DOCSLIB.ORG

Total Synthesis of ( Þ )-Gelsemine Via an Organocatalytic Diels–Alder Approach

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Total Synthesis of ( Þ )-Gelsemine Via an Organocatalytic Diels–Alder Approach ARTICLE Received 13 Jan 2015 | Accepted 16 Apr 2015 | Published 21 May 2015 DOI: 10.1038/ncomms8204 OPEN Total synthesis of ( þ )-gelsemine via an organocatalytic Diels–Alder approach Xiaoming Chen1,2, Shengguo Duan1,2, Cheng Tao1, Hongbin Zhai1 & Fayang G. Qiu2 The structurally complex alkaloid gelsemine was previously thought to have no significant biological activities, but a recent study has shown that it has potent and specific antinociception in chronic pain. While this molecule has attracted significant interests from the synthetic community, an efficient synthetic strategy is still the goal of many synthetic chemists. Here we report the asymmetric total synthesis of ( þ )-gelsemine, including a highly diastereoselective and enantioselective organocatalytic Diels–Alder reaction, an efficient intramolecular trans-annular aldol condensation furnishing the prolidine ring and establishing the configuration of the C20 quaternary carbon stereochemical centre. The entire gelsemine skeleton was constructed through a late-stage intramolecular SN2 substitution. The enantiomeric excess of this total synthesis is over 99%, and the overall yield is around 5%. 1 State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China. 2 Laboratory of Molecular Engineering, and Laboratory of Natural Product Synthesis, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Boulevard, The Science Park of Guangzhou, Guangzhou 510530, China. Correspondence and requests for materials should be addressed to H.Z. (email: [email protected]) or to F.G.Q. (email: [email protected]). NATURE COMMUNICATIONS | 6:7204 | DOI: 10.1038/ncomms8204 | www.nature.com/naturecommunications 1 & 2015 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms8204 lthough gelsemine was isolated1 in as early as 1876 from Results Gelsemium Sempervirens Ait., its structure was not Retrosynthetic analysis. Gelsemine may be synthesized from Adetermined until 1959 by means of nuclear magnetic intermediate RS-1 and oxindole via the condensation of the 2,3 resonance (NMR) spectroscopic techniques and X-ray hemiacetal with oxindole followed by an intramolecular SN2 crystallographic analysis4. This indole alkaloid contains a displacement (Fig. 3). Although the condensation may result in hexacyclic cage structure and seven contiguous chiral carbon four stereoisomers, only two of them may undergo the desired centres (Fig. 1). The complex chemical structures of gelsemine SN2 displacement. The other two isomers, however, may either and other members of the alkaloid family5–8 have attracted stay intact or undergo an elimination followed by a Michael considerable attention from synthetic chemists. So far, in addition addition51,52 to regenerate the four stereoisomers. This to the many synthetic efforts9–37, there are eight total syntheses equilibrium is shifted to form the desired product after the 38–49 reported in the literature (Fig. 2), two of which are intramolecular SN2 displacement, which is irreversible under the 44,48 asymmetric . Although gelsemine was thought to have no reaction conditions (Figs 4 and 5). The SN2 displacement may particular biological activities, a recent report indicated that result in two isomers, one of which is the desired product. gelsemine exhibited potent and specific antinociception in Intermediate RS-1 may be obtained from RS-2 following a chronic pain by acting at the three spinal glycine receptors50. sequence of intramolecular aldol condensation, reduction of the Besides, gelsemine was nonaddictive, indicating that the carbonyl group, formation of the sulfonates and then elimination. mechanism of its action is different from that of morphine. The The intramolecular aldol53,54 condensation deserves further complex structure and the potential medicinal applications discussion due to the fact that both the aldehyde and the of gelsemine prompted us to initiate a more efficient ketone functionalities may undergo enolization under the enantioselective total synthesis. reaction conditions, resulting in epimerization of both Herein we wish to report a 12-step, highly enantioselective stereochemical centres attaching the carbonyl groups. Another organocatalytic total synthesis of ( þ )-gelsemine. issue is the direction of the aldol condensation. Since both of the carbonyl groups may be enolized, the aldol condensation from either one may be consequential. However, Cbz is a bulky 55 17 functional group and it will play a significant role in preventing N O the aldehyde from being enolized prior to the ketone enolization. N O 5 In this case, the potential epimerization of the ketone 21 3 R2 functionality is irrelevant. The third issue is the stereochemistry 7 19 of the hydroxyl group even if aldol condensation occurs in the 19 R2 O N desired direction. This difficulty may be overcome when one O N 18 R realizes that the desired product has a more favourable internal 1 56,57 R1 hydrogen bond than the other isomer. Finally, formation of 19-Hydroxydihydrogelsemine R = H, R = OH RS-3 and its conversion into RS-2 is straightforward. Gelsemine R1 = H, R2 = H, H 1 2 19-Hydroxydihydrogelsevirine Gelsevirine R1 = OMe, R2 = H, H 21-Oxogelsemine R = H, R = O R1 = OMe, R2 = OH 1 2 Synthesis of the ( þ )-gelsemine. On the basis of the above 21-Oxogelsevirine R = OMe, R = O 19-Acetroxydihydrogelsevirine 1 2 analysis, the synthetic strategy seemed feasible. If intermediate 3 R1 = OMe, R2 = OAc is made asymmetric, then gelsemine will be made asymmetric. Figure 1 | The structures of gelsemium alkaloids. The difference between Thus, after a brief literature search58,59, an asymmetric the members of the gelsemium alkaloids is the presence of the functional Diels–Alder reaction was designed and the synthesis began with groups in the unique carbon skeleton. The major difference appeared in dihydropyridine 1 (Fig. 6), which may be prepared from C-19 and C-21. 4-methylpyridine in large scale60. O This work, 2015 Speckamp,1994 Asymmetric Racemic N Cbz N 12 steps, 5% 19 steps, 0.83% O Ts Qin, 2012 Johnson, 1994 N OH MeO C CO Me O Asymmetric 2 2 Racemic N 25 steps 1% 29 steps, 0.58% TBSO Cl OtBu Fukuyama 1996 Danishefsky, 2002 OMe O N Racemic H Racemic 32 steps 0.67% 36 steps, 0.019% O O Gelsemine Fukuyama, 2000 O Hart, 1997 Asymmetric Overman,1999 Racemic 31 steps, 0.86% O Racemic O 23 steps, 0.25% N 26 steps, 1.2% Cl N O OMe O Bn Figure 2 | Schematic summary of the previous total syntheses of gelsemine. Among the seven total syntheses completed so far, two of them were asymmetric and the overall yields were around 1%. This molecule has been an active target of total synthesis during the past two decades. 2 NATURE COMMUNICATIONS | 6:7204 | DOI: 10.1038/ncomms8204 | www.nature.com/naturecommunications & 2015 Macmillan Publishers Limited. All rights reserved. NATURE COMMUNICATIONS | DOI: 10.1038/ncomms8204 ARTICLE Gratifyingly, the yield of the desired endo product was 47% 97% yield, which brought the total yield of the Diels–Alder after reduction of the aldehyde carbonyl group with sodium cycloaddition to 76%. Intermediate 3 was then further selectively borohydride, and its enantio excess was determined using chiral reduced to the hemiacetal 4 using Dibal-H at À 78 °C in 94% high-performance liquid chromatography (HPLC) to be 99.7%, yield. The subsequent Wittig reaction furnished the methyl enol while the exo product was not detected. It was surprising that ether, which was directly treated with trimethyl orthoformate and intermediate 3a was also produced in 30% yield. Since a catalytic amount of p-toluenesulfonic acid to provide intermediate 3 was stable under the reaction conditions, 3a intermediate 5 and 5a (13:1) as a separable mixture in 93% may be a result of the double-bond isomerization of the enal combined yield. Although 5a may be used as well, it was during the catalytic process61, and the rate of the double-bond converted into 5 by treating it with pTSOH in methylene chloride isomerization was comparable to that of the Diels–Alder (DCM) and only 5 was used for the next step. After a cycloaddition (Fig. 7). Fortunately, 3a was converted into 3 conventional ozonolysis of intermediate 5 in DCM, the with DBU (1,8-diazabicycloundec-7-ene) in refluxing toluene in resulting dicarbonyl intermediate was directly treated with sodium methoxide in methanol at 0 °C due to the fact that the dicarbonyl intermediate was unstable for storage. To our delight, Cbz N O the aldol reaction afforded the desired product 6 in 60% N O combined yield. However, the reaction of 6 with the + methanesulfonyl chloride resulted in a complex mixture. Thus, N O OH O N H X the hydroxyketone intermediate 6 was reduced to diol 7 with H Gelsemine RS-1 sodium borohydride (97%) and the formation of disulfonate 8 with methanesulfonyl chloride was quantitative, the structure of Cbz which was confirmed through X-ray crystallographic analysis N O CHO Cbz CbzN O + N (Fig. 8). Treatment of intermediate 8 with DBU (1,8- OH CO R diazabicycloundec-7-ene) in refluxing toluene led to the O 2 OH 9 O RS-3 formation of alkene (85%) and reduction of the Cbz RS-2 protective group to methyl with lithium aluminium hydride in Figure 3 | Retrosynthetic analysis of gelsemine. In principle, gelsemine THF afforded 10 in 86% yield. Subsequent acid hydrolysis of the may be constructed from oxindole and intermediate RS-1, where X is a acetal with aqueous hydrochloric acid in THF provided leaving group. After a few transformations, RS-1 may be synthesized from hemiacetal 11 (96%). intermediate RS-2, which inturn may be obtained from RS-3 following With the key intermediate in hand, we began to test the several reaction steps including ozonolysis. Finally, RS-3 may be condensation of 11 with methoxymethyl oxindole and the synthesized from readily accessible starting materials. subsequent SN2 displacement, another key reaction for Me N O Me Me N O Me N O N OH O N 13 H Me OMs NH NH OMs NH N O OMs O O O O 12b 12a 12 NH 13a Figure 4 | Cyclization of intermediate 9 to form the gelsemine framework.
Load more

Recommended publications
  • Stereoselective Reactions of Enolates: Auxiliaries
    1 Stereoselective reactions of enolates: auxiliaries • Chiral auxiliaries are frequently used to allow diastereoselective enolate reactions • Possibly the most extensively studied are the Evan’s oxazolidinones • These are readily prepared from amino acids O O (EtO)2C=O reduction K CO Ph OH 2 3 HN O Ph OH NH2 NH2 Ph (S)-phenylalanine oxazolidinone chiral auxiliary • Enolate formation gives the cis-enolate (remember enolisation of amides) • Two possible conformations exist - but chelation results in one being preferred Li O O O O Me Me N O LDA N O O Me Me Me 1. n-BuLi Me HN O 2. EtCOCl Me Me Me O O Me Li valine LDA derivative O N O O N O Me Me Me Me 123.702 Organic Chemistry 2 Diastereoselective alkylation of Evan’s enolate Li O O O O Me Me N O PhCH2I N O Ph Me Me Me Me I Ph Li O Bn O O O O O H H Me N Me N H Me Me Me Me iso-propyl group blocks bottom face • Clearly (I hope) one face of the enolate is blocked • Chelation results in a rigid structure that provides maximum steric hindrance • The electrophile can only approach from one face 123.702 Organic Chemistry 3 Diastereoselective alkylation of Evan’s enolate Li O O O O Me Me N O PhCH2I N O Ph Me Me Me Me I Ph Li O Bn O O O O O H H Me N Me N H Me Me Me Me iso-propyl group blocks bottom face • Clearly (I hope) one face of the enolate is blocked • Chelation results in a rigid structure that provides maximum steric hindrance • The electrophile can only approach from one face 123.702 Organic Chemistry 4 Diastereoselective functionalisation Li O O O O Br LDA Me Me N O N O H Ph Ph 96% de H O
    [Show full text]
  • Contemporary Organosilicon Chemistry
    Contemporary organosilicon chemistry Edited by Steve Marsden Generated on 05 October 2021, 02:13 Imprint Beilstein Journal of Organic Chemistry www.bjoc.org ISSN 1860-5397 Email: [email protected] The Beilstein Journal of Organic Chemistry is published by the Beilstein-Institut zur Förderung der Chemischen Wissenschaften. This thematic issue, published in the Beilstein Beilstein-Institut zur Förderung der Journal of Organic Chemistry, is copyright the Chemischen Wissenschaften Beilstein-Institut zur Förderung der Chemischen Trakehner Straße 7–9 Wissenschaften. The copyright of the individual 60487 Frankfurt am Main articles in this document is the property of their Germany respective authors, subject to a Creative www.beilstein-institut.de Commons Attribution (CC-BY) license. Contemporary organosilicon chemistry Steve Marsden Editorial Open Access Address: Beilstein Journal of Organic Chemistry 2007, 3, No. 4. School of Chemistry, University of Leeds, Leeds LS2 9JT, UK doi:10.1186/1860-5397-3-4 Email: Received: 06 February 2007 Steve Marsden - [email protected] Accepted: 08 February 2007 Published: 08 February 2007 © 2007 Marsden; licensee Beilstein-Institut License and terms: see end of document. Abstract Editorial for the Thematic Series on Contemporary Organosilicon Chemistry. The field of organosilicon chemistry has a rich and varied the 1990s, and equivalent to the number appearing in the much history, and has long since made the progression from chemical longer established field of organoboron chemistry
    [Show full text]
  • Page 1 of 108 RSC Advances
    RSC Advances This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. This Accepted Manuscript will be replaced by the edited, formatted and paginated article as soon as this is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/advances Page 1 of 108 RSC Advances Applications of oxazolidinones as chiral auxiliaries in the asymmetric alkylation reaction applied to total synthesis Majid M. Heravi,* Vahideh Zadsirjan, Behnaz Farajpour Department of Chemistry, School of Science, Alzahra University, Vanak, Tehran, Iran Email: [email protected] Abstract Various chiral oxazolidinones (Evans' oxazolidinones) have been employed as effective chiral auxiliaries in the asymmetric alkylation of different enolates. This strategy has been found promising and successful when used as key step (steps) in the total synthesis of several biologically active natural products. In this report, we try to underscore the applications of Manuscript oxazolidinones as chiral auxiliary in asymmetric alkylation, and particularly in crucial chiral inducing steps in the total synthesis of natural products, showing biological activities.
    [Show full text]
  • Aldol Reactions: E-Enolates and Anti-Selectivity
    Utah State University DigitalCommons@USU All Graduate Plan B and other Reports Graduate Studies 5-2005 Aldol Reactions: E-Enolates and Anti-Selectivity Matthew Grant Anderson Utah State University Follow this and additional works at: https://digitalcommons.usu.edu/gradreports Part of the Organic Chemistry Commons Recommended Citation Anderson, Matthew Grant, "Aldol Reactions: E-Enolates and Anti-Selectivity" (2005). All Graduate Plan B and other Reports. 1312. https://digitalcommons.usu.edu/gradreports/1312 This Report is brought to you for free and open access by the Graduate Studies at DigitalCommons@USU. It has been accepted for inclusion in All Graduate Plan B and other Reports by an authorized administrator of DigitalCommons@USU. For more information, please contact [email protected]. ALDOL REACTIONS: E-ENOLATES AND ANTI-SELECTIVITY Prepared By: MATTHEW GRANT ANDERSON A non-thesis paper submitted in partial fulfillment of the requirement for a Plan B Degree of Masters of Science in Organic Chemistry UTAH STATE UNIVERSITY Logan, Utah 2005 Contents Page CONTENTS ...................................................................................... .i LIST OF TABLES, FIGURES AND SCHEMES ....................................... ii,iii ABSTRACT .................................................................................... iv CHAPTER I. ALDOL REACTIONS:E-ENOLATES AND ANTI SELECTIVITY ......... 1 CHAPTER II. SECTION 1. MODELS OF E-ENOLATE FORMATION ...... .... ....... ... 12 SECTION 2. PATERSON ENOLATE PAPER ..... .........................
    [Show full text]
  • Robert Burns Woodward
    The Life and Achievements of Robert Burns Woodward Long Literature Seminar July 13, 2009 Erika A. Crane “The structure known, but not yet accessible by synthesis, is to the chemist what the unclimbed mountain, the uncharted sea, the untilled field, the unreached planet, are to other men. The achievement of the objective in itself cannot but thrill all chemists, who even before they know the details of the journey can apprehend from their own experience the joys and elations, the disappointments and false hopes, the obstacles overcome, the frustrations subdued, which they experienced who traversed a road to the goal. The unique challenge which chemical synthesis provides for the creative imagination and the skilled hand ensures that it will endure as long as men write books, paint pictures, and fashion things which are beautiful, or practical, or both.” “Art and Science in the Synthesis of Organic Compounds: Retrospect and Prospect,” in Pointers and Pathways in Research (Bombay:CIBA of India, 1963). Robert Burns Woodward • Graduated from MIT with his Ph.D. in chemistry at the age of 20 Woodward taught by example and captivated • A tenured professor at Harvard by the age of 29 the young... “Woodward largely taught principles and values. He showed us by • Published 196 papers before his death at age example and precept that if anything is worth 62 doing, it should be done intelligently, intensely • Received 24 honorary degrees and passionately.” • Received 26 medals & awards including the -Daniel Kemp National Medal of Science in 1964, the Nobel Prize in 1965, and he was one of the first recipients of the Arthur C.
    [Show full text]
  • Aldol Condensation
    Chemistry 212 Laboratory Dibenzalacetone via Crossed Aldol Condensation Prelab: Calculate the amounts of all chemicals needed in measurable amounts (i.e. grams or milliliters rather than moles.) Introduction: Aldol condensations are important in organic synthesis, providing a good way to form carbon–carbon bonds. The "aldol" (aldehyde + alcohol) product is a structural unit found in many naturally occurring molecules and pharmaceuticals, and is therefore important. In an Aldol condensation an enolate ion reacts with a carbonyl compound to form a β- hydroxyaldehyde or β-hydroxyketone, followed by dehydration to give a conjugated enone. The general equation is shown in Figure 1. O O O R" B: H R R'" R "R R'" loss of H2O H R' R' Figure 1. The equation for the Aldol Condensation. The reaction involves the nucleophilic addition of an enolate to an aldehyde to form a β-hydroxy carbonyl. The β-hydroxy carbonyl is readily dehydrated under mild conditions. The aldol reaction occurs under both acidic and basic conditions as seen in Figure 2. ENOL pathway (reacts in H O protonated OH form) O O catalytic H+ O O H H R' H2O lost R' R R R' R R H aldol addition product aldol condensation product ENOLATE pathway O O M O M O base O H R' R R' R R enolate H Figure 2. The Aldol reaction and subsequent dehydration under acidic and basic conditions. The reaction we will be doing this week involves the reaction between benzaldehyde and acetone to do a double Aldol Condensation. The overall equation is shown in Figure 3.
    [Show full text]
  • Total Synthesis of Natural Products: a Themed Issue Dedicated to Professor Dr. Dieter Schinzer for His 65Th Birthday”
    molecules Editorial Editorial to the Special Issue “Total Synthesis of Natural Products: A Themed Issue Dedicated to Professor Dr. Dieter Schinzer for His 65th Birthday” Ari M. P. Koskinen Department of Chemistry and Materials Science, Aalto University School of Chemical Engineering, Kemistintie 1, P.O. Box 16100, 02150 Espoo, Finland; ari.koskinen@aalto.fi Received: 4 December 2020; Accepted: 9 December 2020; Published: 10 December 2020 Natural products have intrigued humans throughout history. Plants with physiological activities, fermentation products, extracts with aroma, scent, or other properties have catalyzed the development of physical methods of separation of compounds and eventually the chemical synthesis of compounds. It is no coincidence that the first synthesis of an organic compound was that of a natural product. Since Wöhler’s synthesis of urea (no stereocenters) nearly two centuries ago, the synthesis of natural products has evolved through Komppa’s synthesis of camphor (one independent stereocenter) a century ago to a stage where compounds of enormous complexity can be attained through chemical synthesis (e.g., palytoxin with 64 stereocenters by Kishi in 1994). This development continues undauntedly, and it stimulates the invention of new synthetic reactions, new technological inventions, and new strategic thinking. The synthesis of natural products also stimulates the minds of medicinal chemists to develop ever better pharmaceutical products inspired by nature. Professor Dieter Schinzer had his initial training in organic synthesis with eminent mentors (Professors Manfred Reetz, Clayton Heathcock and Ekkehard Winterfeldt). Despite his wide research interests in organometallic chemistry (especially silicon, tin and manganese), synthetic methodology and medicinal chemistry, Dr. Schinzer is first and foremost a devoted natural product chemist.
    [Show full text]
  • New Mesoporous Silica-Supported Organocatalysts Based on (2S)-(1,2,4-Triazol-3-Yl)-Proline: Efficient, Reusable, and Heterogeneo
    molecules Article New Mesoporous Silica-Supported Organocatalysts Based on (2S)-(1,2,4-Triazol-3-yl)-Proline: Efficient, Reusable, and Heterogeneous Catalysts for the Asymmetric Aldol Reaction Omar Sánchez-Antonio 1 , Kevin A. Romero-Sedglach 1 , Erika C. Vázquez-Orta 1 and Eusebio Juaristi 1,2,* 1 Departamento de Química, Centro de Investigación y de Estudios Avanzados, Avenida IPN # 2508, 07360 Ciudad de México, Mexico; [email protected] (O.S.-A.); [email protected] (K.A.R.-S.); [email protected] (E.C.V.-O.) 2 El Colegio Nacional, Luis González Obregón # 23, Centro Histórico, 06020 Ciudad de México, Mexico * Correspondence: [email protected] or [email protected] Academic Editor: Derek J. McPhee Received: 16 September 2020; Accepted: 1 October 2020; Published: 3 October 2020 Abstract: Novel organocatalytic systems based on the recently developed (S)-proline derivative (2S)-[5-(benzylthio)-4-phenyl-(1,2,4-triazol)-3-yl]-pyrrolidine supported on mesoporous silica were prepared and their efficiency was assessed in the asymmetric aldol reaction. These materials were fully characterized by FT-IR, MS, XRD, and SEM microscopy, gathering relevant information regarding composition, morphology, and organocatalyst distribution in the doped silica. Careful optimization of the reaction conditions required for their application as catalysts in asymmetric aldol reactions between ketones and aldehydes afforded the anticipated aldol products with excellent yields and moderate diastereo- and enantioselectivities. The recommended experimental protocol is simple, fast, and efficient providing the enantioenriched aldol product, usually without the need of a special work-up or purification protocol. This approach constitutes a remarkable improvement in the field of heterogeneous (S)-proline-based organocatalysis; in particular, the solid-phase silica-bonded catalytic systems described herein allow for a substantial reduction in solvent usage.
    [Show full text]
  • Tripeptide-Catalyzed Asymmetric Aldol Reaction Between Α-Ketoesters and Acetone Under Acidic Cocatalyst-Free Conditions
    catalysts Article Tripeptide-Catalyzed Asymmetric Aldol Reaction Between α-ketoesters and Acetone Under Acidic Cocatalyst-Free Conditions Kazumasa Kon 1, Hiromu Takai 2, Yoshihito Kohari 3,* and Miki Murata 1,2,3 1 Graduate School of Manufacturing Engineering, Kitami Institute of Technology, 165 Koen-Cho, Kitami, Hokkaido 090-8507, Japan; [email protected] 2 Graduate School of Materials Science and Engineering, Kitami Institute of Technology, 165 Koen-Cho, Kitami, Hokkaido 090-8507, Japan; [email protected] 3 School of Earth, Energy and Environmental Engineering, Faculty of Engineering, Kitami Institute of Technology, 165 Koen-Cho, Kitami, Hokkaido 090-8507, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-157-26-9432 Received: 17 April 2019; Accepted: 6 June 2019; Published: 9 June 2019 Abstract: Here, we report the tripeptide-catalyzed asymmetric aldol reaction between α-ketoesters and acetone under acidic cocatalysts-free conditions. H-Pro-Tle-Gly-OH 3g-catalyzed reactions between α-ketoesters and acetone resulted in up to 95% yield and 88% ee. Analysis of the transition state using density functional theory (DFT) calculations revealed that the tert-butyl group in 3g played an important role in enantioselectivity. Keywords: organocatalyst; aldol reaction; peptide catalyst; α-ketoesters 1. Introduction Optically active tertiary alcohols are partial structures present in various natural products and biologically active compounds [1–5]. Various synthetic methods for these compounds have been developed. Asymmetric nucleophile addition to functionalized ketones is one of the most useful synthetic methods, because highly functionalized optically active tertiary alcohols, which can undergo various transformations, can be obtained.
    [Show full text]
  • Reaction of Glucose Catalyzed by Framework and Extraframework Tin Sites in Zeolite Beta
    Reaction of Glucose Catalyzed by Framework and Extraframework Tin Sites in Zeolite Beta Thesis by Ricardo Bermejo-Deval In Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy CALIFORNIA INSTITUTE OF TECHNOLOGY Pasadena, California 2014 (Defended 12 May 2014) ii 2014 Ricardo Bermejo-Deval All Rights Reserved iii ACKNOWLEDGEMENTS The past years at Caltech have been one of the most challenging periods of my life, learning to be a better person and being part of the world of science. I feel privileged to have interacted with such talented and inspiring colleagues and scientists, as well as those I have disagreed with. The variety of people I have encountered and the experiences I have gathered have helped me to gain scholarship, wisdom, confidence and critical thinking, as much as to become an open-minded person to any opinion or people. First and foremost, I am very grateful to my advisor and mentor, Professor Mark E. Davis, for his financial, scientific and personal support. I appreciate his patience, flexibility, advice and scientific discussions, helping me to grow and mature scientifically. I would like to thank the thesis committee Professors Richard Flagan, Jay Labinger and Theodor Agapie, for their discussions and kindness. I appreciate everyone in the Davis group for helping me in the lab throughout these years. Special thanks to Yasho for helping me get started in the lab, to Bingjun and Raj for scientific advice, and to Marat for helpful talks. I am also very thankful to Sonjong Hwang for SS NMR, David Vandervelde for NMR and Mona Shahgholi for mass spectrometry.
    [Show full text]
  • Application of Complex Aldol Reactions to the Total Synthesis of Phorboxazole B
    J. Am. Chem. Soc. 2000, 122, 10033-10046 10033 Application of Complex Aldol Reactions to the Total Synthesis of Phorboxazole B David A. Evans,* Duke M. Fitch,1 Thomas E. Smith, and Victor J. Cee Contribution from the Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138 ReceiVed June 29, 2000 Abstract: The synthesis of phorboxazole B has been accomplished in 27 linear steps and an overall yield of 12.6%. The absolute stereochemistry of the C4-C12,C33-C38, and C13-C19 fragments was established utilizing catalytic asymmetric aldol methodology, while the absolute stereochemistry of the C20-C32 fragment was derived from an auxiliary-based asymmetric aldol reaction. All remaining chirality was incorporated through internal asymmetric induction, with the exception of the C43 stereocenter which was derived from (R)-trityl glycidol. Key fragment couplings include a stereoselective double stereodifferentiating aldol reaction, a metalated oxazole alkylation, an oxazole-stabilized Wittig olefination, and a chelation-controlled addition of the fully elaborated alkenyl metal side chain. Introduction and HT29 (3.31 × 10-10 M), as well as leukemia CCRF-CBM (2.45 × 10-10 M), prostate cancer PC-3 (3.54 × 10-10 M), and Phorboxazoles A (1)andB(2) are marine natural products breast cancer MCF7 cell lines (5.62 × 10-10 M).2b In addition isolated from a recently discovered species of Indian Ocean to this impressive anticancer activity, phorboxazoles A and B sponge (genus Phorbas sp.) near Muiron Island, Western also exhibit potent in vitro antifungal activity against Candida Australia.2 These substances are representative of a new class albicans and Saccharomyces carlsbergensis at 0.1 µg/disk in of macrolides differing only in their C hydroxyl-bearing 13 the agar disk diffusion assay.2a stereocenters.
    [Show full text]
  • Bio-Organic Mechanism Game – Simplistic Biochemical Structures and Simplistic Organic Reaction Mechanisms Are Used to Explain Common Biochemical Transformations
    1 Bio-Organic Mechanism Game – Simplistic biochemical structures and simplistic organic reaction mechanisms are used to explain common biochemical transformations. Simplified biochemical molecules are presented first. Many biomolecules have a somewhat complex structure that makes it difficult to write out step by step mechanisms. However, if we simplify those structures to the essential parts necessary to explain the mechanistic chemistry of each step, it becomes much easier to consider each step through an important cycle. I have proposed possible simplified structures that are used in the later examples of biochem cycles and problems. The usual strategy in biochem cycles is to just write names, or perhaps, names and a structure. Occasionally a few mechanistic steps are suggested, but almost never is a detailed sequence of mechanistic steps provided. Since it is hard to find such detailed mechanistic steps anywhere (sometimes they are not known) our proposed steps are, of necessity, somewhat speculative. In this book we are not looking for perfection, which is not possible, but for sound organic logic that is consistent with the biochemical examples presented below. There is great satisfaction in blending organic knowledge with real life reactions that help explain how life works. In working through some of the problems, you may develop an alternative mechanism that is just as good, or even better than the one I have proposed. If you do, I hope you will share it with me and if an improved version of this book ever gets written I can include it the next edition (and give you credit). It is almost certain that I have made some errors and I would appreciate it if you would let me know about them.
    [Show full text]