materials, electronics or biological context. As the surface of silica or siloxane core structure can be easily functionalized with various organic functional groups, there has been a great effort to use them as biological carriers, antibacterial treatments including -the silsesquioxane nanoparticles describes here. Two types of reactive group functionalized fluorescent silsesquioxane naoparticles were prepared by direct hydrolysis and condensation of their respective silane precursors. Particle sizes were controlled upon adjusting the molar ratios of organotrialkoxy silane, base, and emulsifier concentrations. These resulting nanoparticles with reactive amine groups are found to be more advantageous over functionalized silica or organically modified silica nanoparticles due to the higher load of covalently attached ligands and the high solubility in water. Cellular uptake, and antibacterial effect of these nanoparticles in water will be studied for potential applicability for water treatment.

ORGN 813

Cobalt-based capture-and-release of alkynyl peptides

Katherine Windsor, [email protected], Keri A. Tallman, Ned A. Porter. Department of Chemistry, Vanderbilt University, Nashville, TN 37235, United States

Through a recent collaboration, our laboratory developed a method to selectively isolate alkynyl-derivatized phospholipids from whole cell extracts. Treatment of an extract with dicobalt octacarbonyl facilitates the formation of cobalt-alkyne complexes, which can be removed from the phospholipid mixture via solid-phase immobilization. Subsequent decomplexation of the cobalt adducts releases the alkynes, completing the purification process. Current efforts are focused on expanding the scope of this methodology to the isolation of other types of alkyne-containing compounds and pursuing new practical applications for our cobalt “pulldown” method. To that end, we demonstrated proof-of- principle capture-and-release examples of dipeptides and longer (nine-residue) peptides. We are also establishing conditions to facilitate the capture-and-release of proteins. We aim to use the cobalt chemistry to identify sites of protein adduction by lipid-derived electrophiles (e.g. 4-hydroxynonenal (HNE)).

ORGN 814

Development of a practical synthesis of a functionalized pyrrolo[2,1- f][1,2,4]triazine nucleus

Bin Zheng, [email protected], Justin Burt, Melissa Chau, David A. Conlon, Richard M. Corbett, Daniel Hsieh, Dau-Ming Hsieh, William Gallagher, Jale Müslehiddinoğlu, Jeffrey Simon, Agnes Yeboah. Chemical Development, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903, United States Pyrrolotriazinyl amine 5 is a key intermediate used in the preparation of several potent kinase inhibitors. As few methods exist for its facile synthesis, we devised an efficient route to this intermediate starting with condensation of benzyl carbazate and acetal 1 . The key step involves alkylation of an oxosuccinate salt with the resulting bromohydrazone to form diester 2 . Cyclo-dehydration to aminopyrrole 3 , followed by deprotection and condensation with formamidine affords the pyrrolotriazine 4 , which is further elaborated to the desired pyrrolotriazinyl amine 5 . The results of our development activities that led to the successful preparation of the functionalized pyrrolotriazine on multi-100-kilogram scale are described.

ORGN 815

Environmentally benign routes for the synthesis of HDAC inhibitors

Narayanaganesh Balasubramanian, [email protected], Gregory R Cook. Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 58102, United States

Histone deacetylase are zinc dependent hydrolytic enzymes involved in chromatin remodelling and play an important role in the regulation of gene trascription. Numerous small molecule inhibitors have been reported for the past two decades and are used currently in many clinical trials. Here, we report for the first time oxindole based molecules as inhibitors for the recombinant form of human HDACs. oxindole and its metabolites are endogenous to mammals and plants. Numerous plants containing oxindole and isatin are in use for centuries in folk medicine. The present methodology could be used in generating libraries of enantiomerically pure oxindole backbones.

ORGN 816

Convergent synthesis of spiropiperidine sultam and lactam BACE templates via diastereoselective Overman rearrangement

Luis A Martinez-Alsina, [email protected], John C Murray, Brian T O'Neill, Joseph M Young.Neurosciences Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, United States

A convergent synthesis of Lactam (D) and Sultam (E) Spiropiperidine templates is reported. In an effort to efficiently explore the SAR for the BACE Inhibitor program, we sought for a common intermediate that could be assembled rapidly from the Piperidinone (A). A key diastereoselective Overman Rearrangement provided Allylamine (C) which proved to be a very useful intermediate towards the synthesis of novel compounds.

ORGN 817

Enabling the bulk synthesis of 5-HT4 partial agonist, PF-4995274

John C Murray1, [email protected], Daniel W Widlicka2, Michael A Brodney1, Karen J Coffman1, Brian T O'Neill1. (1) Neurosciences Medicinal Chemistry, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, United States (2) Research API-US, Pfizer Worldwide Research & Development, Groton, Connecticut 06340, United States

Current literature suggests 5-HT4 agonists could be beneficial in the treatment of Alzheimer's Disease. PF-4995274, containing a hydroxybenzisoxazole moiety, is a potent partial agonist of the 5-HT4 receptor. Initial attempts to form intermediate hydroxybenzisoxazole 1 were limited by an unexpected rearrangement to benzoxazolinone 2 . The rearrangement was suppressed by switching from an electron donating to an electron withdrawing ortho substituent. This change along with further process optimization enabled a highly efficient synthesis of kilogram quantities of API.

ORGN 818

Investigation of cosolvent effects on the PLE hydrolysis reaction of several substrates using combined HPLC-MS techniques

Maureen E Smith1, [email protected], Souvik Banerjee1, Marlen Schmidt2, Uwe T Bornscheuer3, Douglas S Masterson1. (1) Department of Chemistry and Biochemistry, University of Southern Mississippi, Hattiesburg, Mississippi 39406, United States (2) Enzymicals AG, Greifswald, Germany (3) Department of Biotechnology and Enzyme Catalysis, Greifswald University, Greifswald, Germany

Hydrolases, such as Pig Liver Esterase, are widely used in organic synthesis due to their low cost, stability, and ability to accept a wide range of substrates. It is well known that PLE is composed of at least 6 isoenzymes, which have recently been recombinantly produced. However, the role of each individual isoenzyme in the PLE mixture has not yet been explored completely. It has been demonstrated that the addition of organic co-solvents to the phosphate buffer can dramatically alter the enantiomeric excess (ee) of the reaction. We have found that the addition of just 2% EtOH into our buffer solution greatly increased the enantiomeric excess of compound (1) from 23 %ee to 85 %ee. Additionally, several of the isoenzymes (3-6) displayed a solvent induced inversion of chirality from the (S)-enantiomer to the (R)-enantiomer. However, we have also found that this increase in enantioselectivity is highly substrate specific. For example, addition of varying amount of co-solvent to compound (2) showed only moderate increases in enantioselectivity, and addition of co-solvent to compound (3) did not show any effect. These results and the results of varying the isoenzymes with these substrates will be discussed in detail.

ORGN 819

Novel method for creating controlled in vitro prevascularized hydrogel networks

Lalisa Stutts, [email protected], Aaron Esser Kahn. Department of Chemistry, University of California, Irvine, Irvine, CA 92697, United States

One of the major obstacles for the successful implantation of tissue engineered constructs is insufficient vascularization for the transport of oxygen and nutrients throughout the implant. Material and scaffold design and in vitro prevascularization are promising strategies for enhancing vascularization; however, limitations in tissue size and controllable patterning are still present. Herein, 3-dimensional hydrogel constructs were created utilizing sacrificial fibers to create branched micropatterns, similar to natural capillary networks. Centimeter scale scaffolds were generated from various biocompatible materials, include agar, agarose, polyacrylamide, and gelatin methacrylate (GelMA), with a range of channel diameters from 100-500 μm, to which endothelial cells were seeded to create controlled microvascular networks. ORGN 820

Facile synthesis of vinyl diethers and their analogs, and photooxidation by singlet oxygen

Gregory N Nkepang1,2, [email protected], Praveen K Pogula3, Moses K Bio1,2, Youngjae You1,2. (1) Department of Pharmaceutical Sciences, University of Oklahoma, Oklahoma City, Oklahoma 73117, United States (2) Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States (3) Department of Chemistry and Biochemistry, South Dakota State University, Brookings, South Dakota 57007, United States

The 1,2- cycloaddition reaction of singlet oxygen with electron rich-double (vinyl diether) bond giving two carbonyl fragments via dioxetane intermediate has been proposed as a singlet-oxygen- mediated drug release mechanism. Even though vinyl diethers look simple, their synthesis was not an easy task. Previous methods are limited to symmetric molecules, lengthy steps, and low yields. We first report the facile synthetic method not only for the vinyl diether but also other diheteroatom substituted vinyl diethers and the use of this scheme to build a drug-photosensitizer conjugate via a linker for site specific drug release.

ORGN 821

Designed hydrogen bonding in peptidomimetics

Brian R Linton, [email protected], Benjamin D Brink, Rio S Nomoto, Julie S Hillner. Chemistry, College of the Holy Cross, Worcester, MA 01610, United States

Peptidomimetics have been designed where conformational rigidity is imparted through a combination of restricted rotations and hydrogen bonding arrays. Stability is determined in proportion to the hydrogen bond strength. In addition to intramolecular hydrogen bonding, aggregation between molecules has also been observed.

ORGN 822

Synthesis and characterization of novel thienopyrrole monomers

Elizabeth A Rainbolt, [email protected], Hien Q Nguyen, Mihaela C Stefan. Department of Chemistry, The University of Texas at Dallas, Richardson, Texas 75080, United States

Heterocyclic fused ring polymers are potentially useful in organic electronic applications. The planarity of the monomer unit enhances π-electron delocalization, yielding a polymer with a lower band gap than the widely used poly(3-hexylthiophene) (P3HT). Here is presented the synthesis and characterization of an alkylated thieno[3,2-b]pyrrole monomer. 2-Thiophenecarboxaldehyde reacts with ethyl azidoacetate in the presence of sodium ethoxide. The resulting solid product, ethyl 2-azido-3-(thiophen-2-yl)acrylate, is refluxed in toluene to yield ethyl thieno[3,2-b]pyrrole-5-carboxylate. Then this is alkylated at the N-position using dodecyl bromide in the presence of potassium carbonate and 18-crown-6, refluxed in THF. Purification by column chromatography gives ethyl 1-(dodecyl)thieno[3,2-b]pyrrole-5-carboxylate. This product is allowed to reflux in THF in the presence of potassium hydroxide, forming 1-(dodecyl)thieno[3,2- b]pyrrole-5-carboxylic acid. Refluxing in quinoline in the presence of copper chromite yields 1-(dodecyl)thieno[3,2-b]pyrrole.

ORGN 823

Synthesis of quinoline-5,8-dione analogs

Alicen Teitgen, [email protected], Robert E Sammelson. Department of Chemistry, Ball State University, Muncie, IN 47306, United States

Quinonline-5,8-dione chemistry is a developing field because of its various biological aspects. Lavendamycin and streptonigrin are known antibiotic antitumor agents and the quinolone-5,8-dione functional group is believed to provide their antitumor properties. Most cancer cells show an elevated level of NQO1 enzyme which activates lavendamycin to act as an antitumor agent. Our research goal is to explore different synthetic methods and reactions to produce novel quinolone-5,8-dione analogues with unique structural features while keeping the selectivity cytotoxicity. Lavendamycin contains a β-carboline and streptonigrin has a pyridine connected to the two position of the quinolone-5,8-dione. We will present our synthetic methods to create 1,2,3-triazoles and 1,2-diazoles attached to the quinoline moiety from azides and diazonium salts, respectively.

ORGN 824

Bismuth nitrate-induced novel nitration of estradiol: An entry to new anticancer agents

Debasish Bandyopadhyay1, [email protected], Gildardo Rivera1, Jose C Granados2, Fang-Mei Chang2, John D Short2, Bimal K Banik1. (1) Department of Chemistry, The University of Texas-Pan American, Edinburg, Texas 78539, United States (2) Medical Research Division, University of Texas Health Science Center at San Antonio – Regional Academic Health Center, Edinburg, Texas 78541, United States

Direct nitration of estradiol has been carried out using metal nitrates on solid surfaces under mild condition. Bismuth nitrate pentahydrate/KSF clay is found to be the best reagent to synthesize 2- and 4-nitro estradiol effectively. Herein we report the synthesis and biological evaluation of a series of nitroestradiol derivatives as potential anticancer agents in vitro. ORGN 825

Synthesis of pyrenyl compounds as potential anticancer agents

Debasish Bandyopadhyay1, [email protected], Jose C Granados2, John D Short2, Bimal K Banik1. (1) Department of Chemistry, The University of Texas-Pan American, Edinburg, Texas 78539, United States (2) Medical Research Division, University of Texas Health Science Center at San Antonio – Regional Academic Health Center, Edinburg, Texas 78541, United States

In continuation of our research, we have synthesized a variety of pyrene derivatives that demonstrate excellent and selective anticancer activities.

ORGN 826

Bismuth nitrate catalyzed expeditious synthesis of 2,4,6-triarylpyridines

Debasish Bandyopadhyay, [email protected], R Christopher Gonzales, Sanghamitra Mukherjee, Bimal K Banik. Department of Chemistry, The University of Texas-Pan American, Edinburg, Texas 78539, United States

The pyridine ring occurs in saturated and partially saturated derivatives in biologically active compounds and natural products such as NAD nucleotides including the vitamins niacinamide and pyridoxal. A large number of pyridines are known as pharmaceuticals (antimalarial, vasodilator, anesthetic, anticonvulsant, and antiepileptic), dyes, additives (as antioxidant), agrochemicals (as fungicidal, pesticidal, and herbicidal), veterinary (as anthelmintic, antibacterial, and antiparasitic) etc. We herein report a novel procedure for the synthesis of 2,4,6-triarylpyridines using bismuth nitrate pentahydrate as catalyst which is stable, easy-to-handle, cost effective and widely available. A series of solvents and other bismuth salts have been screened.

ORGN 827

Synthesis of substituted imidazo pyranones using in situ generated cyclic ketene N,N'-acetals

Sabornie Chatterjee1, [email protected], Hondamuni I De Silva2, Charles U. Pittman Jr.2. (1) Center for Renewable Carbon, The University of Tennessee, Knoxville, Knoxville, TN 37996, United States (2) Department of Chemistry, Mississippi State University, Starkville, MS 39762, United States

2-Methylimidazole can be viewed as a tridentate nucleophile that can give three consecutive tandem nucleophilic attacks on electrophiles. A highly functionalized imidazo pyranone ring system (1) was obtained as the major product when 2- methylimidazole was reacted with excess 1,3-dimethyl diacid chloride in presence of a base under mild conditions. Imidazo pyridine dione was the other product. The imidazo pyranone ring system has a 10-membered ring fused to both an imidazole ring and a six-membered ester ring. It has a diene unit cross conjugated with the imidazole ring. Compounds with a similar core structure were previously reported to have anticholinergic properties. Further, reactions of other substituted imidazoles were also explored. Another type of imidazo pyranone was obtained when 2-methylimidazole and cyclobutane-1,1-dicarbonyl dichloride were reacted under similar conditions. These reactions are proposed to proceed through a cyclic ketene acetal intermediate.

ORGN 828

Synthesis and C-N bond rotation of 1,3,5-triazine-2,4,6-triyl tris(dibutylcarbamodithioate)

Sinho Lee1, Jongwoo Son1, Jae Hee Song2, Yeong-Joon Kim1, [email protected]. (1) Department of Chemistry, Chungnam National University, Daejeon, Republic of Korea (2) Department of Chemistry, Sunchon National University, Republic of Korea

We present results on the synthesis of 1,3,5-triazine-2,4,6-triyl tris(dibutylcarbamodithioate) and dynamic behavior of C-N bond rotation of the product. Cyanuric chloride has the advantage that it can be conveniently controlled to react with dithiocarbamate groups. In the presence of base, undesired product, 6-(dibutylamino)- 1,3,5-triazine-2,4-diyl bis(dibutylcarbamodithioate) was merely produced, which is not reported in the literature. Practical synthesis of 1,3,5-triazine-2,4,6-triyl tris(dibutylcarbamodithioate) from 1mmol of cyanuric chloride with 3mmol of dithiocarbamates using base takes place successfully in anhydrous THF at room ‡ temperature. The free energy (ΔGc ) for rotation of C-N bond on dithiocarbamate group of the product was obtained as 76.6kJ/mol from both coalescence temperature and line shape analysis.

ORGN 829 Synthesis and characterization of a new class of porphyrin isomers: Neo- confused porphyrins

Aaron Lammer, [email protected], Timothy D. Lash. Department of Chemistry, Illinois State University, Normal, IL 61761, United States

There is considerable interest in porphyrin isomers, with a special focus on carbaporphyrinoid systems, where one or more internal nitrogen is replaced with a carbon atom. This has previously been seen in structures such as N-confused porphyrins where a pyrrole ring is turned so an sp2 carbon is moved into the core of the porphyrin and the nitrogen is moved to the exterior. An alternative porphyrin isomer is possible where the pyrrole ring is turned so the nitrogen is directly connected to the bridging meso-position. These neo-confused porphyrins 1 can be synthesized in good yields by reacting dipyrrylmethane dialdehydes 2 with dipyrrylmethanes 3 under acidic conditions followed by treatment with an oxidizing agent. The new porphyrin-like systems show strong aromatic character, as well as Uv-vis spectra that are similar to traditional porphyrins.

ORGN 830

Naphthologs variations of bistricyclic aromatic enes

Naela Assadi, [email protected], Sergey Pogodin, Shmuel Cohen, Israel Agranat. Department of Organic Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel 91904, Israel

Bistricyclic aromatic enes (BAEs) are fascinating nonplanar doubly-bridged overcrowded tetraarylenes, displaying thermochromism and a rich stereochemistry. The following variations of BAEs have been adopted: (i) removing one of the bridges (X or Y) leading to mono-bridged tetraarylethlenes (BAEs-1). (ii) introducing naphthalene rings in place of benzene rings. These variations result in naphthologs, analogs of BAEs. The syntheses, crystal structures and conformational spaces of such BAE-1 naphthologs will be described, along with their comparison to BAEs.

ORGN 831

WITHDRAWN

ORGN 832

Efficient synthesisof 2,5-substituted 6-azaindoles from aziridine derivatives via regioselective pyrrole formation followed by intramolecular cyclization

Bong Chan Kim1, [email protected], Hogyu Lee1, Won Koo Lee1, Hyun-Joon Ha2. (1) Chemistry, Sogang University, Seoul, Republic of Korea (2) Chemistry, Hankuk University of Foreign Studies, Yongin, Republic of Korea

Azaindoles and substituted azaindoles are found in various natural products and the importance of azaindole derivatives is also found in pharmacologically and biologically active substances. We were interested in a new strategy for the efficient preparation of 2,5-substituted 6-azaindoles from the sequential reactions including a new pyrrole synthesis followed by subsequent intramolecular cyclization of the azide into the internal acetylenic unit to provide azaindoles.

ORGN 833

Synthesis and photophysical investigation of three 2,5-substituted pyridines and two 2,4-substituted pyrimidines

Andres Villalpando2, [email protected], Kristina Little1, [email protected], Ralph Isovitsch1, [email protected]. (1) Department of Chemistry, Whittier College, Whittier, CA 90608, United States (2) Department of Chemistry, Louisiana State University, Baton Rouge, CA 70803, United States

2,5-dibromopyridine was used to prepare two pyridine derivatives. One derivative had an acetyl group in the 5-position, while the other had a propenone-dimethylamino subsituent in the 5-position. These two pyridine derivatives were in turn used to prepare two pyrimidine derivatives, one with a 2-bromopyridyl substituent and the other with a 2- (chlorophenyl)pyridyl substituent. The photophysical properties of all of the pyridine and pyrimidine derivatives were explored in acetonitrile solution at room temperature. The pyridine and pyrimidine derivatives had absorption maxima in the range of 241-348 and emission maxima in the range 406-430 nm. Excited state lifetimes for the title compounds were all short, 1-2.9 ns, and characterized their emission as fluorescence.

ORGN 834

Regioselective nucleophilic aromatic substitution (SNAr) reactions of 2- substituted-3,5-dichloropyrazines

Stephanie A Scales1, [email protected], Indrawan McAlpine1, Sarah Johnson1, Paul Richardson1, Quyen-Quyen Do1, Fen Wang1, Jerry Hu1, Darius Faizi1, Yadong Wan2, Baojiang Zheng2, Shijian Ren2. (1) Department of Medicinal Chemistry, Pfizer Inc., San Diego, CA 92121, United States (2) WuXi App Tec Co, Shanghai, China

[Figure1]

Aminopyrazines are featured in a variety of medicinal chemistry programs, especially kinase programs, therefore, the regioselective formation of differentially substituted aminopyrazines was of interest to us. Through our research we found intriguing regioselctivity during the SNAr reaction of amines with unsymmetrical 3,5- dichloropyrazines. This study revealed when the 2-position of the pyrazine was occupied with an electron withdrawing group nucleophilc attack occurred preferentially at the 5-position. When the 2-position was substituted with an electron donating group nucleophilic attack occurred preferentially at the 3-position. Structures were confirmed using NOE NMR experiments and in some cases X-ray crystal structure. To help explain the observed selectivity, Fukui function/indices were calculated for the unsymmetrical 3,5-dicholopyrazines and the results support the regioselectivity seen in the SnAr reactions discussed.

ORGN 835

Synthetic efforts toward a scalable route to pyrrole 2,3-dicarboxylate

William P Gallagher, [email protected], Richard M Corbet, Melissa Chau, Bin Zheng, Vasumathy Rajaraman, David Conlon. Chemical Development, Bristol- Myers Squibb, New Brunswick, NJ 08901, United States In a recent program at BMS, the process development team needed to develop a method to produce a pyrrole-2,3-dicarboxylate. Several routes were postulated and explored experimentally. This poster will describe the exploratory synthetic efforts that culminated in a route that was successfully scaled providing the desired pyrrole-2,3- dicarboxylate in a timely fashion.

ORGN 836

Synthesis, photophysical properties and cellular uptake studies of amphiphilic BODIPY derivatives

Alexander Clayton1, Eva Beabout1, Richard Bennet2, Brooke Spitler1, Priya Hewavitharanage1, [email protected]. (1) Department of Chemistry, University of Southern Indiana, Evansville, Indiana 47712, United States (2) Department of Biology, University of Southern Indiana, Evansville, Indiana 47712, United States

Amphiphilic BODIPY derivatives with a hydrophobic alkyl chain at the meso position and 4-hydroxy-1-butynyl groups at the 2, 6 and 4, 4' positions were synthesized. The compounds are highly stable and fluoresce with high quantum yields. They are well soluble in polar solvents and readily taken up and accumulated in human osteosarcoma cells (Saos-2) and mouse fibroblasts (NIH3T3) cells. Details regarding the synthesis, photophysical properties and cellular uptake studies of these novel BODIPY compounds will be presented.

ORGN 837

Serendipitous discovery of an efficient synthesis of 4-chloro chromenes and their derivatives

Jennifer L. Cosman, [email protected], Johnathan Board, Toni Rantanen, Victor Snieckus. Department of Chemistry/Snieckus Innovations, Queen's University, Kingston, Ontario K7L 3N6, Canada

Chromenes and chromanones are widely studied biologically useful molecules, which can serve as intermediates in the total synthesis of certain natural products and medicinal agents. We have employed a method for the synthesis of substituted chromenes utilising mild reaction conditions and commercially available starting materials, which can undergo further reactions to give a wide variety of potentially useful compounds. To the best of our knowledge, synthesis of this particular chromene (2) has not yet been reported.

ORGN 838

Superacid-catalyzed electrocyclizations of unsaturated N-acyliminium ions

Anila Kethe, [email protected], Adam F. Tracy, Douglas A. Klumpp. Department of Chemistry, Northern Illinois University, DeKalb, Illinois 60115, United States

When unsaturated N-acyliminium ions are generated in superacidic CF3SO3H, cyclization products are obtained. A mechanism is proposed involving the formation of a vinylogous enol and subsequent electrocyclization. The results from these studies will be presented.

ORGN 839

Superelectrophilic Diels-Alder reactions

Barada Prasanna Dash, Douglas A. Klumpp, [email protected]. Department of Chemistry, Northern Illinois University, DeKalb, ILlinois 60115, United States

We have found that dicationic N-acyliminium ions are capable of reacting with ethylene in Diels-Alder reactions. The chemistry has been used to prepare functionalized heterocycles. Theoretical calculations show a low-lying LUMO on the superelectrophilic diene and this apparently facilitates the cycloaddition chemistry. The results of these studies will be presented.

ORGN 840

On the electrophilic reactivities of α-carbonyl heterocycles

Jeffrey L. Wells, [email protected], Douglas A. Klumpp, [email protected]. Department of Chemistry, Northern Illinois University, DeKalb, Illinois 60115, United States

Heterocycles with α-carbonyl groups are useful enzyme inhibitors, for example reacting with serine residues to form hemi-ketal adducts. We have sought to evaluate the electrophilic reactivities of carbonyl groups in heterocyclic compounds. Specifically, we have been interested in probing electronic and structural effects that influence the position of carbonyl/hemi-acetal or hemi-ketal equilibria. For example, calculated LUMO levels may be roughly correlated to the electrophilic reactivity of a carbonyl group and the position of the equilibria:

ORGN 841

Synthesis efforts towards tetracyclic GΛC motif for the self-assembly of rosette nanotubes with improved electronic properties

Alaaeddin Alsbaiee, [email protected], Rachel L Beingessner, Hicham Fenniri.National Institute for Nanotechnology, Department of Chemistry, University of Alberta, edmonton, AB T6G2M9, Canada

Rosette nanotubes (RNTs) are tubular nano-architectures obtained through the self- assembly of a bicyclic guanine-cytosine (GΛC) motif. These nano-architectures show high potential for several applications in tissue engineering and drug delivery. Recently, we have demonstrated the ability of RNTs to encapsulate hydrophobic molecules and slowly release them in physiological media. To increase the inner diameter of RNTs for these applications we recently designed a tri-cyclic XGΛC motif having a central pyridyl ring. This motif self-assembles in water to form RNTs with 1.4 nm inner diameter. Interestingly, these RNTs showed a J-type aggregate behavior suggesting an improved electronic communication along the RNT's main axis. In this paper we will present the synthesis and self-assembly of two types of tetracyclic YGΛC motifs (having two central pyridyl rings) for applications in aqueous and organic media. These are expected to self-assemble into RNTs with a 1.7 nm inner diameter having better electronic and photonic properties.

ORGN 842

Controlled apical functionalization of bridged triarylamines for chiroptical studies

Sravan K Surampudi, [email protected], Peyali Chowdury, Daiki Okamoto, Austin Cyphersmith, Michael D Barnes, Venkataraman Dhandapani. Department of Chemistry, University of Massacheusetts Amherst, Amherst, Massacheusetts 01003, United States

Chiral-bridged triarylamines are a class of electroactive heterohelicences, which form stable helical structures for electronic and optical applications. Recently, they have been utilized as probes for circularly polarized luminescence (CPL) and single molecule chiroptical studies. However, selective functionalization of chiral-bridged triarylamines in order to widen the scope of the probes that can be utilized for chiroptical studies remains a challenge due to the symmetry of the molecules. In this poster we will describe the synthesis, structure and resolution of apically functionalized chiral-bridged triarylamines (M -1 /P -1 ) utilizing regioselective copper catalyzed amination. Furthermore, synthesis of novel chiral-bridged triarylamine dimers (M -2 /P -2 ) starting from M -1 and P -1 will also be described.

ORGN 843

Simple and convenient two-step, one-pot synthesis of hetero-imidazoles from nitroaminoaryls catalyzed by ytterbium triflate

Fen Wang, [email protected], Indrawan McAlpine, Sacha Ninkovic, Michelle Tran- Dubé, Sarah Johnson, Stephanie Scales, Michael Collins, John Braganza. Department of Chemistry, Pfizer Inc., San Diego, CA 92121, United States

A simple and convenient two-step, one-pot process synthesis of hetero-imidazole derivatives directly from nitroaminoaryl compounds is described. The reduction of the nitro group by iron in acetic acid and in situ cyclization with triethyl orthoformate, catalyzed by ytterbium triflate, affords the heteroimidazole in good yield. This process avoids the isolation and purification of potentially unstable diamino heterocycles in the traditional two step methods which results in poor yields and slow reaction times. Compared to other one-pot syntheses, this process avoids tin and palladium, thus tolerates a broader range of functional groups. The scope of the reaction includes nitroanilines, nitroaminopyridines, nitroaminothiophenes and nitroaminopyrazines.

ORGN 844

Synthesis of pyridines via electrophilic cyclization of N-propargylic β-enaminones

Metin Zora, [email protected], Sedef Karabiyikoglu. Department of Chemistry, Middle East Technical University, Ankara, Turkey

Pyridines have occupied a unique position in the design and synthesis of novel biologically active agents that exert remarkable antiulcer, antifungal, antihyperglycemic, antileukemic, anti-alzheimer, anti-HIV and anticancer activities. Many synthetic methods have been developed for the synthesis of pyridines and new approaches still continue to appear stimulated by the broad spectrum of biological activity of such compounds. Electrophilic cyclization has recently emerged as valuable tool in organic synthesis. We have shown that upon treatment with molecular iodine, N-propargylic β-enaminones 2 , prepared readily from acetylenic ketones 1 , undergo electrophilic cyclization to afford 4- iodopyridine derivatives 3 in good to high yields. The resulting iodine-containing products have been further elaborated to a wide range of functionally substituted pyridines using subsequent metal-catalyzed coupling processes. The scope, limitations and mechanism of these reactions will be discussed.

ORGN 845

Synthesis and development of pH responsive fluorescence probes with long wavelength emission from silicon analog of fluorescein

Narsimha Sattenapally, [email protected], Quinn A Best, Chuangjun Liu, Lichang Wang, Matthew Mccarroll, Colleen Scott. Department of Chemistry and Biochemistry, Southern Illinois University Carbondale, Carbondale, Illinois 62901, United States

pH responsive fluorescence probes with emission in long wavelength region for example near infra red and infra red region are highly useful in biological applications. Fluorescence probes which emit at near IR and IR wavelength region have very less biological auto-fluorescence from the cell organelles in imaging and other biological applications. There is a growing increase for fluorescence probe which has good solubility, excellent biocompatibility, and emit at long wavelength region. Here in this report, we are going to present our ongoing efforts in synthesis and development of fluorescence probes with emission in IR and near IR wavelength region and have response to pH and other biological applications.

ORGN 846 Synthesis of highly substituted pyridines by Pd-catalyzed Sonogashira and Suzuki-Miyaura couplings of 4-iodopyridines

Metin Zora, Yılmaz Kelgökmen, [email protected], Nihan Zülay Kılıçaslan. Department of Chemistry, Middle East Technical University, Ankara, Turkey

Pyridines are popular targets for synthetic chemists primarily because of their diverse and potent biological and pharmacological activities. We have recently displayed that N- propargylic β-enaminones 1 produce 4-iodopyridine derivatives 2 upon electrophilic cyclization with molecular iodine. Subsequently, in the present study, we have investigated the Pd-catalyzed Sonogashira and Suzuki-Miyaura couplings of 4- iodopyridines 2 with terminal alkynes and boronic acids, respectively, yielding a variety of highly substituted pyridines 3 and 4 in good to excellent yields. The scope and limitations of these reactions will be discussed.

ORGN 847

Understanding, predicting, and modulating aryne regioselectivities

Adam E. Goetz, [email protected], Sarah M. Bronner, [email protected], Neil K. Garg. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90024, United States

Substituted heterocycles are of great importance in medicinal chemistry, ligand design, and total synthesis. One unique method for synthesizing substituted heterocycles relies on using hetarynes, or the aryne derivatives of heterocycles.

This presentation will describe routes that we have developed to access 4,5-, 5,6-, and 6,7-indolynes and their reactivity with a variety of trapping agents. Observed variations in the regioselectivity of nucleophilic addition to the indolyne can be rationalized in terms of distortion energy. We will present a straightforward model that can be used to predict the regioselectivity of nucleophilic additions to unsymmetrical arynes. Additionally, we will demonstrate how the use of substituents can enhance or overturn the inherent regioselectivities in indolyne reactions. Finally, we will show how this strategy has allowed for a synthesis of indolactam V using our indolyne approach, and allowed progress towards other complex indole-based targets.

ORGN 848

Synthesis and reactions of a highly-strained open geodesic polyarene

Hee Yeon Cho1, [email protected], Sarah N Spisak2, Marina A Petrukhina2, Lawrence T Scott1. (1) Department of Chemistry, Boston College, Chestnut Hill, MA 02467-3860, United States (2) Department of Chemistry, University at Albany, Albany, NY 12222, United States

Open geodesic polyarenes constitute a novel family of hydrocarbons that hold just as much fascination as their closed geodesic cousins, the fullerenes. Circumtrinedene (1 ) is the largest member of this family and was first prepared in our laboratories. Cyclopropanation of circumtrindene proceeds with bromomalonate and DBU to afford 2 in good yield. This represents the first example of a Bingel reaction of a non-fullerene polycyclic hydrocarbon. Unique structural/electronic properties of 1 as well as its reactivity toward metal complexation will also be presented.

ORGN 849

Synthesis of a novel PET sensor based on response selectivity in addition to the binding selectivity for monitoring citrate, maleate, and pyruvate metabolites

Chuangjun Liu, [email protected], Narsimha Sattenapally, Quinn A Best, Lichang Wang, Matthew Mccarroll, Colleen Scott. Department of Chemistry and Biochemistry, Southern Illinois University Carbondale, Carbondale, Illinois 62901, United States

Monitoring metabolites like small carboxylates, e.g. citrate, maleate, and pyruvate represents a real and important problem in biology especially in medicine. For example, sensing of these metabolites can monitor the effects of diabetes in early pregnancy. The uniqueness of our sensing method is the ability to discriminate in the binding response of these analytes. In other words, our probe selectively binds these three metabolites in a biological medium; however, each of these three molecules gives a different fluorescence response upon binding. So, this newly designed sensor can show specificity at both the binding and the fluorescence emission and thereby can surpass the specificities that are commonly achieved.

ORGN 850

Expanded bacteriochlorins

Lalith P Samankumara1, [email protected], Sarah Wells2, Matthias Zeller3, Christian Brückner1. (1) Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269, United States (2) Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States (3) Department of Chemistry, Youngstown State University, One University Plaza, Yougstown, Ohio 44555, United States

Due to their intrinsic long wavelength absorption and emission, bacteriochlorins have become a highly targeted class of photosensitizers in areas like photomedicine and artificial light harvesting. Presented here is the first synthesis of novel meso- tetraarylbacteriochlorin analogues in which both pyrrolidines of a bacteriochlorin are formally replaced by morpholino moieties. Oxidative cleavage (sNaIO4 on silica gel) of the two vic-diols of meso-tetraaryl-2,3,12,13-tetraolbacteriochlorins 1 , followed by an acid induced ring closure of the corresponding secobacteriochlorin aldehyde afforded the meso-tetraaryl-bis-(dimethoxymorpholino)-bacteriochlorin 2 , in a single step. Further treatment of 2 with acid causes a unidirectional double ring-fusion to form the bis-phenyl-fused bismorpholinobacteriochlorin 3 . Bacteriochlorin analogues 2 (λmax = 790 nm) and 3 (λmax = 735 nm) possess strongly bathochromically shifted UV-vis spectra compared to the starting tetraol 1 (λmax = 708 nm). The double ring expansion also resulted in a dramatic distortion to the macrocycle conformation, as determined by single crystal X-ray diffraction.

ORGN 851

Selective synthesis of aziridinofullerenes through the acid-promoted denitrogenation of triazolinofullerenes

Tsubasa Mikie, [email protected], Nobuhide Tanaka, Koji Nakagawa, Naohiko Ikuma, Ken Kokubo, Takumi Oshima.Division of applied chemistry, Graduate school of engineering, Osaka University, Suita, Osaka 565-0871, Japan

1,3-Dipolar cycloaddition reaction of azides with fullerene C60 at [6,6] conjunct double bond is a valuable method for chemical modification. The reaction gives triazolinofullerene intermediate, followed by thermal extrusion of nitrogen molecule affording the opened [5,6]-azafulleroid and/or the closed [6,6]-aziridinofullerene on the nature of substituent of the azide. In the most cases, the closed [5,6]-azafulleroids are more thermodynamically stable than the latter. Therefore it is difficult to synthesize the aziridinofullerenes by thermal denitrogenation. In this study, we report the acid- promoted denitrogenation of various triazolinofullerenes is exclusively afforded the corresponding aziridinofullerenes. The reaction seems to proceed through a Sn1-like reaction involving a fullerene cation intermediate. Furthermore, the reaction is markedly accelated by trifluoromethane sulfonic acid.

ORGN 852

Synthesis and functionalisation of imidazolones

Frederik Diness1, [email protected], Morten P. Meldal2. (1) Department of Medicinal Chemistry, University of Copenhagen, Copenhagen, Denmark (2) Department of Chemistry, University of Copenhagen, Copenhagen, Denmark Imidazolones are pharmaceutically interesting compounds and constitute essential substructures of several receptor antagonists with activities in the low nanomolar regime.[1] Imidazolones are also found in potent PDE4 inhibitors, in subtype selective β3-adrenergic receptor agonists and in GABAA receptor ligands.[1] We here present our results of exploring the chemistry of amino aldehydes in the Pictet-Spengler reaction, in imidazolone formation and subsequent transformations.[1]

[1] Diness, F., Meldal, M. Chem. Eur. J. 2009 , 15, 7044 and references cited herein.

ORGN 853

Strongly twisted arenes by Scholl cyclizations with unexpected regioselectivity

Anirban Pradhan, Harald Bock, Pierre Dechambenoit, Fabien Durola, durola@crpp- bordeaux.cnrs.fr. Centre de Recherche Paul Pascal, Pessac, Aquitaine 33600, France

The regioselectivity of the intramolecular Scholl reaction has been investigated with the study of test molecules bearing bulky tert-butyl substituents and offering competing cyclization pathways to non-congested products and highly congested alternatives. Surprisingly, even a strong steric hindrance has no marked effect on regioselectivity and highly twisted polycyclic aromatic hydrocarbons are preferentially formed. These results, including a synthesis of triply helical hexa-tert-butyl-hexabenzotriphenylene, suggest that this reaction may be considered for the synthesis of highly strained polycyclic aromatic hydrocarbons.

ORGN 854

Synthesis of biologically important novel pyridobenzimidazoles attached to indole or benzo[b]thiophene structures

Kimberly M. Mendoza, [email protected], Sukanta Kamila, Haribabu Ankati, Ed Biehl. Chemistry, Southern Methodist University, Dallas, TX 75275, United States

The pyridobenzimidazoles N2-phenylpyridine-2,3-diamine were prepared from corresponding nitro compounds by tin chloride di-hydrate reduction and microwave irradiation under solvent free conditions. Furthermore, the starting nitro compounds were prepared from 2-chloro-3-nitropyridine and suitably substituted aniline under MW conditions. A new synthetic method was developed that provides ready access to a novel pyridobenzimidazoles derivates. In addition, a synthetic route for the preparation of amines under solvent free conditions was demonstrated. Lastly, detailed biological activity studies (antibacterial, fungal, cancer and neuroprotective kinase inhibitor activity) of these important compounds are being carried out and preliminary results indicate that many of these compounds exhibit excellent neuroprotecting properties

ORGN 855

Utilization of the hydroxyalkylation reaction to prepare bis(benzocrown ethers)

Matthew Zielinski, Adam F. Tracy, [email protected], Douglas A. Klumpp, [email protected]. Department of Chemistry, Northern Illinois University, DeKalb, IL 60115, United States

The hydroxyalkylation reaction has been used to condense benzocrown ethers with various aldehydes and ketones. The condensation reactions are catalyzed by triflic or sulfuric acid. The products from the reactions are bis(benzocrown ethers) and they are formed in good yields. The chemistry may also be used to prepare A2B2 condensation polymers from dibenzocrown ethers.

ORGN 856

New synthetic methodology for the preparation of substituted urazoles

Weirui Chai, [email protected], Yuan Chang, John D Buynak. Chemistry, Southern Methodist University, Dallas, Texas 75275, United States

Synthetic methodology leading to production of substituted urazoles is currently quite limited. As a prelude to the investigation of this heterocycle as a scaffold for drug design, we have investigated the synthesis of urazoles, particularly including substituted and bicyclic urazoles. We have also obtained the crystal structures of a number of functional urazoles, including strained urazoles which show significant pyrimidalization of the amide nitrogens.

ORGN 857

[3,3]-Sigmatropic rearrangements of N-allyl-S,N-ketene acetals

Kolawole F Ayinuola, [email protected], Silvana S Dormi, Juliette Rivero-Castro, Matt McIntosh. Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701, United States

As part of a general program investigating novel aspects of [3,3]-sigmatropic rearrangements, we have recently begun examining azoles as platforms for these studies. Building on earlier work by the Kurth and Tunge groups, we have developed two approaches to N-allyl-S,N-ketene acetals. One approach involves a Horner-Wittig reaction using a phosphonate derived from benzothiazole, and the other approach begins with 2-alkyl(benzo)thiazoles. The ketene acetals undergo smooth rearrangement to 2-butenyl-thiazoles. Details of the studies and potential applications will be described.

ORGN 858

Microwave-assisted preparation of 1,4-dihydropyridines from 1,3-diones and hexamethylenetetramine

Mary T. Hannon, Roger D. Sommer, [email protected]. Chemistry, DePaul University, Chicago, Illinois 60614, United States

The microwave assisted reaction of 1,3 diones with hexamethylenetetramine (HMTA) produces 1,4-dihydropyridines in good yield without a catalyst. Several new X-ray crystal structures of Hanztsch-type heterocycles are reported. HMTA supplies the methylene carbon and ring nitrogen to make four equivalents of product. The reaction tolerates phenyl and ester groups on one, but not both ends of the dione. This reaction provides a fast and convenient route to 1,4-dihydropyridines and symmetrically substituted pyridines with no R-group at the 4 position.

ORGN 859

Synthesis of a nitrogen-containing PPV precursor monomer

Samuel Pina, [email protected], Jose J Gutierrez. Chemistry, The University of Texas Pan American, Edinburg, Texas 78539, United States

The synthesis of 2,5-bis(bromomethyl)aniline - a nitrogen-containing PPV precursor- was attempted. Benzylic bromination (NBS/BPO) of 2,5-dimethyl aniline (1) was unsuccessful, maybe due to the nucleophilic nature of nitrogen. To lower the reactivity of the amino group, 1 was protected upon reaction with acetic anhydride or trifluoroacetic anhydride to yield the corresponding acetamides 2a , and 2b . Benzilic bromination of 2a was unsuccessful while that of 2 b resulted in the formation of monobrominated trifluoroacetamides 3a and 3b .

ORGN 860

Flow-based synthesis of indolizines via a tandem Sonogashira coupling/cyclization sequence

Paul P Lange, [email protected], Keith James. Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, United States

A flow-based synthesis of indolizines via a 2-step reaction sequence including a Sonogashira coupling and intramolecular cyclization is presented.

The use of flow reactor technology allows this reaction to be conducted within minutes. In comparison to earlier synthetic approaches, the new protocol affords good yields, much shorter reaction times and a much more functionalized substrate scope. The catalyst system performs well at high concentrations and multigram quantities of material can be obtained in short time employing a continous flow set-up.

ORGN 861

Quinolizidine and indolizidine alkaloid synthesis via an intramolecular pinacol coupling

Srikanth Maddali, [email protected], Harriet A Lindsay. Department of Chemistry, Eastern Michigan University, Ypsilanti, MI 48197, United States

We have employed an intramolecular pinacol coupling to access the bicyclic core of quinolizidine and indolizidine alkaloids. In addition to forming the alkaloid B ring, the coupling reaction establishes the C1/C8a relative stereochemistry and provides a handle for the installation of a stereocenter at C2. The scope and limitations of the reductive coupling as well as efforts to access natural and unnatural hydroxylated alkaloids will be reported.

ORGN 862

Synthesis of cyclotri(3,3ꞌꞌ-para-terphenyldiyl ethynylene), a novel shape- persistent macrocyclic carbon single-wall nanotube precursor

Thomas S. Hughes, [email protected], Jonathan C. Bennion, Jenna I. Gifford, Katelyn E. Bunker, Joshua C. Kranick. Department of Chemistry and Biochemistry, Siena College, Loudonville, NY 12211, United States

Shape-persistent phenylene ethynylene macrocycles have attracted attention because of their relative ease of synthesis and their supramolecular properties. However, the reactivity of the alkyne moieties could allow conversion of the nominally planar title compounds into compounds with a dimensionality along the axis of the cycle; or precursor structures to make single-wall carbon nanotube segments. The synthetic sequence towards one such phenylene ethynylene macrocycle containing para- terphenylene units is presented. The synthesis of the ethynylterphenyl monomer was followed by the statistical macrocyclization under Sonogashira cross-coupling conditions at high dilution. The photophysical and supramolecular interactions of this macrocycle are also presented.

ORGN 863

Development of carboxylated ethynylarenes as fluorescent chemosensors for divalent cations in aqueous solution

James T. Fletcher, [email protected], Audrey T. Gallagher, Douglas E. Deever. Department of Chemistry, Creighton University, Omaha, NE 68178, United States New fluorescence chemosensors comprised of ethynylarene fluorophore units and carboxylate analyte-recognition units were prepared via efficient two-step reaction sequences. Sonogashira coupling between a variety of haloarenes and 3-ethynylaniline resulted in diamino- and triaminophenylethynylarene intermediate products. Condensation with each of three different cyclic anhydrides (succininc, glutaric and diglycolic anhydrides) produced a family of dicarboxylated and tricarboxylated small molecule sensors. High-throughput fluorescence binding assays allowed rapid screening of this family of arenes against various metal chloride salts in pH 7.5 TRIS- HCl aqueous buffer. Dicarboxylated analogs detected Zn(II), Cd(II) and Pb(II) while not signaling an interaction with Ca(II), Mg(II), Hg(II), Co(II), Cu(II) or Sr(II). Fluorescence responses were dependent on ethynylarene regioisomer identity, with meta isomers displaying solution-phase bathochromic shifts in fluorescence signals, while para isomers produced fluorescent precipitates. Tricarboxylated sensor output varied significantly with carboxylate analyte-recognition unit identity. Details of the preparation, characterization and high-throughput fluorescence assays will be presented.

ORGN 864

Comparison of N- vs. O-alkylation of 2-pyridones under Mitsunobu conditions

Matthew C. Torhan, [email protected], John D Williams, Norton P Peet, Terry L Bowlin.Microbiotix, Inc., Worcester, MA 01605, United States

The Mitsunobu reaction is well known for forming aryl ethers, and while the use of N- nucleophiles is less common, the Mitsunobu reaction has also been used to form C-N bonds using relatively acidic nitrogen-containing heterocycles such as indoles, benzimidazoles, and purines. 2-Pyridones exist as a mixture of both pyridone and hydroxypyridine tautomers, and we have observed the formation of both N- and O- alkylated products using Mitsunobu conditions.

We have investigated the factors influencing the ratio of N- and O-alkylation in the Mitsunobu reaction of 2-pyridones. We have found that the ratio of products is strongly influenced by the substitution pattern on the pyridone ring. The ratios of N- and O- alkylation products using various substituted pyridones will be discussed.

ORGN 865

Novel and practical method for the synthesis of indoles and other heterocycles

Kalyan C. Nagulapalli Venkata, [email protected], Nicos A. Petasis. Department of Chemistry and Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, CA 90089-1661, United States Indole derivatives are among the most important scaffolds in many natural products and synthetic drugs. Due to their biological significance, a variety of synthetic methods have been developed. However, all of the existing methods have shortcomings towards certain substitution patterns on the heterocyclic ring. Herein we report a novel and practical approach towards the synthesis of indole derivatives from readily available starting materials. This methodology is quite versatile and allows the synthesis of a large variety of highly substituted indoles and related heterocyclic systems that contain substituents that are difficult to introduce. A number of examples of this chemistry will be presented.

ORGN 866

ROMP-derived oligo phosphate reagents: Synthesis and application in parallel and flow platforms

Pradip K Maity1, [email protected], Alan Rolfe1, Quirin M Kainz4, Saqib Faisal1,2,3, Toby R Long1,2, Oliver Reiser4, Paul R Hanson1,2. (1) Chemistry, University of Kansas, Lawrence, Kansas 66045, United States (2) NIH Center for Chemical Methodologies and Library Development at the University of Kansas (KU-CMLD), Lawrence, Kansas 66047, United States (3) H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan (4) Organic Chemistry, University of Regensburg, Regensburg, Germany

The development of new ROMP-derived oligomeric phosphorus reagents (oligomeric benzyl phosphates, oligomeric triazole phosphates), chromatography-free Mitsunobu protocols and surface-initiated polymerization from Nb-tagged silica (Nb-Si) and Nb- tagged Cobalt-graphite (Nb-Co/C) magnetic nanoparticles for use in parallel synthesis are reported. A Monomer-on-Monomer (MoM) Mitsunobu protocol utilizing norbornenyl- tagged benzylethyl azodicarboxylate (Nb-BEAD) and Nb-tagged triphenylphosphine (Nb-TPP) is presented whereby purification/ sequestration of Nb-tagged reagents is rapidly achieved using ring-opening metathesis (ROM) polymerization. Additional efforts utilizing surface-initiated polymerization from Nb-tagged silica (Nb-Si) and Nb-tagged Cobalt-graphite (Nb-Co/C) magnetic nanoparticles is also discussed. Application of Silica supported ROMP Reagents in Flow through cartridge for the syntheses of small molecule have been carried out in purification-free process.

ORGN 867 Microwave-assisted one-pot nitrene insertion-decarboxylation synthesis of substituted indoles

Elise Miner, [email protected], Graham Jones, Nadeesha Ranasinghe. Department of Chemistry, Northeastern University, Boston, MA 02115, United States

Functionalized heterocycles are emerging as fundamental components of organic chemistry, and synthesis pathways for these molecules are increasingly gaining attention from chemists and pharmaceutical companies. This research involves Hemetsberger-Knittel nitrene insertion reaction coupled with decarboxylation of the azidocinnamate to yield the subsequent azido acid. This acid is exposed to microreactor technology, instigating thermal cyclization and producing substituted indole products. We are optimizing synthesis of substituted indoles by investigating time and temperature variations during microwave-assisted synthesis as well as solvent environments for the azido acid cyclization, and use of copper chromite catalyst during the reaction. These factors are tested on 2, 3, and 4-substituted azido acids and effectiveness of the reaction conditions is quantified based on product purity versus presence of starting material or formation of intermediates. One-pot nitrene insertion- decarboxylation is being explored in attempt to eliminate issues with product decomposition during thermolysis and low product purity after reaction completion.

ORGN 868

Heterocycles functionalizing ferrocenyl chalcones core

Juan C Aponte-Santini, [email protected], Ingrid Montes-González. Department of Chemistry, University of Puerto Rico-Río Piedras Campus, San Juan, Puerto Rico 00931-3346, Puerto Rico

Destabilization of tubulin, inhibits polymerization of cancerous cells, leading new pathways for the prevention of cancer and guides the discovery of drugs with this potential. Analogue compounds of combretastatin A-4 and the inclusion of chalcones scaffold have been reported with biological and pharmacological properties. Furthermore, ferrocene advantages and specific properties described for decades, impart the attention to lead our research design. Based on this we are synthesizing and studying ferrocenyl derivatives. Ferrocenyl chalcones have been synthesized from moderate to good yields in our laboratory, which are precursors, as indicated in the literature, for multiple functional group interconvertion. Likewise, heterocyclic compounds have attracted our attention due to their anticancer potential, cytotoxicity, and biological activity. We propose that the incorporation of heterocycles in the chalcone core will open new approaches to a synthetic conglomerate of products that can present biological activity. To have a discriminatory agent in relation to the compounds to be synthesized in the investigation, an examination by molecular modeling has been taken into account. This theoretical parameters give us an idea where to direct our efforts and determine a rational drug design that can be modified or re-evaluated. Moreover, different methodologies have been tried for epoxides derivatives synthesis. These compounds have been difficult to achieve, and several methods have been tried without successful results. However, the development of an efficient epoxidation method will be explored in our laboratory to achieve our specific goal. Furthermore, the synthesis of isoxazole derivatives has been started and will be developed further. The synthetic methodology and characterization of these compounds will be elaborated.

ORGN 869

Findings on the gold catalyzed intramolecular cyclization of 3-methylene-5-phenylpent-4-yn-1-ol

Spencer P Heins1, [email protected], Charnsak Thongsornkleeb2. (1) Department of Chemistry, Fort Lewis College, Durango, Colorado 81301, United States (2) Department of Medicinal Chemistry, Chulabhorn Research Institute, Bangkok, Laksi 10210, Thailand

Various Au(I) and Au(III) catalysts have been used to activate π systems for nucleophilic addition. But, gold chemistry is still a relatively new field of research. Gold catalysts can be fine-tuned to effect very selective reactions. The "alkynophilicity" of gold compounds is attractive to us due its potential to selectively activate the alkyne of an enyne for nucleophilic addition. This research has looked at various gold catalysts in selectively activating the alkyne functionality of 3-methylene-5-phenylpent-4-yn-1-ol to produce the dihydrofuran derivative of type 3 which contains the s-cis diene. Spectral data provides support for the formation of the unstable dihydrofuran derivative. The formation of the s-cis diene embedded in dihydrofuran would be very useful for synthetic chemists as it could be used as a building block for the construction of various benzofuranoids, a moiety found in many biologically active natural products and drug molecules.

ORGN 870

Zinc catalyzed atom efficient synthesis of amides and amidines

Simge Davulcu, [email protected], Liana C Allen, Jonathan MJ Williams. Department of Chemistry, University of Bath, Bath, United Kingdom

Catalytic amounts of the cheap, commercially available zinc complex, Zn(OTf)2 promotes the nucleophilic addition of amines to nitriles to yield amidines under anhydrous conditions. The reactions involving primary amines provide a feasible synthetic route to N,N'-disubstituted amidines with high yields. Subsequent hydrolysis of the amidines leads to secondary amides in moderate to high yields.

Zinc catalyzed synthesis of amides via amidines

ORGN 871

Synthesis of CEP-32215: Development and scale-up of an optimized route using a Suzuki coupling

Roger P Bakale, Katrin Przyuski, Renee Roemmele, [email protected], Yi Wang. Cephalon, Inc., Malvern, PA 19355, United States

The evolution of the process to prepare CEP-32215, a Histamine H3 receptor antagonist, will be presented. Two routes detailing preparation of supplies for biological screening will be discussed along with the final optimized process used to manufacture preclinical supplies. Details regarding a novel Suzuki coupling approach used in the scale-up campaign will be presented.

ORGN 872

Preparation of novel peptide isosteres through a zinc-carbenoid mediated homologation reaction

Matthew P Mower, [email protected], Charles K Zercher. Department of Chemistry, University of New Hampshire, Durham, New Hampshire 03824, United States

Implementation of peptidomimetics has been shown to effectively inhibit HIV's aspartyl protease, as well as serine proteases and other enzymes. Many current methods of preparing peptide mimics are lengthy, low yielding, and without fine stereocontrol. A novel class of symmetrical, amino acid derived peptide isosteres has been prepared in good yield utilizing efficient, one-pot methodology. Novel, amino-acid derived β-diketone substrates are converted directly into γ-keto cyclopropanols through a zinc-carbenoid mediated homologation-cyclopropanation reaction. A unique rearrangement process has been identified which interconverts isomers formed during this reaction. This process can be affected through variations in reaction conditions. The isomeric products may also be interconverted after they have been isolated from the crude reaction mixture. This rearrangement was initially studied with a model aliphatic system, and has recently been investigated with several different amino acid derived systems.

ORGN 873 Anti-Markonikov olefin hydration of unsaturated alcohols: Toward the formation of terminal glycols

Peili Teo1,2, [email protected], Robert H Grubbs1. (1) Department of Chemistry, California Institute of Technology, Pasadena, California 91125, United States (2) Institute of Chemical and Engineering Sciences, Singapore, Singapore

Alcohol synthesis is critical to the chemical and pharmaceutical industries. Addition of water across olefins to form primary alcohols (anti-Markovnikov olefin hydration) would be a broadly useful reaction, but has largely proven elusive; an indirect hydroboration/oxidation sequence requiring stoichiometric borane and oxidant is currently the most practical methodology. For glycol formation, two equivalents of borane and oxidant are required to oxidize a diene. Recently, we have reported a more direct approach to terminal alcohol formation from olefins using a triple relay catalysis system that couples palladium-catalyzed oxidation, acid-catalyzed hydrolysis and ruthenium-catalyzed reduction cycles. Herein, we report the usage of this triple relay catalysis system to obtain terminal glycols from unstaurated alcohols. Unsaturated alcohols are converted to terminal glycols by net reaction with water in good yield and excellent regioselectivity.

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ORGN 874

Allene ligands in copper-mediated cross-coupling reactions

Tioga J Martin, [email protected], Eric K Chen, Katerina M Korch, Craig A Merlic. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angels, California 90024, United States

Ligands strongly promote the copper-mediated oxidative coupling (modern Ullmann) reaction of vinylboronate esters and alcohols for the synthesis of vinyl ethers. We found that alkenes and alkynes have a π-ligand effect that enhances this reaction. Furthering this unusual application of π-ligands, allenes were found to facilitate the desired transformation with improved yields as well as overcome limitations in reaction scope. Allenes are proposed to assist the disproportionation and reductive elimination mechanistic steps by acting as π-Lewis bases to Cu(I) and Cu(III) intermediates. Experimental observations correlated exceptionally well with computational studies.

ORGN 875

Air-stable, nitrile-ligated, iron-based Shvo-type compounds as transfer hydrogenation catalysts Taylor N Plank, [email protected], Jessica L Drake, Timothy W Funk. Department of Chemistry, Gettysburg College, Gettysburg, Pennsylvania 17325, United States

Replacing precious metal catalysts with abundant, low-toxicity metals is an important step in developing sustainable processes. An iron hydride structurally similar to Shvo's catalyst (a diruthenium bridging hydride) exhibits reactivity analogous to it. Unfortunately the iron hydride is air-sensitive, which may limit its potential as a practical catalyst. We have been developing air-stable pre-catalysts and exploring their catalytic activity. The application of nitrile-ligated (cyclopentadienone)iron dicarbonyl complexes as catalysts in transfer reductions of aldehydes and ketones will be presented.

ORGN 876

Oppenauer-type oxidations using an air-stable, nitrile-ligated (cyclopentadienone)iron catalyst

Daniel K Kim, [email protected], Jessica L Drake, Timothy W Funk. Department of Chemistry, Gettysburg College, Gettysburg, Pennsylvania 17325, United States

Platinum-group metals play an important and diverse role as catalysts in organic transformations. Unfortunately they are expensive and considered harmful even in low concentrations. For these reasons the replacement of platinum-group metal catalysts with catalysts based on abundant, inexpensive, and low-toxicity metals is an important step toward developing more sustainable chemical processes. For example, it was recently show by Casey and Guan that an air-sensitive iron hydride exhibited reactivity similar to Shvo's diruthenium bridging hydride catalyst. Our interest has been on developing air-stable pre-catalysts similar to the iron hydride and exploring their catalytic activity. The application of nitrile-ligated (cyclopentadienone)iron dicarbonyl complexes as catalysts in Oppenauer-type oxidations of alcohols as a practical replacement for the air-sensitive iron hydride will be presented.

ORGN 877

Magnetically separable heterogeneous Pd nano-catalyst for C-O and C-C bond formation reactions in water Amit Saha, [email protected], John Leazer, Rajender S. Varma. Department of NRMRL, STD, U. S. Environmental Protection Agency, Cincinnati, Ohio 45268, United States

[Fe3O4] nanoparticles were functionalized by dopamine to immobilize Pd on the surface of heterogeneous magnetic ferrite support and the ensuing nano-catalyst, [Fe3O4- Dopamine-Pd], has been used in aqueous C-O bond formations via O-allylation of phenols with allylic acetates in good yields under open aerial atmosphere. Aqueous C-C bond formations via Heck coupling of aryl iodides and electron deficient alkenes were also accomplished using this Pd nano-catalyst. Easy magnetic recovery, efficient recycling of the catalyst and ambient reaction conditions make these protocols more economic and sustainable.

ORGN 878

Propargyl acetals as new substrates in transition metal-mediated radical C-C bond formation reactions

Gagik G Melikyan, Erin Voorhees, [email protected], McKinzie Garrison. Department of Chemistry and Biochemistry, California State University Northridge, Northridge, California 91330, United States

A novel method for the generation of alpha-alkoxy propargyl radicals was developed, using the respective carbocations as precursors. It utilizes propargyl acetals as substrates, cobaltocene as a one-electron reducing agent, and a dicobalthexacarbonyl group as a stabilizing and stereodirecting auxiliary moiety. An experimental protocol includes a low-temperature treatment of propargyl acetals with triflic anhydride and the reduction of requisite propargyl triflates, leading to a radical C-C bond formation alpha to the metal core. The reaction design and a choice of reagents allowed for avoiding strong acids, such as tetrafluoroboric acid, and carrying out the reaction sequence under neutral conditions. The substrate base was expanded to include ketals and cyclic acetals, as well as intramolecular cyclizations of bis-propargyl acetals. The secondary transformations of alpha-alkoxy 1,5-alkadiynes and 1,5-cyclodecadiynes will be presented, along with an X-ray crystallographic analysis and oxidative decomplexation of radical dimers. ORGN 879

Novel syntheses of polysubstituted, alkynylated cycloalkanes via transition metal-mediated radical cyclizations

Gagik G Melikyan, Vahe Darabidian, [email protected], Deborah Meron. Department of Chemistry and Biochemistry, California State University, Northridge, Northridge, CA 91330-8403, United States

A novel method for the generation of transition metal-stabilized, alpha-alkyl bis- propargyl cations and their subsequent reduction was developed. A bulky, dicobalthexacarbonyl core was used, as an auxiliary, to stereodirect the formation of carbon-carbon bonds, yielding d,l- and meso-1,2-bis-alkynylated cycloalkanes (C5-C7), otherwise hardly accessible. The stereoselectivity of cyclization – favoring mostly d,l- configuration – was dependent upon the reducing agent (Zn, cobaltocene), the bulkiness of a gamma-substituent (1,3-steric induction), and also the composition and rigidity of carbon tethers. The scope of the reaction was expanded toward topologically diverse, bi- and tricyclic cycloalkanes, heterocycles, as well as bridged systems. The intimate structural details of cobalt-stabilized bis-propargyl cations were studied by means of low-temperature, multinuclear NMR spectroscopy (1H, 13C, 11B, 19F). The computational data, an X-ray crystallographic analysis, and oxidative decomplexation of metal-bonded radical dimers will also be presented.

ORGN 880

Versatile oxidant of organic compounds: Benzotriazole-chromium trioxide complex

Edward J Parish1, Yu-Chen Lo2, Hiroshi Honda3, [email protected]. (1) Department of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849, United States (2) Department of Biomedical Engineering, University of California, Los Angeles, CA 90095, United States (3) Department of Bioengineering, Northwestern Polytechnic University, Fremont, CA 94539, United States

Chromium oxidation has been well known and widely used in organic chemistry. By complexing chromium trioxide with various amines, a number of new reagents has been produced which are able to bring about selective oxidations.

ORGN 881

Iron-catalyzed asymmetric epoxidation of β,β-disubstituted enones

Yasuhiro Nishikawa, [email protected], Hisashi Yamamoto. Department of Chemistry, The University of Chicago, Chicago, IL 60637, United States

Our novel phenanthroline ligands with Fe(OTf)2 enables the catalytic asymmetric epoxidation of acyclic β,β-disubstituted enones which have been heretofore inaccessible substrate classes. The reactions provide highly enantioenriched α,β- epoxyketones (up to 92% ee) which are further converted to functionalized β- ketoaldehydes and 2-isooxazolidines with quaternary centers. It is noteworthy that our system gives diastereomerically pure epoxide while the conventional method to synthesize epoxides from β,β-disubstituted enones, such as Weitz-Scheffer type epoxidation, suffers from low diastereocontrol.

ORGN 882

Thermally stable, latent olefin metathesis catalysts

Renee M Thomas, [email protected], Robert H Grubbs. Department of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, United States

Highly thermally stable N-aryl,N-alkyl N-heterocyclic carbene (NHC) ruthenium catalysts were designed and synthesized for latent olefin metathesis. These catalysts showed excellent latent behavior toward metathesis reactions, whereby the complexes were inactive at ambient temperature and initiated at elevated temperatures, a challenging property to achieve with second generation catalysts. A sterically hindered N-tert-butyl substituent on the NHC ligand of the ruthenium complex was found to induce latent behavior toward cross-metathesis reactions, and exchange of the chloride ligands for iodide ligands was necessary to attain latent behavior during ring-opening metathesis polymerization (ROMP). Iodide-based catalysts showed no reactivity toward ROMP of norbornene-derived monomers at 25 °C, and upon heating to 85 °C gave complete conversion of monomer to polymer in less than 2 hours. All of the complexes were very stable to air, moisture, and elevated temperatures up to at least 90 °C, and exhibited a long catalyst lifetime in solution at elevated temperatures.

ORGN 883

Rosette nanotube-supported palladium nanoparticles as efficient catalysts for Suzuki-Miyaura cross-coupling in water at ambient temperature

Mohammad R Hassan, [email protected], Hicham Fenniri. Departments of Chemistry and Biomedical Engineering, National Institute for Nanotechnology (NINT-NRC) and University of Alberta, Edmonton, AB T6G 2M9, Canada

Over the last few years nanoparticles (NPs) have been successfully employed as potential replacements of molecular catalysts for a variety of organic reactions. Specially, molecular systems used in homogeneous catalysis are difficult to isolate from the reaction medium and are often used in organic solvents with potentially toxic phosphine ligands. NP catalysts have the advantage of operating as efficiently as molecular catalysts and yet they can be effectively recycled and isolated from the reaction media.

Though inorganic oxide supported NPs have been extensively investigated nanobiomaterial-supported NPs for catalysis is a new topic that offers greener reaction conditions. In this paper we will discuss about newly designed rosette nanotubes- supported palladium NPs and their catalytic activity towards Suzuki-Miyaura cross- coupling reactions. Our studies show the utility and scope of RNT/Pd-NP catalysts for a range of different aryl halides and boronic acids under aqueous conditions at ambient temperature. Our catalysts were found to be active at least up to the 10th reaction cycle without any apparent loss of catalytic activity. We have also applied this system to the synthesis of key intermediates of the drug sartans and fungicide Boscalid.

ORGN 884

Syntheses of cyclic allyl vinlyl ethers via Pd(II)-catalyzed isomerizations of alkynyl epoxides and alkynyl allyl alcohol

Xi Lin, [email protected], Zezhou Wang, Rudy Luck, Shiyue Fang. Department of Chemistry, Michigan Technological University, Houghton, MI 49931, United States Cyclic allyl vinyl ethers are synthesized by Pd(II)-catalyzed isomerizations of alkynyl epoxides and an alkynyl allyl alcohol. Two allyl vinyl ethers were further converted to piperidine derivatives by thermal rearrangement.

ORGN 885

Selective formation of β-hydroxyboronate esters through an aldehyde diboration/Matteson homologation sequence

Peter C. Cannamela, [email protected], Casey R. Medina, Cameron M. Moore, Timothy B. Clark. Department of Chemistry and Biochemistry, University of San Diego, San Diego, CA 92110, United States

The (ICy)CuOt-Bu complex, reported by Sadighi, has been shown to catalyze the diboration of aldehydes and ketones. The resulting diboration products have potential synthetic utility based on the unique α-oxoboronate ester functional group. Reactions involving this intermediate have been explored as potential routes to valuable functional group motifs. The Matteson homologation was expected to result in β-hydroxyboronate esters, containing two valuable functional groups with orthogonal reactivity. Homologation of protected α-hydroxyboronate esters with ClCH2Li provided the corresponding β-oxoboronate esters, but moderate to low yields were observed. Direct homologation (of the crude diboration products) using excess ClCH2Li provided b- hydroxyboronate esters in moderate to high yields. Replacement of bis(pinacolato)diboron with bis[(+)-pinanediolato]diboron provides α- and β- hydroxyboronate esters with high asymmetric induction. The resulting products have been subjected to further reactions involving the C–B bond, demonstrating the synthetic versatility of these intermediates.

ORGN 886

Zirconium mediated one-pot synthesis of α-amino acid using CO2

Yoon Ju Kim, [email protected], Susumu Oda, Shizue Mito. Department of Chemistry, University of Texas at El Paso, El Paso, Texas 79968, United States

A zirconium mediated one-pot synthesis of α-amino acid using CO2 has been investigated. It is known that zirconaaziridines can be prepared from lithiated secondary amines and zirconocene complexes. We examined a variety of lithiated amines R1(R2)CHN(Li)R3 to prepare zirconaaziridines in different conditions. The insertion of CO2 into the Zr-C bond of zirconaaziridine yields corresponding zirconocene α- aminocarboxylate. A successful release of amino acids from the carboxylates with an appropriate cleavage reagent is crucial.

ORGN 887

Zirconium-mediated synthesis of γ-amino acids from carbon dioxide

Ashley X Cooke1,2, [email protected], Shizue Mito1. (1) Department of Chemistry, University of Texas at El Paso, El Paso, Texas 79968-0513, United States (2) Department of Chemistry, Durham University, Durham, County Durham DH1 3LE, United Kingdom

This project aims to develop a novel method for the preparation of γ-amino butanoic acid (GABA) derivatives – one which utilizes CO2 as a C-1 building block via transition metal-mediated synthesis. The synthesis of novel artificial amino acids remains a subject of considerable interest and γ-amino acids have demonstrated a broad range of biological activity such as antibacterial, antidepressant, anti-inflammatory, and anticonvulsant activity. However, current synthetic methodologies for accessing them require many reaction steps and purifications. This project proposes a more efficient route using CO2. Our proposed methodology begins with the incorporation of CO2 to form a 5-membered zirconacycle. Reaction with Eschenmoser's Salt via transmetallation to copper is followed by hydrolysis to afford the desired γ-amino acids. Our procedure offers an expansion of the synthetic methodologies available to access a wide range of γ-amino acids.

ORGN 888

Substrate-directable Heck reactions with arenediazonium salts: The regio- and stereoselective arylation of allylamine derivatives

Patricia Prediger, [email protected], Carlos Roque Duarte Correia, Laís Ferreira Barbosa. Chemistry Institute, State University of Campinas, Campinas, São Paulo 13083-970, Brazil

The palladium-catalyzed, substrate-directable Heck-Matsuda reaction of allylamine derivatives with arenediazonium salts has been studied in our laboratory. The reaction proceeds under mild conditions, with excellent regio- and stereochemical control as a function of coordinating groups present in the allylamine substrate. Severals N- allylcarbamates, N-allylamides and allyltosylamide were used in the Heck reaction with different arenediazonium salts. The Heck adducts were obtained in yields ranging from 52-99% with a ratio trans/cis/1,1-substituted between 86/7/7-100/0/0. Our efforts are focused on application of this protocol in the total synthesis of biologically active compounds such as alverine, a muscle relaxant drug, and cinacalcet hydrochloride, a hyperparathyroidism drug, employing the Heck-Matsuda arylation as the key step.

Another goal for this work is the use of this methodology in Heck-Matsuda diarylation. Allylamines diarylated are precursors for the synthesis of severals bioactive compounds, such as tolpropamine and prenylamine.

ORGN 889

General strategy for sphingosine congeners synthesis via Heck-Matsuda reaction

Pablo David Grigol Martinez, [email protected], Carlos Roque Duarte Correia, Guilherme Fonseca Dal Poggetto. Chemistry Institute, State University of Campinas, Campinas, Sao Paulo 13083-970, Brazil

Drug discovery process usually optimizes pharmacological properties of a starting candidate, tuning its chemical structure through modification of the carbon/functional group array. As natural products constitute a valuable template to find biological active molecules, strategies that enable the synthesis of not only the natural entities but related compounds from a common precursor are strongly desirable. Herein we present the progress in the synthesis of sphingosine (cellular proliferation agent) and its analogues such as safingol (an inhibitor of sphingosine kinase) using a diastereoselective Heck-Matsuda arylation of a pyroglutamic acid-derived enecarbamate which afforded a versatile building block, the trans-5-aryl-2- hydroxymethyl-3-pyrroline. This intermediate provided a ent-safingol precursor using a directed-substrate epoxidation, benzylic C-N hydrogenolysis that opens the pyrrolidine ring, followed by an aromatic oxidative degradation and carboxylic acid reduction. In order to complete the safingol synthesis the chain elongation with an alkylcuprate remains to be done.

ORGN 890

Palladium-catalyzed C-H bond functionalization of amine derivatives

Enrico T Nadres, [email protected], Olafs Daugulis. Department of Chemistry, University of Houston, Houston, Texas 77004, United States

A palladium-catalyzed method for the C–H bond functionalization of the γ– and δ– positions of amine derivatives was developed. Functionalization of the sp2 and sp3 C-H bonds employs 2-picolinic acid as directing group. A variety of aryl and alkyl iodides provided good yield of products. Cyclization to form five– and six–membered rings was also achieved.

ORGN 891 Iron-catalyzed coupling of aryl grignard reagents with alkyl halides

Anna Hedström, [email protected], Per-Ola Norrby. Department of Organic Chemistry, Chemistry, Gothenburg, Sweden

Mechanistic studies of the iron-catalyzed coupling of aryl grignard and alkyl halide were carried out by a Hammett study of the nucleophilic partner and EPR measurements of the active iron specie. This required finding conditions where the iron catalyst is stable in the presence of excess Grignard reagent. The selectivity determining step seems to be the transmetallation, occurring either before or after the oxidative addition step. EPR analysis indicates an active iron(I)-specie.

ORGN 892

Investigation of the aggregation states of chiral lithium amides using DOSY NMR

Chicheung Su, [email protected], Paul Williard, Jie Guang. Chemistry, Brown University, Providence, Rhode Island 02912, United States

The dimeric structure of a lithiated chiral amine ((S)-N1,N1-bis(2-methoxyethyl)-N2,3- dimethylbutane-1,2-diamine) was characterized by X-ray crystallography. The dimeric structure in solution state was also characterized by Li6 and H-DOSY NMR as well as diffusion coefficient-formula weight correlation. An analog of the above amine were also synthesize. Although the crystal structure of the analog was unable to obtain, the aggregation state of the lithiated analog was also characterized by Li6 and H-DOSY NMR and the result suggested that it was also a dimer.

ORGN 893

One-pot three component synthesis of β–amino carbonyl compounds catalyzed by Giant Ball

Hooshang Vahedi, [email protected], Abdolhossien Massoudi, Fatemeh Ghaani. Department of Chemistry, Payame Noor University, Tehran, Tehran 19395- 4697, Iran (Islamic Republic of)

An efficient three-component, one-pot synthesis of β-amino carbonyl compounds from acetophenone, aromatic aldehydes, and aromatic amines using a nanoscaled polyoxomolybdate clusters, Giant Ball, at room temperature is described. This method provides a novel three-component Mannich-type reaction in terms of mild reaction conditions, good yields, simple workup using a very small quantity of inexpensive and reusable catalyst (0.04 mol %).

ORGN 894

Highly diastereoselective synthesis of (E)-disubstituted alkenes containing a p- methoxyphenyl moiety via organoboranes

Narayan G. Bhat, [email protected], Dina D. Cardenas. Chemistry, The University of Texas, Edinburg, TX 78539, United States The (Z)-1-alkenyboronate esters easily prepared by the reaction of (Z)-1- bromoalkenylboronate esters with potassium triisopropoxy borohydride (KIPBH), readily react with p-methoxyphenyl magnesium bromide in ether at -78 oC for 1 hour to provide the corresponding "ate" complexes. These "ate" complexes in methanol are then treated with iodine in methanol at -78 oC for 3 hours provide the corresponding (E)-disubstituted alkenes containing a p-methoxyphenyl moiety. These products are then purified by column chromatography over alumina and the structures of these compounds are confirmed by NMR spectral data. These compounds are obtained in good yields (65%- 78%).

ORGN 895

Highly diastereoselective synthesis of both (Z)- and (E)-trisubstituted alkenes containing phenyl and tolyl moieties

Narayan G. Bhat, [email protected], Lillian Duran, Benjamin Guzman. Chemistry, The university of Texas-Pan American, Edinburg, Texas 78539, United States

The synthesis of trisubstituted alkenes has been well cited in literature but these alkenes were produced with severe limitations with regards to the alkene substituents. Using organoborate ester intermediates allows for a convenient method that provides a vehicle for the stereoselective synthesis of (Z) and (E)- trisubstituted alkenes. (Z)- 1- bromo- 1 –alkenylboronate, readily available from literature, smoothly react with phenyl lithium in diethyl ether at -78 ° C to produce tetra-coordinated boron complexes. The boron “ate” complexes undergo intramolecular nucleophilic substitution to provide (E)-1- alkenylboronate esters with a phenyl moiety. This compound reacts with p-toluene magnesium bromide in ether. The addition of iodine in methanol will induce the migration of the toluene from the boron to the adjacent carbon creating the final product, being the (Z)- trisubstituted alkene isomer. In order to create the (E) isomer, the reagents must be added in reverse order meaning that p-toluene magnesium bromide be added first then the phenyl lithium, followed by iododebromonation.These steps produced eight trisubstituted alkenes within reasonable percent yields (43%-85%) which were conclusively determined to be pure. The resulting procedures proved to be a viable process for the synthesis of all eight of the trisubstituted alkenes.

ORGN 896

Transition metal mediated synthesis of N-alkyl anilines

Qun Xu, [email protected], Donald Watson. Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, United States

A method for the transition metal catalyzed alkylation of anilines will be presented. Substrate scope, reaction mechanism, and its application to the synthesis of complex molecules will be discussed. ORGN 897

Mechanistic investigations of alkene carboacylation via C-C bond activation in quinolinyl ketones

J. Patrick Lutz, [email protected], Colin M Rathbun, [email protected], Jeffrey B Johnson. Department of Chemistry, Hope College, Holland, MI 49423, United States

Carbon-carbon single bonds form the framework for many organic molecules, but in most cases, they cannot be functionalized. This presentation will summarize the mechanistic investigation of the rhodium-catalyzed intramolecular carboacylation of an alkene, proposed to proceed through carbon-carbon bond activation. A kinetic analysis revealed an unusual first order rate law with no rate dependence upon substrate. Additional experiments identified the catalytic resting state, while determining activation parameters and 12C/13C kinetic isotope effects. Further studies indicate that electron- donating groups increase the rate of reaction. This conclusion is consistent with the kinetics of the parent compound, as electron-donating substituents would be expected to stabilize the high-energy, electron-deficient intermediate of the rate-limiting C-C insertion step. A related mechanistic investigation with a second rhodium catalyst has revealed a similar but distinct mechanism. The combined insight from these studies promises to guide the development of new carbon-carbon single bond activation methodologies.

ORGN 898

Rhodium- and copper-catalyzed formation of 2-talosamine derivatives from D- galactal 3-carbamates

Julia S. Caine, [email protected], Rabia Iqbal, Kari Mosleh, Christian M Rojas. Department of Chemistry, Barnard College, New York, New York 10027, United States

In our quest to achieve chemoselective amidoglycosylation of D-galactal 3-carbamates as a means for 2-aminotalose synthesis, we have explored factors that affect the fate of primary-carbamate-derived acyl nitrene 1 . This reactive intermediate can lead to either desired amino sugar 2 or to C3-oxidized dihydropyranone 3 . With rhodium nitrenoids, we have found that 4O-tert-butyldimethylsilyl-6O-tosyl protection is optimal, and we observed a corresponding conformational shift in the carbamate precursor as judged by 4 JH2,H4 W-coupling (or lack thereof). Furthermore, switching to copper catalysis provided even higher chemoselectivity.

ORGN 899

Highly selective C-H acyloxylation using environmentally benign sodium perborate

Pär G Janson, [email protected], Lukasz T Pilarski, Kálmán J Szabó. Department of Organic Chemistry, Stockholm University, Stockholm, Sweden

We have developed a chemo- and regioselective palladium-catalyzed procedure for allylic C-H bond functionalization under mild conditions (typically at 40-60°C in MeCN). In this procedure we have used a sodium perborate/carboxylic acid anhydride mixture as a combined oxidant and source of nucleophile. The scope of the reaction is wide, tolerating many functional groups; both terminal and internal alkenes can be functionalized. The reaction is very robust, proceeding under air in non-dry solvent.

ORGN 900

Palladium-catalyzed β-carbon elimination of fluorinated triarylmethanols

James R Bour, [email protected], Jacob C Green, Jeffrey B Johnson. Department of Chemistry, Hope College, Holland, MI 49423, United States

Due to their stability, carbon-carbon δ-bonds are inert under a vast majority of reaction conditions. Recently, however, methods have been developed for the activation of such species through the use of transition metal catalysts. The palladium catalyzed β-carbon elimination of triarylmethanols is an example of such a methodology (Miura et. al. J. Org. Chem., 2003, 68, 5236). The presented research describes the mechanistic investigation of this palladium-catalyzed reaction, specifically the influence of fluorinate triarylmethanols on the rate and selectivity of C-C bond activation. Fluorine substituted triarylmethanols were chosen because of the sterically unhindered and electronically active nature of fluorine, which has been hypothesized to participate in an agostic-type interaction with the metal center to enhance intermediate stability. Analysis of the product ratios and yields generated data to help elucidate the mechanism by which this reaction proceeds and provide additional insight into the factors that influence carbon- carbon bond activation.

ORGN 901

Chemoselctive reduction of an internal alkyne to a trans-alkene: A key step for the synthesis of a HCV polymerase inhibitor

Su Yu, [email protected], James Napier, Jean C. Califano, Mark Oinen, Calvin Becker, David M. Barnes. Department of Process Chemistry, GPRD, Abbott Laboratories, North Chicago, IL 60064, United States

A trans diaryl alkene was synthesized by utilizing a sequence of a Sonogashira reaction and a reduction of the resulting alkyne to the trans alkene. A method was developed to chemoselectively reduce a diaryl alkyne to a trans diaryl alkene with hexamethyldisilane/water or triethylsilane/water in the present of a palladium catalyst. The alkyne was reduced to a cis alkene before isomerized to a trans alkene. High selectivity (E/Z => 99%) and high yield (85%) were achieved with both reagents. The reaction with triethylsilane/water provided better control of exothermal when scaling up.

ORGN 902

Macrocyclizations of Ynals: Application of regioselective nickel-catalyzed reductive couplings

Allison R Knauff, [email protected], John Montgomery. Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, United States

Advances in regioselective macrocyclizations using nickel catalysis have been made. This methodology involves the nickel-catalyzed reductive coupling of tethered aldehyde and alkyne moieties utilizing trialkylsilanes as reducing agents. Formation of either the endo- or exocyclic regioisomer as the major product is achieved by varying the structure of the N-heterocyclic carbene ligand on the nickel center. Preliminary results show moderate yields and excellent to moderate regioselectivities with 20 mol% catalyst loading, indicating that the desired transformation can be realized. This work further illustrates the generality of ligand-controlled regioselective aldehyde-alkyne couplings, expanding on prior developments of intermolecular three component reductive couplings.

ORGN 903

Designing recyclable polyisobutylene-bound azobenzene ligands

Nilusha Priyadarshani, [email protected], Yanfei Yang, David E Bergbreiter. Department of Chmeistry, Texas A and M University, College Station, College Stataion, TX 77842, United States Polyisobutylene (PIB), a polymer that is selectively soluble in nonpolar solvents such as heptane, has previously been used as a support to synthesize arene-containing ligands for recyclable homogeneous catalysts. These ligand syntheses involve electrophilic aromatic substitutions and proceed via intermediate PIB-bound anilines that can be converted to azobenzenes using isoamyl nitrite in nonpolar solvents with Lewis acid catalysis. Here we describe using PIB-bound azobenzenes to form palladacycle precatalysts for Heck and Suzuki cross coupling reactions. These Pd complexes are soluble in miscible mixtures of heptane/DMF or in a mixture of THF, DMF and a low melting hydrocarbon solid at elevated temperatures where catalysis occurs. These PIB- bound Pd complexes can then be recovered either in heptane or entrapped in a solid hydrocarbon wax on cooling. In the heptane/DMF case, the Pd complex is separated by a liquid/liquid separation. In the second case, the wax-entrapped Pd complex solid was simply physically separated from the solution of product.

ORGN 904

Application of insertion reactions to the nonactin scaffold

Alicia J. Frantz, [email protected], Mark C. McMills. Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio 45701, United States

Alicia Frantz , [email protected]; Mark C. McMills*, [email protected]. Department of Chemistry and Biochemistry, Ohio University, 100 University Terrace, 380 Clippinger Laboratories, Athens, Ohio 45701, United States

The use of carbon-hydrogen or X-H insertion reactions has been widely used for the synthesis of various organic compounds. We report herein the synthesis of novel analogs of nonactin as a scaffold for novel biological activity. Through various substitutions of the X group, the new moiety can be utilized to prepare the corresponding five, six, or seven membered ring compounds (Figure 1).

ORGN 905 Medium ring photoactivated enediyne via ring closing metathesis

Daniel W Klosowski, [email protected], Suzanne Burke, Graham B Jones. Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States

Enediynes continue to attract interest due to their chemical and physical properties, including antitumoral agents, conducting polymers, and radical initiators. While many of the naturally occurring members of this class are prodrugs which require molecular activation; there exists the possibility of designing enediynes which are triggered by photo chemical processes. In this presentation we will outline de novo synthesis of a class of cyclic enediynes and report on their photoactivity. A key process in the synthesis of these agents was ring closure metathesis using Grubbs II catalyst.

ORGN 906

Investigating the conjugate addition of lithium dialkylcuprates to enones

Ross A Moretti, [email protected], Jeffrey K Bratz, Jennifer L Rutherford. Department of Chemistry, Lafayette College, Easton, PA 18042, United States

The 1,4-addition of a lithium dialkylcuprate reagent to an α,β-unsaturated ketone was probed for insight into the details of this reaction. The transformation was studied over a range of conditions by varying temperature, order of addition, and reagent stoichiometry. Studies have focused on the role of cuprate pre-formation and the need for 2:1 Cu(I):alkyllithium for successful transformation. The role of competing 1,2- addition in this reaction was investigated as well. Experiments were also observed in real time using an in situ-ATR-IR to probe for intermediate species.

ORGN 907

Role of nanoparticles in the Au-catalyzed rearrangement of allyl aryl ethers

Kevin B Smith, [email protected], Heidi E Dimmitt, Colin C Hanson, Nicole C Koeppen, David A Rider, Steven R Emory, James R Vyvyan. Department of Chemistry, Western Washington University, Bellingham, WA 98225, United States

Depending on the catalyst precursors, a gold nanoparticle film forms on the walls of the reaction vessel during the formal Claisen rearrangement of allyl aryl ethers catalyzed by Ph3PAuOTf. In some cases, the film maintains catalytic activity after removal of the reaction mixture and rinsing the film. Recent results concerning nanoparticle film formation, characterization and reactivity will be presented.

ORGN 908

Palladium-catalyzed cross-coupling of benzyl thioacetates and aryl halides Krista M Wager, [email protected], Matthew Daniels. Department of Chemistry, Merck Research Laboratories, Boston, Massachusetts 02115, United States

A method for the synthesis of benzyl aryl thoethers from protected thiols has been developed and optimized. In situ deprotection is utilized to generate the reactive free thiol species from thioacetates, which subsequently undergo palladium-catalyzed arylation. Thioethers are obtained in good to excellent yields from an array of sterically and electronically diverse aryl halides and thioesters. The observation of aryl/aryl exchange with Xantphos is also discussed.

ORGN 909

Utility of 1,2,4-triazole based non precious complexes in biomass conversion and ORR

Chinmay N Dabke1, [email protected], Ashesh S Belapure1, Ramez Elgammal1, Gabriel Goenaga2, Alex Papandrew2, Tom Zawodzinski2, Shane Foister1. (1) Department of Chemistry, University of Tennesee, Knoxville, TN 37996, United States (2) Chemical and Biomolecular Engineering Department, University of Tennesee, Knoxville, Tennessee 37996, United States

The work done in our group includes the use of complexes of 1,2,4-triazoles with non precious metals (NPMs) including Fe, Mn, Cu and Co, for the conversion of several types of biomass including switchgrass, hard wood, soft woods, in addition to isolated lignin, like Kraft lignin, to organic building blocks. Our catalysts operate under mild conditions and a wide range of pH using either hydrogen peroxide or molecular oxygen, as co-oxidants.

Similarly, 1,2,4-triazole ligands, covalently anchored on the surface of carbon and complexed with Cu(II) salts are active as catalysts in oxygen reduction reaction (ORR). We have explored various methods to covalently anchor these ligands on the surface of carbon and also used a variety of different carbon surfaces. These immobilized catalysts appear to be comparable in activity to their adsorbed counterparts, while showing enhanced durability.

ORGN 910

Optimization and substrate scope for direct arylation polymerization

Calvin Wiley1, [email protected], Shiloh Stone1, Andrey Rudenko2,3,4, Keenan Woods1, Allyson Dorsey1, Robert Springer1, Erin Cyffka1, Lindsay Lawrence1, Barry C Thompson2,3,4, John F Tannaci1. (1) Department of Chemistry, California Lutheran University, Thousand Oaks, CA 91360, United States (2) Department of Chemistry, University of Southern California, Los Angeles, CA 90089, United States (3) Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, CA 90089, United States (4) Center for Energy Nanoscience, University of Southern California, Los Angeles, CA 90089, United States

Direct arylation has emerged as a "green" approach to carbon-carbon bond formation with high atom economy. However, this chemistry has not been readily applied to polymerization reactions. Therefore, we utilized small-molecule model systems to develop palladium-catalyzed conditions for direct arylation polymerization. More recently, we have applied these optimized conditions to a variety of conjugated monomers. Both studies, optimization and substrate scope, will be presented in detail.

ORGN 911

Palladium(II) catalyzed intramolecular insertions for polycyclic ring synthesis

Jonathan L Kuo, [email protected], Robert G Iafe, Craig A Merlic. Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095, United States

An intramolecular regioselective and stereoselective Pd(II)-catalyzed coupling of boronate esters with alkene or alkyne insertion has been developed. This methodology provides convenient access to substituted fused or spiro polycyclic ring systems. The reaction involves competing transmetallations and insertions. Furthermore, we have designed substrates that explore the competitive rates of vinyl and aryl transmetallation versus alkene and alkyne insertion.

ORGN 912

Variations of the N-heterocyclic carbene ligand of ruthenium based Z-selective catalysts Paresma R. Patel, [email protected], Benjamin K. Keitz, Koji Endo, Myles B. Herbert, Robert H. Grubbs. Department of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, United States

Described here are variations to the N-heterocyclic carbene (NHC) ligand for the recently reported ruthenium based Z-selective catalyst. We investigated changes to both the adamantyl group and aryl ring of the reported NHC. Perturbations of the adamantyl group prevented the necessary -CH activation necessary for the synthesis of desired catalysts. Nonetheless, subtle steric and electronic changes to the aryl ring of the NHC provided stable, isolable catalysts that possess excellent conversions and Z- selectivity for cross metathesis of a range of olefinic substrates.

ORGN 913

Very low catalyst loadings for the selective isomerization of various heterofunctionalized compounds using a bifunctional catalyst

Casey R Larsen, [email protected], Douglas B Grotjahn. Department of Chemistry & Biochemistry, San Diego State University, San Diego, CA 92182-1030, United States

Transition metal mediated catalysis of the isomerization of alkenes is atom economical, but selectivity can be difficult to control. Various isomerization catalysts and conditions are known to operate over an array of substrate functionality and chain length, but in general, the major challenges are difficulty in controlling E:Z product selectivity and position of the double bond. We have developed a bifunctional catalyst which efficiently isomerizes a wide variety of heterofunctionalized alkene derivatives, with published examples using at least 2 mol% catalyst. Here we report optimized conditions using as little as 0.01-0.5 mol% catalyst, at 25oC, still resulting in exclusive (E)-selectivity. Isomerization of neat or dissolved substrate can lead to near-quantitative isolation of pure product. Quantitative kinetic studies of one example show that our catalyst migrates double bonds over 3.5 million times faster than (E)-to-(Z)-geometrical isomerism. The result is optimized conditions useful for application by organic chemists.

ORGN 914

Ruthenium(II)-catalyzed intermolecular [2+2+2] co-trimerization of haloalkynes with internal and terminal alkynes

James S Oakdale, [email protected], Valery V Fokin. Department of Chemistry, The Scripps Research Institute, La Jolla, California 92122, United States

The piano stool Ru(II) complexes, such as CpRuCl(cod), catalyze the intermolecular [2+2+2] cycloaddition of 3-halopropargylic amides and alkynes leading to fully substituted, dihalogenated benzenes with excellent chemoselectivity and high regioselectivity. Haloalkynes are necessary reaction partners playing a crucial role in increasing the regioselectivity of the cyclotrimerization of activated alkynes. The reaction is experimentally simple and proceeds at ambient temperature in ethanol without special precautions.