Banaras Hindu University Logic of Organic Synthesis
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Organic Synthesis: Handout 1
Prof Tim Donohoe: Strategies and Taccs in Organic Synthesis: Handout 1 Organic Synthesis III 8 x 1hr Lectures: Michaelmas Term Weeks 5-8 2016 Mon at 10am; Wed at 9am Dyson Perrins lecture theatre Copies of this handout will be available at hEp://donohoe.chem.ox.ac.uk/page16/index.html 1/33 Prof Tim Donohoe: Strategies and Taccs in Organic Synthesis: Handout 1 Organic Synthesis III Synopsis 1) Introduc5on to synthesis: (i) Why do we want to synthesise molecules- what sort of molecules do we need to make? (ii) What aspects of selecvity do we need to accomplish a good synthesis (chemo-, regio- and stereoselecvity)? (iii) Protecng group chemistry is central to any syntheAc effort (examples and principles) (iv) What is the perfect synthesis (performed in industry versus academia)? 2) The chiral pool: where does absolute stereochemistry come from? 3) Retrosynthesis- learning to think backwards (revision from first and second year). Importance of making C-C bonds and controlling oxidaAon state. Umpolung 4) Some problems to think about 5) Examples of retrosynthesis/synthesis in ac5on. 6) Ten handy hints for retrosynthesis 7) Soluons to the problems Recommended books: General: Organic Chemistry (Warren et al) Organic Synthesis: The DisconnecRon Approach (S. Warren) Classics in Total Synthesis Volumes I and II (K. C. Nicolaou) The Logic of Chemical Synthesis (E. J. Corey) 2/33 View Article Online / Journal Homepage / Table of Contents for this issue 619461 Strychniqae and BYucine. Pavt XLII. 903 Prof Tim Donohoe: Strategies and Taccs in Organic Synthesis: Handout 1 (i) Why do we want to synthesise complex molecules? Isolated from the Pacific Yew in 1962 Prescribed for prostate, breast and ovarian cancer Unique mode of acRon 1x 100 year old tree = 300 mg Taxol Isolated in 1818- poisonous Stuctural elucidaon took R. -
Artificial Intelligence for Computer-Aided Synthesis
ORIGINAL RESEARCH published: 04 August 2020 doi: 10.3389/fceng.2020.00005 Artificial Intelligence for Computer-Aided Synthesis In Flow: Analysis and Selection of Reaction Components Pieter P. Plehiers 1,2, Connor W. Coley 1, Hanyu Gao 1, Florence H. Vermeire 1, Maarten R. Dobbelaere 2, Christian V. Stevens 3, Kevin M. Van Geem 2* and William H. Green 1* 1 Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States, 2 Laboratory for Chemical Technology, Department of Materials, Textiles and Chemical Engineering, Ghent University, Ghent, Belgium, 3 SynBioC Research Group, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent Edited by: University, Ghent, Belgium René Schenkendorf, Technische Universitat Braunschweig, Germany Computer-aided synthesis has received much attention in recent years. It is a challenging Reviewed by: topic in itself, due to the high dimensionality of chemical and reaction space. It becomes Richard Anthony Bourne, even more challenging when the aim is to suggest syntheses that can be performed in University of Leeds, United Kingdom Alexei Lapkin, continuous flow. Though continuous flow offers many potential benefits, not all reactions University of Cambridge, are suited to be operated continuously. In this work, three machine learning models United Kingdom have been developed to provide an assessment of whether a given reaction may benefit *Correspondence: from continuous operation, what the likelihood of success in continuous flow is for a Kevin M. Van Geem [email protected] certain set of reaction components (i.e., reactants, reagents, solvents, catalysts, and William H. Green products) and, if the likelihood of success is low, which alternative reaction components [email protected] can be considered. -
Elucidating How Wood Adhesives Bond to Wood Cell Walls Using High-Resolution Solution-State NMR Spectroscopy
Elucidating How Wood Adhesives Bond to Wood Cell Walls using High-Resolution Solution-State NMR Spectroscopy Daniel J. Yelle U.S. Forest Service, Forest Products Laboratory Madison, WI, 53726, USA [email protected] Introduction Lignin, 25-30% of wood, is a phenolic polymer made Some extensively used wood adhesives, such as up of branched phenylpropanoid units that are capable of pMDI (polymeric methylene diphenyl diisocyanate) and reacting with other phenols during adhesive bonding. PF (phenol formaldehyde) have shown excellent adhesion Model compound studies have shown that under alkaline properties with wood. However, distinguishing whether conditions and ≥100 °C, β-aryl ether linkages release for- the strength is due to physical bonds (i.e., van der Waals, maldehyde to give vinyl ether linkages (Figure 2a) [10]. London, or hydrogen bond forces) or covalent bonds be- Phenylcourmaran linkages release formaldehyde in a simi- tween the adherend and the adhesive is not fully under- lar fashion to give stilbene linkages (Figure 2b) [10]. 13C stood. Previous studies, where pMDI model compounds NMR spectroscopy showed that most of this released for- were reacted with wood, showed that carbamate (urethane) maldehyde ends up as the methylene bridge between the 5- formation with wood polymers is only possible when: 1. positions on guaiacyl units (Figure 2c) [11]. the number of moles of isocyanate is significantly higher a. HO H O than the moles of water molecules in the wood, 2. high γ γ HO β β α O 4 α β O 4 α O 4 temperatures are used, and 3. the isocyanate-based com- OCH3 OCH - OH 3 OCH3 O + CH pound is of low molecular weight [1]. -
Synthesis, Structure and Attempted Polymerization of a Diepoxide Macrocycle Paul Yarincik Sacred Heart University
Sacred Heart University DigitalCommons@SHU Chemistry & Physics Faculty Publications Chemistry and Physics 10-2012 Synthesis, Structure and Attempted Polymerization of a Diepoxide Macrocycle Paul Yarincik Sacred Heart University Jeffrey H. Glans Sacred Heart University, [email protected] Follow this and additional works at: http://digitalcommons.sacredheart.edu/chem_fac Part of the Polymer Chemistry Commons Recommended Citation Yarincik, Paul and Glans, Jeffrey H., "Synthesis, Structure and Attempted Polymerization of a Diepoxide Macrocycle" (2012). Chemistry & Physics Faculty Publications. 1. http://digitalcommons.sacredheart.edu/chem_fac/1 This Article is brought to you for free and open access by the Chemistry and Physics at DigitalCommons@SHU. It has been accepted for inclusion in Chemistry & Physics Faculty Publications by an authorized administrator of DigitalCommons@SHU. For more information, please contact [email protected]. Letters in Organic Chemistry, 2012, 9, 545-548 545 Synthesis, Structure and Attempted Polymerization of a Diepoxide Macrocycle Paul Yarincik and Jeffrey H. Glans* Department of Chemistry, Sacred Heart University, Fairfield, CT 06825, USA Received October 19, 2011: Revised December 31, 2011: Accepted January 04, 2012 Abstract: A novel diepoxide containing paracyclophane was synthesized by peracid oxidation of a known paracyclo- phane diene. The resulting diepoxide was characterized. It was investigated as a potential monomer for a cyclophane con- taining polyether by cationic ring opening polymerization. None of the standard catalyst systems for such a polymeriza- tion were successful in producing polymer. Keywords: Cationic polymerization, cyclophane, diepoxide, macrocycle. R INTRODUCTION R O O O+ Cationic polymerization of olefins is one of the major R+ routes to high molecular weight polymers [1]. The mecha- O O+ O nism involves nucleophilic attack of the alkene functional group on the electron poor initiator (initiation) or the grow- ing cationic chain end (propagation). -
Or· 8-Annoquriioltlmb WITH. NIT~~~OI,4
BIBIUD.~; TliE REACTION 8-AnNOQuriiOLtlmB WITH. NIT~~~OI,4 •' >'•' • or·I,' ",i. by Hugh Bu:rknla·p.·,:Ilona.hoe B.s.• ,. Rookhurst College, 194.3 M.A.,, Univ&rESi.ty of ICansas, · 1947 . Submitted to the Department of ·chemistry and the Faculty. of. the . G:raduate School or the University of Kansas in partial fulfillment ot the ?'equirements for the de• gree of Doctor ot Philosophy. Advisory Committee · May, 19.$0 AOKNOWLEOOMENT The author wishes to ex.press his thanks and appreciation to Dr. J. H. Burokhalter,, who suggested this problem, and Dr. a. A. Vanderwerf for ·their helpful suggestions and guidance during the course of this work. H.B.D. TABLE OF OONTEN'TS Chapter Page I • THE PROBLE?i Olr MALARIA. A. Introduction • • • • • . • • 1 B. The types of malaria. • • • • • • •• 2 O. The biology of malarial infection • • 3 D. The prophylaxis and treatment of malaria: •. ;•' •. • • •. • . ;.. • • : •••• ·• • • ., 6 II. ·Atfl'IMALARIAL ·:DRUGS. :· • · ,, A. Olassific at ion and. screening of antimalarial drugs • • . ,, . .. ' . • • • • 12 B. Historical • • • • • • • • • • • • • 1~ c. Quinine • .. • • • .. • • • • • • • • • 16 D. Synthetic substitutes • • • • • • • • 19 l. Plasmochin • • • • • .. • • • • • 19 2 •. Quinaorine • • • • • .. • • • • • 21 3. Ohloroquine • • • • • • • • • •• 21 q.. Pentaquine •• • • • • • • • • • 23 s. Paludrine • • • • • • • • • • • • 2q. E. Me(lhanism ot action of antimalarial drugs • • • • • • • •• • • • • • • • 2$ 1. The metabolite-antimetaboli te relationship • • • • • • • •• • 2.$ 2. The quinoid•Quinonimine theory • 26 3. Conclusions • • • • • • • • • •• 28 · -Ohapter III.· THE ANTIMALARIAL PROGRAM 1941-1945 . .A. The overall program • • • • • • • • • 30 .a. :._ Tb(j ·4•aminoquinolinea • • • • • • • • .32 · <h ·. The 8-aminoqu.inolines • : • . • • • • • • 34. IV. • DISCUSSION Of THE PROBLEM ) • • • • • .• • • • .38 ·V. · DISCUSSION OF· RESULTS. · - . A.;, Unsymmetrical hybrids related to '. propanediemine * • • • • •. • • • • • 46 B. ··Symmetrical: hybrida related to prc,pan~di8J1iinet ~d methanediamine • • S2 . -
Retrosynthetic Design of Metabolic Pathways to Chemicals Not Found in Nature
Retrosynthetic design of metabolic pathways to chemicals not found in nature The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Lin, Geng-Min et al. "Retrosynthetic design of metabolic pathways to chemicals not found in nature." Biology 14 (April 2019): 82-107 © 2019 The Authors As Published http://dx.doi.org/10.1016/J.COISB.2019.04.004 Publisher Elsevier BV Version Final published version Citable link https://hdl.handle.net/1721.1/125854 Terms of Use Creative Commons Attribution-NonCommercial-NoDerivs License Detailed Terms http://creativecommons.org/licenses/by-nc-nd/4.0/ Available online at www.sciencedirect.com Current Opinion in ScienceDirect Systems Biology Retrosynthetic design of metabolic pathways to chemicals not found in nature Geng-Min Lin1, Robert Warden-Rothman1 and Christopher A. Voigt Abstract simpler chemical building blocks derived from pe- Biology produces a universe of chemicals whose precision and troleum or other sources [1]. Chemicals that are large complexity is the envy of chemists. Over the last 30 years, the and complex with many functional groups and ster- expansive field of metabolic engineering has many successes eocenters have required Herculean efforts to build; in optimizing the overproduction of metabolites of industrial in- for example, halichondrin B has 32 stereocenters (4 terest, including moving natural product pathways to production billion isomers) and requires a sprawling total syn- hosts (e.g., plants to yeast). However, there are stunningly few thesis whose longest linear path is 47 reactions [2]. examples where enzymes are artificially combined to make a Solutions have been found to incredibly challenging chemical that is not found somewhere in nature. -
Organic Synthesis: New Vistas in the Brazilian Landscape
Anais da Academia Brasileira de Ciências (2018) 90(1 Suppl. 1): 895-941 (Annals of the Brazilian Academy of Sciences) Printed version ISSN 0001-3765 / Online version ISSN 1678-2690 http://dx.doi.org/10.1590/0001-3765201820170564 www.scielo.br/aabc | www.fb.com/aabcjournal Organic Synthesis: New Vistas in the Brazilian Landscape RONALDO A. PILLI and FRANCISCO F. DE ASSIS Instituto de Química, UNICAMP, Rua José de Castro, s/n, 13083-970 Campinas, SP, Brazil Manuscript received on September 11, 2017; accepted for publication on December 29, 2017 ABSTRACT In this overview, we present our analysis of the future of organic synthesis in Brazil, a highly innovative and strategic area of research which underpins our social and economical progress. Several different topics (automation, catalysis, green chemistry, scalability, methodological studies and total syntheses) were considered to hold promise for the future advance of chemical sciences in Brazil. In order to put it in perspective, contributions from Brazilian laboratories were selected by the citations received and importance for the field and were benchmarked against some of the most important results disclosed by authors worldwide. The picture that emerged reveals a thriving area of research, with new generations of well-trained and productive chemists engaged particularly in the areas of green chemistry and catalysis. In order to fulfill the promise of delivering more efficient and sustainable processes, an integration of the academic and industrial research agendas is to be expected. On the other hand, academic research in automation of chemical processes, a well established topic of investigation in industrial settings, has just recently began in Brazil and more academic laboratories are lining up to contribute. -
Converting Disulfide Bridges in Native Peptides to Stable Methylene Thioacetals
Chemical Science View Article Online EDGE ARTICLE View Journal | View Issue Converting disulfide bridges in native peptides to stable methylene thioacetals† Cite this: Chem. Sci.,2016,7, 7007 C. M. B. K. Kourra and N. Cramer* Disulfide bridges play a crucial role in defining and rigidifying the three-dimensional structure of peptides. However, disulfides are inherently unstable in reducing environments. Consequently, the development of strategies aiming to circumvent these deficiencies – ideally with little structural disturbance – are highly sought after. Herein, we report a simple protocol converting the disulfide bond of peptides into highly stable methylene thioacetal. The transformation occurs under mild, biocompatible conditions, enabling the conversion of unprotected native peptides into analogues with enhanced stability. The developed Received 23rd May 2016 protocol is applicable to a range of peptides and selective in the presence of a multitude of potentially Accepted 24th July 2016 reactive functional groups. The thioacetal modification annihilates the reductive lability and increases the DOI: 10.1039/c6sc02285e serum, pH and temperature stability of the important peptide hormone oxytocin. Moreover, it is shown www.rsc.org/chemicalscience that the biological activities for oxytocin are retained. Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Introduction disulde bond engineering emerged as an important strategy to improve the metabolic stability of disulde-containing peptides, Peptides have recently been enjoying a renewed interest in whilst maintaining their biological activity. For instance, their application as therapeutic agents.1 They provide a large replacements of the disulde group with a lactam,10 thioether,11 a chemical space with a diverse array of molecular frameworks selenium12 or dicarba13 analogues have been reported.5 Many of for the development of novel therapeutics for a plethora of these methods require signicant modication of the synthetic biomedical applications. -
Highly Enantioselective Synthesis of Γ-, Δ-, and E-Chiral 1-Alkanols Via Zr-Catalyzed Asymmetric Carboalumination of Alkenes (ZACA)–Cu- Or Pd-Catalyzed Cross-Coupling
Highly enantioselective synthesis of γ-, δ-, and e-chiral 1-alkanols via Zr-catalyzed asymmetric carboalumination of alkenes (ZACA)–Cu- or Pd-catalyzed cross-coupling Shiqing Xu, Akimichi Oda, Hirofumi Kamada, and Ei-ichi Negishi1 Department of Chemistry, Purdue University, West Lafayette, IN 47907 Edited by Chi-Huey Wong, Academia Sinica, Taipei, Taiwan, and approved May 2, 2014 (received for review January 21, 2014) Despite recent advances of asymmetric synthesis, the preparation shown in Schemes 1 and 2 illustrate the versatility of ZACA of enantiomerically pure (≥99% ee) compounds remains a chal- represented by the organoaluminum functionality of the ini- lenge in modern organic chemistry. We report here a strategy tially formed ZACA products. Introduction of the OH group for a highly enantioselective (≥99% ee) and catalytic synthesis by oxidation of initially formed alkylalane intermediates in of various γ- and more-remotely chiral alcohols from terminal Scheme 2 is based on two considerations: (i) the proximity of the alkenes via Zr-catalyzed asymmetric carboalumination of alkenes OH group to a stereogenic carbon center is highly desirable for (ZACA reaction)–Cu- or Pd-catalyzed cross-coupling. ZACA–in situ lipase-catalyzed acetylation to provide ultrapure (≥99% ee) di- oxidation of tert-butyldimethylsilyl (TBS)-protected ω-alkene-1-ols functional intermediates, and (ii) the versatile OH group can R S α ω produced both ( )- and ( )- , -dioxyfunctional intermediates (3) be further transformed to a wide range of carbon groups by – ee ≥ ee in 80 88% , which were readily purified to the 99% level tosylation or iodination followed by Cu- or Pd-catalyzed cross- by lipase-catalyzed acetylation through exploitation of their high α ω coupling. -
Structure and Conformation of Bilirubin
364 C. C. KUENZLE, M. H. WEIBEL AND R. R. PELLONI Kuenzle, C. C. (1970b) Biochem. J. 119, 411-435 Kuenzle, C. C., Weibel, M. H., Pelloni, R. R. & Kuenzle, C. C. (1973) in Metabolic Conjugation andMeta- Hemmerich, P. (1973), Biochem. J. 133, 364-368 bolic Hydrolysis (Fishman, W. H., ed.), vol. 3, Academic von Dobeneck, H. & Brunner, E. (1965) Hoppe-Seyler's Press, New York, in the press Z. Physiol. Chem. 341, 157-166 APPENDIX Structure and Conformation of Bilirubin OPPOSING VIEWS THAT INVOKE TAUTOMERIC EQUILIBRIA, HYDROGEN BONDING AND A BETAINE MAY BE RECONCILED BY A SINGLE RESONANCE HYBRID By CLIVE C. KUENZLE,* MATTHIAS H. WEIBEL,* RENATO R. PELLONI* and PETER HEMMERICHt * Department ofPharmacology and Biochemistry, School of Veterinary Medicine, University ofZurich, CH-8057 Zurich, Switzerland and t Department ofBiology, University ofKonstanz, D-7750 Konstanz, Germany A novel conformational structure of bilirubin is presented which obtains maximum stabilization through a system of four intramolecular hydrogen bonds. Two hydrogen bonds link oxygen and nitrogen atoms of each end ring to the contralateral carboxyl group. The proposed structure can explain a variety of uncommon features of bilirubin, and reconciles many seemingly contradictory hypotheses by accommodating them in individual structures which are mesomeric forms of one resonance hybrid. In the light of this newly conceived structure the following characteristics of bilirubin are re-evaluated: the stability of the compound, its reaction with diazomethane, the conformational beha- viour of its dimethyl ester, its spectral properties, the chirality of the compound when complexed to serum albumin, and the structure of its metal chelates. The basic structure of bilirubin was elucidated by when bilirubin is esterified with diazomethane Fischer's group (Fischer et al., 1941; Fischer & (Kuenzle, 1970a). -
Articles Conformational Analysis of Chirally Deuterated Tunicamycin As an Active Site Probe of UDP-N-Acetylhexosamine:Polyprenol
13248 Biochemistry 2004, 43, 13248-13255 Articles Conformational Analysis of Chirally Deuterated Tunicamycin as an Active Site Probe of UDP-N-Acetylhexosamine:Polyprenol-P N-Acetylhexosamine-1-P Translocases† Lin Xu,‡ Michael Appell,§,| Scott Kennedy,‡ Frank A. Momany,§,| and Neil P. J. Price*,‡,§,⊥ USDA-ARS-NCAUR, Fermentation Biotechnology Research Unit, and Plant Polymer Research Unit, 1815 North UniVersity Street, Peoria, Illinois 61604, and UniVersity of Rochester Medical Center, 601 Elmwood AVenue, Rochester, New York 14642 ReceiVed August 4, 2004; ReVised Manuscript ReceiVed August 19, 2004 ABSTRACT: Tunicamycins are potent inhibitors of UDP-N-acetyl-D-hexosamine:polyprenol-phosphate N-acetylhexosamine-1-phosphate translocases (D-HexNAc-1-P translocases), a family of enzymes involved in bacterial cell wall synthesis and eukaryotic protein N-glycosylation. Structurally, tunicamycins consist of an 11-carbon dialdose core sugar called tunicamine that is N-linked at C-1′ to uracil and O-linked at C-11′ to N-acetylglucosamine (GlcNAc). The C-11′ O-glycosidic linkage is highly unusual because it forms an R/â anomeric-to-anomeric linkage to the 1-position of the GlcNAc residue. We have assigned the 1H and 13C NMR spectra of tunicamycin and have undertaken a conformational analysis from rotating angle nuclear Overhauser effect (ROESY) data. In addition, chirally deuterated tunicamycins produced 2 by fermentation of Streptomyces chartreusis on chemically synthesized, monodeuterated (S-6)-[ H1]glucose have been used to assign the geminal H-6′a, H-6′b methylene bridge of the 11-carbon dialdose sugar, 4 tunicamine. The tunicamine residue is shown to assume pseudo-D-ribofuranose and C1 pseudo-D- galactopyranosaminyl ring conformers. -
Sc-Homoaromaticity
This is a repository copy of Modern Valence-Bond Description of Homoaromaticity. White Rose Research Online URL for this paper: https://eprints.whiterose.ac.uk/106288/ Version: Accepted Version Article: Karadakov, Peter Borislavov orcid.org/0000-0002-2673-6804 and Cooper, David L. (2016) Modern Valence-Bond Description of Homoaromaticity. Journal of Physical Chemistry A. pp. 8769-8779. ISSN 1089-5639 https://doi.org/10.1021/acs.jpca.6b09426 Reuse Items deposited in White Rose Research Online are protected by copyright, with all rights reserved unless indicated otherwise. They may be downloaded and/or printed for private study, or other acts as permitted by national copyright laws. The publisher or other rights holders may allow further reproduction and re-use of the full text version. This is indicated by the licence information on the White Rose Research Online record for the item. Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ Modern Valence-Bond Description of Homoaromaticity Peter B. Karadakov; and David L. Cooper; Department of Chemistry, University of York, Heslington, York, YO10 5DD, U.K. Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, U.K. Abstract Spin-coupled (SC) theory is used to obtain modern valence-bond (VB) descriptions of the electronic structures of local minimum and transition state geometries of three species that have been con- C sidered to exhibit homoconjugation and homoaromaticity: the homotropenylium ion, C8H9 , the C cycloheptatriene neutral ring, C7H8, and the 1,3-bishomotropenylium ion, C9H11.