DOCSLIB.ORG

Studies on the Generation and Use of Functionalised Organozinc Carbenoids for the Synthesis of Aminocyclopropanes and Related Congeners

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Studies on the Generation and Use of Functionalised Organozinc Carbenoids for the Synthesis of Aminocyclopropanes and Related Congeners STUDIES ON THE GENERATION AND USE OF FUNCTIONALISED ORGANOZINC CARBENOIDS FOR THE SYNTHESIS OF AMINOCYCLOPROPANES AND RELATED CONGENERS A Thesis Presented by Guillaume Begis In Partial Fulfilment of the Requirements for the Award of the Degree of DOCTOR OF PHILOSOPHY OF THE UNIVERSITY OF LONDON Christopher Ingold Laboratories Department of Chemistry University of London London W C1H0AJ September 2004 UMI Number: U602451 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U602451 Published by ProQuest LLC 2014. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract ABSTRACT The present thesis describes a range of studies on the generation and reactivity of organozinc carbenoid species possessing adjacent nitrogen functionality for the preparation of aminocyclopropanes and related congeners. This thesis opens with two distinct introductory reviews. The first one focuses on the description of the different general methods already available for the synthesis of aminocyclopropanes. The second one is concerned with the generation and reactivity of organozinc carbenoids encountered in the literature. The results and discussion chapter firstly describes the successful generation of an organozinc carbenoid from an acetal moiety contiguous to a nitrogen atom of a simple cyclic amide using a mixture of zinc amalgam and chlorotrimethylsilane. This new organometallic species is found to undergo cyclopropanation reactions with a range of alkenes to yield amidocyclopropanes. Subsequent studies directed towards the design of carbenoid precursors which can lead to the preparation of primary aminocyclopropanes are then discussed. A method for the synthesis of chiral protected aminocyclopropanes in two steps from their corresponding alkenes is described. An investigation of the preparation of TV-substituted cyclopropyl amino alcohols and acids is presented. From this study, an TV-substituted cyclopropyl glycine derivative is prepared. Finally, this thesis discusses the attempted palladium-catalysed cross-coupling reactions between amino cyclopropylsilanes and aryl iodides and the successful Tamao-Fleming oxidation of the carbon-silicon bond of vicinal amino cyclopropylsilanols to give the corresponding amino cyclopropanols. The thesis terminates with a full description of the experimental procedures used and the compounds prepared. 2 Declaration DECLARATION The research described in this thesis is, to the best of my knowledge, original except where due reference is made to other authors. 3 Contents CONTENTS Abstract 2 Declaration 3 Contents 4 Acknowledgements 7 Abbreviations 8 Stereochemical notation 11 Chapter 1 Introduction 12 1 Introduction 13 1.1 Synthesis of cyclopropylamines 13 1.1.1 By cyclopropyl migration via a Hofmann or Curtius rearrangement 14 1.1.2 By cyclopropanation of enamines and enamides 16 1.1.3 By titanium-mediated cyclopropanation of carboxamides and nitriles 18 1.1.4 Reactions involving 1,3-ring-closure 21 1.1.5 By reaction with a “cyclopropanone equivalent” 22 1.1.6 Via palladium-catalysed C-N bond formation 24 1.1.7 By reduction of nitrocyclopropanes 24 1.1.8 By addition of aminocarbenes or carbenoids to alkenes 25 1.1.9 Summary 26 1.2 Organozinc carbenoids 27 1.2.1 Carbenes and carbenoids 27 1.2.2 Organozinc carbenoid chemistry 28 1.2.2.1 From gem-dihalo compounds 28 1.2.2.1.1 Background 28 1.2.2.1.2 The “cyclopropanating agent” 31 1.2.2.1.3 Theoretical studies on cyclopropanation reactions 32 1.2.2.1.4 Evolution of the “cyclopropanating agent” 34 1.2.2.2 From diazoalkanes and zinc salts 37 1.2.2.3 From carbonyl compounds 38 1.2.2.3.1 The Clemmensen reduction of carbonyl compounds 3 8 4 Contents 1.2.2.3.2 The controlled generation of organozinc carbenoids from carbonyl compounds 42 1.2.2.3.3 Evolution of organozinc carbenoid chemistry within our group 45 1.3 Summary and perspectives 52 Chapter 2 Results and Discussion 53 2 Introduction 54 2.1 Background - The attempted aminocyclopropanation reaction using dimethylformamide dimethyl acetal 54 2.2 Preliminary study on the amidocyclopropanation reaction using A-diethoxymethyl-2-pyrrolidinone as the carbenoid precursor 55 2.3 Methods used to determine the stereoselectivity of the cyclopropanation reaction 57 2.4 Further study on the amidocyclopropanation of allylbenzene using JV-diethoxymethyl-2-pyrrolidinone as the carbenoid precursor 58 2.5 Scope and limitation of this novel amidocyclopropanation reaction 59 2.5.1 Cyclopropanation of unfunctionalised alkenes 59 2.5.2 Cyclopropanation of functionalised alkenes 61 2.5.2.1 Cyclopropanation of electron rich double bonds 61 2.5.2.2 Cyclopropanation of electron deficient double bonds 63 2.6 Extension of this novel amidocyclopropanation reaction 64 2.6.1 Study of the amidocyclopropanation reaction using JV-benzyl- -A-diethoxymethylacetamide as the carbenoid precursor 64 2.6.2 Study of the amidocyclopropanation reaction using TV-formyl amides as the carbenoid precursor 65 2.7 Studies toward the preparation of primary aminocyclopropanes 66 2.7.1 Study of the cyclopropanation reaction using vV-diethoxymethyl phthalimide as the carbenoid precursor 66 2.7.2 Study of the preparation of primary aminocyclopropanes using 7/-diethoxymethyl-2,3-dihydroisoindol-1 -one as the carbenoid precursor 68 2.7.3 Preliminary study of the use of A-diethoxymethyl oxazolidinones as carbenoid precursors 69 2.7.4 A proposed mechanism to account for the stereochemistry observed 73 5 Contents 2.7.5 Scope of the cyclopropanation reaction using (±)-iV-diethoxymethyl- -4,5-diphenyloxazolidinone 74 2.7.6 Synthesis of chiral cyclopropane derivatives 76 2.7.7 Deprotection of 4,5-diphenyloxazolidinone cyclopropanes 77 2.7.8 Studies towards the preparation of primary arylcyclopropylamines 81 2.7.8.1 Use of a different carbenoid precursor 81 2.7.8.2 Studies of alternative methods for the cleavage of the diphenyloxazolidinone ring 82 2.8 Studies on the synthesis of ^/-substituted cyclopropyl amino alcohols and acids 85 2.9 Studies on the synthesis of arylcyclopropanes via a palladium-catalysed cross-coupling reaction 90 2.9.1 Palladium-catalysed cross-coupling reactions involving cyclopropyl halides 91 2.9.2 Palladium-catalysed cross-coupling reactions involving cyclopropyl organometallic species 92 2.9.3 Palladium-catalysed cross-coupling reactions of organosilicon compounds 93 2.9.3.1 Background 93 2.9.3.2 A preliminary study towards the palladium-catalysed cross­ coupling reactions of cyclopropylsilanes 95 2.10 Preparation of vicinal amino cyclopropanols 98 2.10.1 Background 98 2.10.2 The use of the Tamao-Fleming oxidation of cyclopropylsilanes leading to the preparation of vicinal amino cyclopropanols 99 Chapter 3 Conclusions and perspectives 102 Chapter 4 Experimental 108 4 General experimental 109 4.1 Experimental Procedures 111 Chapter 5 References 209 Chapter 6 Appendix 219 6 Acknowledgements ACKNOWLEDGEMENTS I would firstly like to thank my supervisor, Professor Willie Motherwell, for his guidance, help and encouragements over the past three years. I am also very grateful to my industrial supervisor at AstraZeneca, Doctor David Cladingboel, for his advice, enthusiasm and having arranged my very enjoyable three-month industrial placement in Loughborough. I would like also to thank various members of the “WBM family”, firstly the ‘Maman’ of the group, Robyn, for her help in the lab and also for her kindness to proofread a part of this manuscript (and for having informed me that the use of “promiscuity” is not proper when one would like to refer to “proximity” of two atoms), Rob and Ela for all the very good time spent inside and outside of the lab, Steve of being always ready to ‘give a hand’, Tom for being the only one always interested in talking about organozinc carbenoids and having proofread the Introduction of this manuscript, Alex for his enthusiasm in the lab and (particularly) in the pub, Lynda, Beatrice, Camilla and Oliver for helping me to settle in my first year. I am also very grateful to all the ‘technical’ staff at UCL Chemistry Department, especially to Dr. Abil Aliev for NMR and John Hill and his colleagues for mass spectra. I would like to thank all the people from the AstraZeneca site of Loughborough who have contributed to make my stay a very interesting and pleasant experience. I also wish to express my gratitude to AstraZeneca for its financial support. A special thank to Dr. Yvain Roue for all his time spent on my initiation to practical organic chemistry. Most of all I would like to thank my parents, Dominique and Marie-Christine, for their constant support and help, and Mina-chan for her encouragements during my PhD, having left her so loved Japan to join me in Europe and all the happiness that she is bringing to me. 7 Abbreviations ABBREVIATIONS Ac acetyl All allyl Ar unspecified aryl group arom aromatic BINAP 2,2’-bis(diphenylphosphino)-l,r-binaphthyl Boc fer/-butoxycarbonyl Bu butyl Bn benzyl br broad c cyclo cat. catalytic Cl chemical ionisation A reflux dba dibenzylideneacetone DCE dichloroethane DMF V^V-dimethylformamide
Load more

Recommended publications
  • Simple Molecules, Highly Efficient Amination 1
    1 1 Simple Molecules, Highly Effi cient Amination Shunsuke Chiba and Koichi Narasaka 1.1 Introduction In the last two decades, explosive progress has been made in synthetic methods for production of amino compounds, due to their rapidly increasing applications in pharmaceutical and material sciences. Development of amination reagents for the construction of new carbon – nitrogen bonds is one of the most important and basic processes for the synthesis of amino molecules, and this chapter introduces simple and useful amination reagents classifi ed by reaction type, such as electro- philic amination reagents, including transition metal – nitrene and nitrido complexes, radical- mediated amination reagents, and nucleophilic amination (Gabriel - type) reagents. 1.2 Hydroxylamine Derivatives Hydroxylamine derivatives are one of the most versatile and simple amination reagents, leading the variety of nitrogen - containing compounds. This section mainly focuses on recent advances in electrophilic amination of carbon nucleo- philes with various hydroxylamine derivatives. 1.2.1 O - Sulfonylhydroxylamine Tamura has reported the synthesis of O - mesitylsulfonylhydroxylamine (MSH; 1 ; Figure 1.1 ) and related compounds and has examined their reactions with various nucleophiles in detail [1] . With regard to the formation of C − N bonds by the use of MSH, however, the applicable carbanions were quite limited – to stabilized enolates only – and the product yields of the resulting amines were quite low. The electrophilic amination of organolithium compounds with the methyllithium - methoxyamine system, long recognized as a potentially useful Amino Group Chemistry. From Synthesis to the Life Sciences. Edited by Alfredo Ricci Copyright © WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-31741-7 2 1 Simple Molecules, Highly Effi cient Amination Figure 1.1 Tamura reagent (MSH) 1 .
    [Show full text]
  • Ep 2097400 B1
    (19) TZZ ZZZ_T (11) EP 2 097 400 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: C07D 401/04 (2006.01) C07D 401/14 (2006.01) of the grant of the patent: C07D 491/052 (2006.01) C07D 498/04 (2006.01) 03.07.2013 Bulletin 2013/27 A61K 31/47 (2006.01) A61P 31/04 (2006.01) (21) Application number: 07860629.0 (86) International application number: PCT/JP2007/075434 (22) Date of filing: 28.12.2007 (87) International publication number: WO 2008/082009 (10.07.2008 Gazette 2008/28) (54) FUSED SUBSTITUTED AMINOPYRROLIDINE DERIVATIVE ANELLIERTES SUBSTITUIERTES AMINOPYRROLIDINDERIVAT DÉRIVÉ D’AMINOPYRROLIDINE SUBSTITUÉ LIÉ PAR FUSION (84) Designated Contracting States: • TSUDA, Toshifumi AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Edogawa-ku HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE Tokyo 134-8630 (JP) SI SK TR • NAKAYAMA, Kiyoshi Edogawa-ku (30) Priority: 05.01.2007 JP 2007000667 Tokyo 134-8630 (JP) 22.03.2007 JP 2007074991 • TAKEMURA, Makoto Edogawa-ku (43) Date of publication of application: Tokyo 134-8630 (JP) 09.09.2009 Bulletin 2009/37 • YOSHIDA, Kenichi Edogawa-ku (60) Divisional application: Tokyo 134-8630 (JP) 12186361.7 / 2 540 715 • MIYAUCHI, Rie Edogawa-ku (73) Proprietor: Daiichi Sankyo Company, Limited Tokyo 134-8630 (JP) Chuo-ku • NAGAMOCHI, Masatoshi Tokyo 103-8426 (JP) Edogawa-ku Tokyo 134-8630 (JP) (72) Inventors: • TAKAHASHI, Hisashi (74) Representative: Fairbairn, Angus Chisholm Edogawa-ku Marks & Clerk LLP Tokyo 134-8630 (JP) 90 Long Acre • KOMORIYA, Satoshi London Edogawa-ku WC2E 9RA (GB)
    [Show full text]
  • Art-Of-Drugs-Synthesis.Pdf
    THE ART OF DRUG SYNTHESIS THE ART OF DRUG SYNTHESIS Edited by Douglas S. Johnson Jie Jack Li Pfizer Global Research and Development Copyright # 2007 by John Wiley & Sons, Inc. All rights reserved. Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permission. Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate.
    [Show full text]
  • Asymmetric Nitrene Transfer Reactions with Azides Via Co(II)-Based Metalloradical Catalysis (MRC) Jingran Tao University of South Florida, [email protected]
    University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School January 2013 Asymmetric Nitrene Transfer Reactions with Azides via Co(II)-Based Metalloradical Catalysis (MRC) Jingran Tao University of South Florida, [email protected] Follow this and additional works at: http://scholarcommons.usf.edu/etd Part of the Chemistry Commons Scholar Commons Citation Tao, Jingran, "Asymmetric Nitrene Transfer Reactions with Azides via Co(II)-Based Metalloradical Catalysis (MRC)" (2013). Graduate Theses and Dissertations. http://scholarcommons.usf.edu/etd/4590 This Dissertation is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Asymmetric Nitrene Transfer Reactions with Azides via Co(II)-Based Metalloradical Catalysis (MRC) by Jingran Tao A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Department of Chemistry College of Arts and Sciences University of South Florida Major Professor: X. Peter Zhang, Ph.D. Jon Antilla, Ph.D. Wayne Guida, Ph.D. Xiao Li, Ph.D. Date of Approval: April 3rd , 2013 Keywords: cobalt, porphyrin, catalysis, aziridination, C–H amination, azide, asymmetric Copyright © 2013, Jingran Tao Dedication I dedicate this dissertation to my beloved parents. Acknowledgments I need to begin with thanking Dr. Peter Zhang for his continuous guidance and support. I learned the words “determination” and “believe” from him. I also need to thank my committee members: Dr. Jon Antilla, Dr. Wayne Guida Dr. Xiao Li and Chair Dr.
    [Show full text]
  • Table of Contents
    STUDIES TOWARDS THE TOTAL SYNTHESIS OF RISTOCETIN A AND ORIENTICIN C AGLYCONES by DIANA V. CIUREA Submitted in partial fulfillment of the requirements for the Degree of Doctor of Philosophy Thesis Advisor: Professor Anthony J. Pearson Department of Chemistry CASE WESTERN RESERVE UNIVERSITY January, 2008 2 3 Dedicated to my family 4 Table of Contents List of Schemes……………………………………………………………………………7 List of Tables……………………………………………………………………………...9 List of Figures……………………………………………………………………………10 Acknowledgments………………………………………………………………………..11 List of Abbreviations…………………………………………………………………….12 Abstract…………………………………………………………………………………..18 Chapter 1. Glycopeptide Natural Products: Their Total Synthesis and Possible Applications of Arene-Ruthenium Chemistry 1.1 Introduction ……………………………………….……………………………..22 1.2 Biosynthesis and Chemical Synthesis of Glycopeptide Antibiotics ……..……...27 1.2.1 Classical Ullmann Diaryl Ether Coupling Reaction …………………….30 1.2.2 Triazene-Driven Diaryl Ether Synthesis – Variation on the Ullmann Ether Synthesis; Nicolaou’s Total Synthesis of Vancomycin …………………31 1.2.3 Palladium-Catalyzed Diaryl Ether Synthesis ………………..…………..33 1.2.4 TTN-Mediated Oxidative Phenolic Coupling……………………………34 1.2.5 Boronic Acid-Driven Diaryl Ether Synthesis……………………………37 1.2.6 Potassium Fluoride-Alumina Driven SNAr Reaction …………………...37 1.2.7 o-Nitro-Activated SNAr Reaction ……………………………………….38 1.2.8 Metal-Mediated SNAr Methodology …………………………………….41 5 1.3 Conclusions ……………………………………………………………………...52 1.4 References ……………………………………………………………………….53 Chapter 2. Synthetic Studies towards Ristocetin A via Ruthenium-Mediated SNAr Reaction 2.1 Introduction………………………………………………………………………65 2.2 Retrosynthetic Analysis………………………………………………………….65 2.3 Synthesis of the Required Amino Acid Derivatives……………………………..70 2.3.1 Synthesis of E Building Block 2.7……………………………………….70 2.3.2 Synthesis of F Building Block 2.9……………………………………….72 2.3.3 Synthesis of G Building Block 2.10 …………………………………..
    [Show full text]
  • Design, Synthesis and Evaluation of Organic and Metal Based Antimicrobial Agents
    Design, Synthesis and Evaluation of Organic and Metal Based Antimicrobial Agents Niamh Anne Dolan, B.Sc. A thesis submitted to the National University of Ireland Maynooth in accordance with the requirements for the Degree of Doctor of Philosophy in the Faculty of Science November 2013 Department of Chemistry NUI Maynooth Supervisors: Dr. John C. Stephens and Dr. John McGinley Head of Dept.: Dr. John C. Stephens Declaration of Authorship I hereby certify that the work presented within this thesis, except where acknowledged and cited, is my own work and has not been previously submitted for a Degree to this University or elsewhere. Niamh Anne Dolan National University of Ireland, Maynooth November 2013 II Acknowledgements Firstly, I would like to thank my supervisors, Dr. John C. Stephens and Dr. John McGinley. I thank you both for not only giving me the opportunity to carry out this research but also for your help and guidance throughout these last few years, your kind words, encouragement and support, thank you so much. Thank you to Prof. John Lowry and Dr. John C. Stephens for the opportunity to carry out this research at NUI Maynooth. I would also like to thank Dr. Kevin Kavanagh for giving me the opportunity to carry out all of my biological studies in the Medical Mycology laboratory at NUIM and for all of your advice and help. To all of the postgrads in the Medical Mycology lab, thank you for all of your help. It was always a pleasure to work in your lab. Thank you to Dr. Karen Thomkins, Dr.
    [Show full text]
  • Application of the Curtius Rearrangement to the Synthesis of 1’-Aminoferrocene-1-Carboxylic Acid Derivatives W
    Application of the Curtius rearrangement to the synthesis of 1’-aminoferrocene-1-carboxylic acid derivatives W. Erb, G. Levanen, T. Roisnel, V. Dorcet To cite this version: W. Erb, G. Levanen, T. Roisnel, V. Dorcet. Application of the Curtius rearrangement to the syn- thesis of 1’-aminoferrocene-1-carboxylic acid derivatives. New Journal of Chemistry, Royal Society of Chemistry, 2018, 42 (5), pp.3808-3818. 10.1039/c7nj05020h. hal-01740157 HAL Id: hal-01740157 https://hal-univ-rennes1.archives-ouvertes.fr/hal-01740157 Submitted on 26 Apr 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Application of the Curtius rearrangement to the synthesis of 1'- aminoferrocene-1-carboxylic acid derivatives William Erb,*a Gael Levanen,a Thierry Roisnel,a and Vincent Dorceta The shortest synthesis of N-protected 1’-aminoferrocene-1-carboxylic acid from readily available ferrocene-1,1’-dicarboxylic acid is reported. 1’-Azidocarbonylferrocene-1-carboxylic acid was first obtained by reaction of the latter with diphenylphosphoryl azide. It was then converted into four amino acids by a Curtius rearrangement conducted in the presence of tert-butanol, benzyl alcohol, 9-fluorenemethanol or allyl alcohol.
    [Show full text]
  • A Stereodivergent Synthesis of the Anti-Inflammatory Agent BIRT-377
    University of Calgary PRISM: University of Calgary's Digital Repository Graduate Studies The Vault: Electronic Theses and Dissertations 2014-12-15 A Stereodivergent Synthesis of the Anti-Inflammatory Agent BIRT-377. Approaches to the Synthesis of Gephyrotoxin Johnson, Aaron Johnson, A. (2014). A Stereodivergent Synthesis of the Anti-Inflammatory Agent BIRT-377. Approaches to the Synthesis of Gephyrotoxin (Unpublished master's thesis). University of Calgary, Calgary, AB. doi:10.11575/PRISM/25038 http://hdl.handle.net/11023/1961 master thesis University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. Downloaded from PRISM: https://prism.ucalgary.ca i UNIVERSITY OF CALGARY A Stereodivergent Synthesis of the Anti-Inflammatory Agent BIRT-377. Approaches to the Synthesis of Gephyrotoxin by Aaron Johnson A THESIS SUBMITTED TO THE FACULTY OF GRADUATE STUDIES IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE GRADUATE PROGRAM IN CHEMISTRY CALGARY, ALBERTA DECEMBER, 2014 © Aaron Johnson 2014 ii Abstract The potent anti-inflammatory agent, BIRT-377, contains an α-quaternary center in a hydantoin ring. Due to requirements for clinical testing on enantiopure compounds, the need for enantioselective routes to chiral compounds, such as BIRT-377, are highly sought. Enantioselective syntheses of compounds containing α-quaternary amine moieties are difficult because steric hinderance precludes the use of many standard synthetic procedures.
    [Show full text]
  • An Update on the Stereoselective Synthesis of γ-Amino Acids
    Tetrahedron: Asymmetry 27 (2016) 999–1055 Contents lists available at ScienceDirect Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy Tetrahedron: Asymmetry report number 163 An update on the stereoselective synthesis of c-amino acids ⇑ ⇑ Mario Ordóñez a, , Carlos Cativiela b, , Iván Romero-Estudillo c a Centro de Investigaciones Químicas–IICBA, Universidad Autónoma del Estado de Morelos, 62209 Cuernavaca, Morelos, Mexico b Departamento de Química Orgánica, Universidad de Zaragoza–CSIC, ISQCH, 50009 Zaragoza, Spain c CONACyT Research Fellow–Centro de Investigaciones Químicas–IICBA, Universidad Autónoma del Estado de Morelos, 62209 Cuernavaca, Morelos, Mexico article info abstract Article history: This review outlines the most recent papers describing the stereoselective synthesis of c-amino acids. In Received 29 July 2016 this update, the c-amino acids have been classified according to the type of compounds, position and Accepted 5 August 2016 number of substituents, and depending on the type of substrate, acyclic, carbocyclic or azacyclic deriva- Available online 22 September 2016 tives, following in the first case an order related to the strategy used, whereas in the second and third cases the classification is based on the ring size. Ó 2016 Elsevier Ltd. All rights reserved. Contents 1. Introduction . ..................................................................................................... 1000 2. Stereoselective synthesis of acyclic c-amino acids . ..............................................................
    [Show full text]
  • HERATH-DISSERTATION-2018.Pdf (2.637Mb)
    APPROACHES TOWARD THE TOTAL SYNTHESIS OF OROIDIN ALKALOIDS: NAGELAMIDE A, C AND AGELIFERIN By APSARA K. HERATH Presented to the Faculty of the Graduate School of The University of Texas at Arlington in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY THE UNIVERSITY OF TEXAS AT ARLINGTON April 2018 I Copyright © by Apsara K. Herath 2018 All Rights Reserved II ACKNOWLEDGEMENT First, I would like to thank my research advisor, Dr. Carl Lovely for his tremendous support and encouragement and throughout my graduate studies in UTA. His guidance and patience helped me to build up my career as a scientist which I have grown to become today. I would also like to thank the members of my dissertation committee, Professor Alejandro Bugarin, Professor Frank Foss and Professor Subhrangsu Mandal for their time and valuable advice during the course of my research. Also, I would like to thanks past and present Lovely group members, Dr. Jayanta Das, Dr. Xiaofeng Meng, Dr. Abhisek Ray, Nicole Khatibi, Andy Seal, Ravi Singh and Moumita Singha Roy for their support. I also would like to thank Chuck Savage, Dr. Brian Edwards, and Roy McDougald for all the support they have provided to throughout my research studies. Also, my gratitude goes to Dr. Delphine Gout and Dr. Muhammed Yousufuddin for their support in X-ray crystallographic analysis of my samples. Moreover, I would like to thank Maciej Kukula for his support in mass analysis of my synthesized compounds and to the Shimadzu center for Advanced Analytical Chemistry for providing the instrumental support.
    [Show full text]
  • Click Chemistry (PDF File)
    Click Chemistry “Click Chemistry” is a term which was first described by K. B. Sharpless in 2001 to describe reactions that afford products in ● Research of Various Pharmaceutical high yields and in excellent selectivities by carbon-hetero bond Lead Candidates formation reactions. The term “Click” means joining molecular a) Application of Anti-HIV Agent Discovery 3) pieces as easily as clicking together the two pieces of a seat belt Whiting and Sharpless et al. have reported the synthesis of a buckle. In general, the definition of click chemistry is described as series of 1,4-disubstituted-1,2,3-triazoles as potential candidates follows: for HIV protease inhibitors in a combination of azide-containing fragments with a diverse array of functionalized alkyne- 1. give very high chemical yields of desired products containing building blocks by using click chemistry. After further 2. combination of readily available simple building blocks optimization, it was revealed that 1 has the highest activity, 3. generate almost no byproducts exhibiting 8 nM of Ki value. 4. simple product isolation by non-chromatographic methods O 5. reaction proceeds in water, as well as in organic solvents R HN O O (36 Alkynes) Ph R = N Cl Ph HN O CuSO4, Cu N Ph N t N While there are a number of reactions that fulfill this criteria, the Ph BuOH / H2O (1 : 1), N Ki = 23 nM (minimum) N3 50 C°, 5 days R Hüisgen 1,3-dipolar [3 + 2] cycloaddition1) of azides and alkynes has emerged as the frontrunner. In general, the 1,2,3-triazole ring O is not almost oxidized or reduced, which makes it possible to HN O Ph (CH2O)n Ph strongly connect two substrates.
    [Show full text]
  • Short Communications
    SHORT COMMUNICATIONS SOME REACTIONS OF 0,O-DIPHENYLPHOSPHORYL AZIDE [Manuscript received 6 February 19731 Abstract Diphenylphosphoryl azide, in contrast to N,N'-disubstituted phosphorodiamidic azides, undergoes nucleophilic displacement of the azido group by reaction with water, butanol, ammonia, and amines. Possible mechanisms for the conversion of diphenyl- phosphoryl azide into urethanes and amides are briefly discussed. Pyrolysis of N,N'- dicyclohexylphosphorodiamidicazide gave the phosphenimidic amide dimer. 0,O-Diphenylphosphoryl azide (1) has been obtained by reaction of the phos- phorochloridate with sodium azide. This compound undergoes pseudohalogen replacement of the azido group by treatment with nucleophilic reagents, such as water, butanol, ammonia, and various amines. Thus with aniline, the corresponding N-phenylphosphoramidate (2; R = Ph) was formed in high yield: With strong bases, like ammonia and aliphatic amines, the reaction was rapid and exothermic at room temperature; but with weaker bases, like aniline, there was no apparent reaction at room temperature. The reactivity of the azide (1) towards nucleophiles resembled the behaviour of sulphonyl azides,' but differed markedly from that of N,Nf-disubstituted phosphoro- diamidic azides which were very stable towards nucleophilic substitution at phos- phor~~.~ However, efforts to obtain a phosphoryl nitrene insertion reaction, by heating the azide (1) with boiling o-xylene under similar conditions to those successfully used for the analogous reaction with sulphonyl azides,' were unsuccessful. The stability of the azide (1) towards heating was shown by its distillation at 157OY3and by the fact that vigorous evolution of nitrogen was not observed until a temperature of 175" had been reached. * Department of Chemical Sciences, The Hatfield Polytechnic, Hatfield, Hertfordshire, England.
    [Show full text]