Syllabus CHEM 6352 2014
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Studies Directed Towards the Stereoselective Total Synthesis of Miyakolide
Studies Directed Towards the Stereoselective Total Synthesis of Miyakolide by Jinhua Song Submitted to the Department of Chemistry in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Organic Chemistry at the Massachusetts Institute of Technology February, 1999 @1999 Jinhua Song All rights Reserved The author hereby grants MIT permissions to reproduce and to distribute publicly paper and electronic copies of this thesis document in whole or in part. Signature of Author: Department of Chemistry September 25, 1998 Certified by: Professor Satoru Masamune A. C. Cope Professor of Chemistry Thesis Supervisor Accepted by:, ProfessotDietmar Seyferth, Chairman Departmental Committee on Graduate Students MASSACHUSETTS INSTITUTE OF TECHNOLOGY LrL J This doctoral thesis has been examined by a committee of the Department of Chemistry as follows: Professor Timothy M. Swager Chairman Professor Satoru Masamune Thesis Supervisor Professor Rick L. Danheiser , 2 Studies Directed Towards the Stereoselective Total Synthesis of Miyakolide by Jinhua Song Submitted to the Department of Chemistry on September 25, 1998, in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Organic Chemistry Abstract Presented are the stereoselective syntheses of the A (C18-C28), B (C14-C17), C (C6-C13), D (Cl-C5), C'D' (C1-C13) fragments and the efficient coupling of B and C'D' fragments of the marine natural product miyakolide, a 24-membered polyketide macrolide which exhibits anti-cancer activity. Fragment A was synthesized from the chiral aldehyde 4-4 through the successful application of the newly developed boron mediated anti-selective aldol methodology using the chiral ester 3-4. -
The Synthesis and Applications of N-Alkenyl Aziridines
The Synthesis and Applications of N-Alkenyl Aziridines by Nicholas A. Afagh A thesis submitted in conformity with the requirements for the degree of Master of Science Department of Chemistry University of Toronto © Copyright by Nicholas A. Afagh 2010 The Synthesis and Applications of N-Alkenyl Aziridines Nicholas A. Afagh Master of Science Department of Chemistry University of Toronto 2010 Abstract N-alkenyl aziridines are a unique class of molecules that do not behave as typical enamines as a result of the inability of the nitrogen atom lone-pair of electrons to delocalize. The attenuated nucleophilicity of these enamines presents opportunities for the selective functionalization and reactivity not available to classical enamines. An operationally simple and mild copper-mediated coupling has been developed that facilitates the preparation of a broad range of N-alkenyl aziridines not available through existing methods. The preparation and reactivity of highly- functionalized N-alkenyl aziridines are reported. Also reported is the application of the chemoselective amine/aldehyde/alkyne (A 3) multicomponent coupling involving amphoteric aziridine aldehydes as the aldehyde component. This coupling allows access to propargyl amines with pendent aziridine functionality. ii Acknowledgments First and foremost, I would like to thank my supervisor, Professor Andrei K. Yudin for his continuous support and encouragement over the past two years. His wealth of knowledge and profound insight into all matters chemistry made for many interesting discussions. In addition, I would like to thank all the members of the Yudin group past and present with whom I have had the distinct pleasure of working alongside and shared many late evenings. -
Radical Approaches to Alangium and Mitragyna Alkaloids
Radical Approaches to Alangium and Mitragyna Alkaloids A Thesis Submitted for a PhD University of York Department of Chemistry 2010 Matthew James Palframan Abstract The work presented in this thesis has focused on the development of novel and concise syntheses of Alangium and Mitragyna alkaloids, and especial approaches towards (±)-protoemetinol (a), which is a key precursor of a range of Alangium alkaloids such as psychotrine (b) and deoxytubulosine (c). The approaches include the use of a key radical cyclisation to form the tri-cyclic core. O O O N N N O O O H H H H H H O N NH N Protoemetinol OH HO a Psychotrine Deoxytubulosine b c Chapter 1 gives a general overview of radical chemistry and it focuses on the application of radical intermolecular and intramolecular reactions in synthesis. Consideration is given to the mediator of radical reactions from the classic organotin reagents, to more recently developed alternative hydrides. An overview of previous synthetic approaches to a range of Alangium and Mitragyna alkaloids is then explored. Chapter 2 follows on from previous work within our group, involving the use of phosphorus hydride radical addition reactions, to alkenes or dienes, followed by a subsequent Horner-Wadsworth-Emmons reaction. It was expected that the tri-cyclic core of the Alangium alkaloids could be prepared by cyclisation of a 1,7-diene, using a phosphorus hydride to afford the phosphonate or phosphonothioate, however this approach was unsuccessful and it highlighted some limitations of the methodology. Chapter 3 explores the radical and ionic chemistry of a range of silanes. -
Properties of Silicon Hafensteiner
Baran Lab Properties of Silicon Hafensteiner Si vs. C Siliconium Ion - Si is less electronegative than C - Not believed to exist in any reaction in solution - More facile nucleophilic addition at Si center J. Y. Corey, J. Am. Chem. Soc. 1975, 97, 3237 - Pentacoordinate Si compounds have been observed Average BDE (kcal/mol) MeSiF4 NEt4 Ph3SiF2 NR4 C–C C–Si Si–Si C–F Si–F 83 76 53 116 135 - Lack of cation justified by high rate of bimolecular reactivity at Si C–O Si–O C–H Si–H Mechanism of TMS Deprotection 86 108 83 76 OTMS O Average Bond Lengths (Å) C–C C–Si C–O Si–O 1.54 1.87 1.43 1.66 Workup Si Si Silicon forms weak p-Bonds O O F F NBu4 p - C–C = 65 kcal/mol p - C–Si = 36 kcal/mol Pentavalent Silicon Baran Lab Properties of Silicon Hafensteiner Nucleophilic addition to Si b-Silicon effect and Solvolysis F RO–SiMe3 RO F–SiMe3 SiMe3 Me H H vs. Me3C H Me3C H OSiMe O Li 3 H OCOCF H OCOCF MeLi 3 3 A B Me-SiMe3 12 kA / kB = 2.4 x 10 Duhamel et al. J. Org. Chem. 1996, 61, 2232 H H SiMe Me b-Silicon Effect 3 vs. Me3C H Me3C H - Silicon stabalizes b-carbocations H OCOCF3 H OCOCF3 - Stabalization is a result of hyperconjugation 4 kA / kB = 4 x 10 SiR3 CR3 Evidence for Stepwise mechanism vs. Me3Si SiMe2Ph SiMe2Ph A B Me3Si SiMe2Ph *A is more stable than B by 38 kcal/mol * Me3Si SiMe2Ph Me3Si Jorgensen, JACS, 1986,107, 1496 Product ratios are equal from either starting material suggesting common intermediate cation Baran Lab Properties of Silicon Hafensteiner Evidence for Rapid Nucleophilic Attack Extraordinary Metallation Me SiMe3 SiMe3 Li Si t-BuLi Me SnCl4 Cl Me3Si Cl Me2Si Cl SiMe MeO OMe 3 OMe OMe Me2Si Cl vs. -
Synthetic Strategies to Access Biologically Important Fluorinated Motifs: Fluoroalkenes and Difluoroketones by Ming-Hsiu Yang Su
Synthetic Strategies to Access Biologically Important Fluorinated Motifs: Fluoroalkenes and Difluoroketones By Ming-Hsiu Yang Submitted to the graduate degree program in Medicinal Chemistry and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy Chairperson Ryan A. Altman Michael D. Clift Apurba Dutta Michael F. Rafferty Jon A. Tunge Date Defended: April 26, 2017 The Dissertation Committee for Ming-Hsiu Yang certifies that this is the approved version of the following dissertation: Synthetic Strategies to Access Biologically Important Fluorinated Motifs: Fluoroalkenes and Difluoroketones Chairperson Ryan A. Altman Date Approved: April 26, 2017 ii Abstract Ming-Hsiu Yang Department of Medicinal Chemistry, April 2017 The University of Kansas Fluorine plays an important role in drug design, because of some unique features imparted by fluorine. The incorporation of fluorine into small molecules can modulate molecular physicochemical properties, metabolic stability, lipophilicity, and binding affinity to the target proteins. However, few fluorinated molecules are biosynthesized by enzymes. This means incorporating fluorine into the molecules relies on synthetic methods. Thus, efficient synthetic strategies to access the molecules bearing a variety of privileged fluorinated moieties are important for drug discovery. Fluoroalkenes are an isopolar and isosteric mimic of an amide bond with distinct biophysical properties, including decreased H-bond donating and accepting abilities, increased lipophilicity, and metabolic stability. Moreover, fluoroalkenes can also serve as probes for conducting conformational analyses of amides. These potential applications require the development of efficient methods to access fluoroalkenes. In chapter 2, a Shapiro fluorination strategy to access peptidomimetic fluoroalkenes is demonstrated. -
Shapiro Reaction
MANA TV programme SHAPIRO REACTION P. Kiran Kumar Lecturer in Chemistry SGA Government Degree College Yellamanchili SHAPIRO REACTION Treatment of tosyl hydrazone of an aldehyde or a ketone with a strong base leads to the formation of vinyl anion which on hydrolysis given an olefin. Hydrazine Phenyl Hydrazine Tosyl hydrazide (p-Toluenesulfonyl hydrazide) Tosyl hydrazone Formed by Nucleophilic addition between aldehyde or ketone and Tosyl hydrazide (p-Toluenesulfonyl hydrazide) and subsequent loss of carbonyl oxygen Mechanism Deprotonation of Tosyl hydrazone with a strong base to form Hydrazone aza enolate. Elimination of aryl sulfinate gives an unstable anion. Loss of Nitrogen leads to vinyl anion Hydrazone aza enolate unstable anion Vinyl anion Vinyl anions can be trapped by number various electrophiles 1. Hydrolysis gives an Alkene 2. Reaction with D2O gives Deuterated Alkene 3. Reaction with CO2 gives α, β-unsaturated acid 4. Reaction with formaldehyde gives Primary alcohol Vinyl anionsanions can can be be trapped trapped by by number number various various electrophiles – –Cont’dCont’d 5. Reaction with DMF gives an α, β-unsaturated aldehyde 6. Reaction with Alkyl chloride gives an Alkyl substituted alkene 7. Reaction with (CH3)3SiCl gives a Vinyl Silane Shapiro reaction involving cyclic ketones Cyclohexanone Shapiro reaction involving cyclic ketones Mechanism Mechanisms Mechanisms Mechanism Shapiro reaction involving unsymmetrical ketones unsymmetrical ketones gives predominantly less substituted olefins Shapiro reaction involving unsymmetrical ketones Removal of proton from the more substituted carbon atom Not formed Stability of the carbanion: secondary versus tertiary Secondary carbanion Tertiary carbanion Secondary carbanion more stable than primary carbanion. -
Therapeutic Review Exploring Antimicrobial Potential of Hydrazones As Promising Lead
Available online a t www.derpharmachemica.com Scholars Research Library Der Pharma Chemica, 2011, 3(1):250-268 (http://derpharmachemica.com/archive.html) ISSN 0975-413X CODEN (USA): PCHHAX Therapeutic Review Exploring Antimicrobial Potential of Hydrazones as Promising Lead Goldie Uppal, Suman Bala*, Sunil Kamboj and Minaxi Saini M.M. College of Pharmacy, Maharishi Markandeshwar University, Ambala, Haryana, India ______________________________________________________________________________ ABSTRACT This review includes detailed study of structures of various hydrazones synthesized and evaluated for their antimicrobial activity. Hydrazone is a class of organic compounds with structure R 1R2C=NNH 2. Hydrazones containing an azomethine -NHN=CH- proton which leads to an important class of compounds for new drug development. Hydrazones are present in many of the bioactive heterocyclic compounds that are of very important use because of their various biological and clinical applications. Therefore, many researchers have synthesized these compounds as target structures and evaluated their antimicrobial activities. These observations have been guiding for the development of new hydrazones that possess varied biological activities. Key Words: Hydrazones, Hydrazide, Antifungal Activity, Antimicrobial Activity. ______________________________________________________________________________ INTRODUCTION The need to design new compounds to deal with the resistant strains has become one of the most important areas of research today. Hydrazone is a versatile moiety that exhibits a wide variety of biological activities. A hydrazone is a class of organic compounds with the structure R1R2C=NNH 2. Hydrazones are basically related to ketones and aldehydes. Hydrazones are formed by the replacement of the oxygen of carbonyl compounds with the -NNH 2 functional group. Hydrazones act as reactants in many important reactions e.g. -
Appendix I: Named Reactions Single-Bond Forming Reactions Co
Appendix I: Named Reactions 235 / 335 432 / 533 synthesis / / synthesis Covered in Covered Featured in problem set problem Single-bond forming reactions Grignard reaction various Radical couplings hirstutene Conjugate addition / Michael reaction strychnine Stork enamine additions Aldol-type reactions (incl. Mukaiyama aldol) various (aldol / Claisen / Knoevenagel / Mannich / Henry etc.) Asymmetric aldol reactions: Evans / Carreira etc. saframycin A Organocatalytic asymmetric aldol saframycin A Pseudoephedrine glycinamide alkylation saframycin A Prins reaction Prins-pinacol reaction problem set # 2 Morita-Baylis-Hillman reaction McMurry condensation Gabriel synthesis problem set #3 Double-bond forming reactions Wittig reaction prostaglandin Horner-Wadsworth-Emmons reaction prostaglandin Still-Gennari olefination general discussion Julia olefination and heteroaryl variants within the Corey-Winter olefination prostaglandin Peterson olefination synthesis Barton extrusion reaction Tebbe olefination / other methylene-forming reactions tetrodotoxin hirstutene / Selenoxide elimination tetrodotoxin Burgess dehydration problem set # 3 Electrocyclic reactions and related transformations Diels-Alder reaction problem set # 1 Asymmetric Diels-Alder reaction prostaglandin Ene reaction problem set # 3 1,3-dipolar cycloadditions various [2,3] sigmatropic rearrangement various Cope rearrangement periplanone Claisen rearrangement hirstutene Oxidations – Also See Handout # 1 Swern-type oxidations (Swern / Moffatt / Parikh-Doering etc. N1999A2 Jones oxidation -
Organic & Biomolecular Chemistry
Organic & Biomolecular Chemistry View Article Online PAPER View Journal | View Issue Diastereoselective synthesis of trisubstituted olefins using a silicon-tether ring-closing Cite this: Org. Biomol. Chem., 2020, 18, 2297 metathesis strategy† Stéphane Wittmann,‡ Alexander F. Tiniakos and Joëlle Prunet * The diastereoselective synthesis of trisubstituted olefins with concomitant C–C bond formation is still adifficult challenge, and olefin metathesis reactions for the formation of such alkenes are usually not high yielding or/and diastereoselective. Herein we report an efficient and diastereoselective synthesis of trisubstituted olefins flanked by an allylic alcohol, by a silicon-tether ring-closing metathesis strategy. Both E-andZ-trisubstituted alkenes were synthesised, depending on the method employed Received 30th November 2019, to cleave the silicon tether. Furthermore, this methodology features a novel Peterson olefination for Accepted 4th March 2020 the synthesis of allyldimethylsilanes. These versatile intermediates were also converted into the DOI: 10.1039/c9ob02563d corresponding allylchlorodimethylsilanes, which are not easily accessible in high yields by other Creative Commons Attribution 3.0 Unported Licence. rsc.li/obc methods. Introduction However, there are much fewer examples of RCM reactions with O–Si–C tethers. The reported formations of trisubstituted The trisubstituted E olefin motif with a methyl substituent is olefins from allyl silanes lead to bicyclic products,8 and the present in numerous polyketide natural products. Among others focus on vinyl silanes.9 We propose a strategy for an these, callipeltoside A1 and dolabelide C2 possess another efficient and diastereoselective synthesis of trisubstituted This article is licensed under a common feature: an allylic alkoxy group on the lone substitu- olefins flanked by an allylic alcohol, which involves a RCM ent of the trisusbstituted olefin (highlighted in red in reaction with a O–Si–C tether. -
Bridging Mcmurry and Wittig in One-Pot
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 1755 Bridging McMurry and Wittig in One-Pot Olefins from Stereoselective, Reductive Couplings of Two Aldehydes via Phosphaalkenes JURI MAI ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6214 ISBN 978-91-513-0536-3 UPPSALA urn:nbn:se:uu:diva-368873 2019 Dissertation presented at Uppsala University to be publicly examined in Häggsalen, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, Friday, 15 February 2019 at 10:15 for the degree of Doctor of Philosophy. The examination will be conducted in English. Faculty examiner: Professor Dr. Christian Müller (Freie Universität Berlin, Institute of Chemistry and Biochemistry). Abstract Mai, J. 2019. Bridging McMurry and Wittig in One-Pot. Olefins from Stereoselective, Reductive Couplings of Two Aldehydes via Phosphaalkenes. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 1755. 112 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-513-0536-3. The formation of C=C bonds is of great importance for fundamental and industrial synthetic organic chemistry. There are many different methodologies for the construction of C=C bonds in the literature, but currently only the McMurry reaction allows the reductive coupling of two carbonyl compounds to form alkenes. This thesis contributes to the field of carbonyl olefinations and presents the development of a new synthetic protocol for a one-pot reductive coupling of two aldehydes to alkenes based on organophosphorus chemistry. The coupling reagent, a phosphanylphosphonate, reacts with an aldehyde to yield a phosphaalkene intermediate which upon activation with a base undergoes an olefination with a second aldehyde. A general overview of synthetic methods for carbonyl olefinations and the chemistry of phosphaalkenes is given in the background chapter. -
Convergent Total Synthesis and Preliminary Biological Investigations
Norrislide: Convergent Total Synthesis and Preliminary Biological Investigations Author: Krista Elizabeth Granger Persistent link: http://hdl.handle.net/2345/731 This work is posted on eScholarship@BC, Boston College University Libraries. Boston College Electronic Thesis or Dissertation, 2009 Copyright is held by the author, with all rights reserved, unless otherwise noted. Boston College The Graduate School of Arts and Sciences Department of Chemistry NORRISOLIDE: CONVERGENT TOTAL SYNTHESIS AND PRELIMINARY BIOLOGICAL INVESTIGATIONS a dissertation by KRISTA ELIZABETH GRANGER submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy August 2009 © copyright by KRISTA ELIZABETH GRANGER 2009 Norrisolide: Convergent Total Synthesis and Preliminary Biological Investigations Krista Elizabeth Granger Thesis Advisor: Professor Marc L. Snapper Abstract • Chapter 1: A review of Shapiro reactions as a coupling strategy in natural product total synthesis. The syntheses of lycoramine, galanthamine, yuehchukene analogues, ovalicin, studies toward the ingenol core, haemanthidine, pretazettine, tazettine, crinamine, Taxol, colombiasin A, elisapterosin B, the AB ring fragment of spongistatin 1 and 8-epipuupewhedione are discussed. Ar O S O nBuLi Li E+ E NH R' R' N R R R' R • Chapter 2: The convergent total synthesis of the marine natural product norrisolide is described. Both subunits, the hydrindane core and the norrisane side chain, are prepared in an asymmetric fashion through kinetic resolution and enantioselective cyclopropanation, respectively. A Shapiro reaction couples the two fragments and a Peterson olefination installs the 1,1-disubstituted olefin. O O MeO OTBS AcO MeO O O O O N Me Me Me MeO O O Me Li O OP H H Me Me Me Me norrisolide H Me Me • Chapter 3: Preliminary experiments to isolate the biological target of norrisolide through reductive alkylation and tritium labeling are investigated. -
Science Fair Project
OrganicOrganic ChemistryChemistry ofof LowLow--CoordinateCoordinate PhosphorusPhosphorus CompoundsCompounds Tom Hsieh University of Toronto Organic and Biological Seminar November 12, 2007 I.I. Background:Background: MakingMaking BondsBonds AnalogousAnalogous toto CC--CC DoubleDouble BondsBonds 2 BreakingBreaking thethe ““DoubleDouble BondBond RuleRule”” Generally held belief: elements outside the first row do not form multiple bonds Phosphaalkene chemistry deals with 3p-2p (P=C) π-bonds!! 3 CarbonCarbon--SiliconSilicon MultipleMultiple BondsBonds 1981: West discovered Si=Si double bond C N Si P 1981: Brook discovered Si=C double bond West, Fink, Michl. Science. 1981, 214, 4527. Brook, Abdesaken, Gutekunst, Gutekunst, Kallury. J. Chem. Soc., Chem. Commun. 1981, 191. 4 CarbonCarbon--NitrogenNitrogen MultipleMultiple BondsBonds C-N bonds are ubiquitous C N Si P C=N and C=C double bonds are stable Reactivity requires either: high-lying HOMOs accessible, low-lying LUMOs π-bonds, strained rings, electron deficient species, etc. 5 UltravioletUltraviolet PhotoelectronPhotoelectron SpectroscopySpectroscopy (UPS)(UPS) UPS determines molecular energy levels in the valence region Helium discharge lamp is used as the photon source Measures the kinetic energy spectra of electrons emitted by UV photons 6 UltravioletUltraviolet PhotoelectronPhotoelectron SpectroscopySpectroscopy (UPS)(UPS) Each of the peaks in the spectrum corresponds to the - 10.30 MO energy level - 10.70 (in eV) of one valence-region He (eV) 7 MethanimineMethanimine vs.vs. EthyleneEthylene UV photoelectron spectroscopic measurements C N Si P HOMO of methanimine is the lone pair π-bond lies much lower in energy Consequently, methanimine usually reacts through its lone pair before through its π-bond Lacombe, Gonbeau, Cabioch, Pellerin, Denis, Pfister-Guillouzo. J. Am. Chem. Soc.