DOCSLIB.ORG

Synthesis of Substituted Azetidines and Spirocyclic

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

A Thesis Submitted for the Degree of PhD at the University of Warwick Permanent WRAP URL: http://wrap.warwick.ac.uk/102606/ Copyright and reuse: This thesis is made available online and is protected by original copyright. Please scroll down to view the document itself. Please refer to the repository record for this item for information to help you to cite it. Our policy information is available from the repository home page. For more information, please contact the WRAP Team at: [email protected] warwick.ac.uk/lib-publications Synthesis of Substituted Azetidines and Spirocyclic Diazetidines by Alpa Kishor Pancholi A thesis submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Chemistry Department of Chemistry, University of Warwick September 2017 1 Table of Contents Acknowledgements ...................................................................................................... 5 Declaration ................................................................................................................... 6 Abstract ........................................................................................................................ 7 Abbreviations ............................................................................................................... 8 Chapter 1: Asymmetric Synthesis of 2-Substituted Azetidin-3-ones ........................ 13 1.1 Introduction to Azetidines ............................................................................... 14 1.1.1 Structure and Properties of Azetidines .................................................... 14 1.2 Application of Azetidines ............................................................................... 16 1.2.1 Azetidines in Natural Products ................................................................ 16 1.2.2 Azetidines in Drug Discovery.................................................................. 17 1.2.3 Azetidines as Chiral Ligands ................................................................... 18 1.3 Synthetic Routes to Azetidines ....................................................................... 20 1.3.1 Cyclisation by Nucleophilic Substitution ................................................ 20 1.3.2 Cyclisation by C‒C Bond Formation ...................................................... 23 1.3.3 Synthesis via Cycloaddition Reactions .................................................... 26 1.3.4 Reduction of Azetidin-2-ones .................................................................. 28 1.4 Introduction to Azetidin-3-ones ...................................................................... 31 1.4.1 Medicinal Relevance of Azetidin-3-ones ................................................ 32 1.5 Synthesis of Azetidin-3-ones .......................................................................... 33 1.5.1 Synthesis by Carbonyl Group Generation ............................................... 33 1.5.2 Synthesis by Ring Closure ....................................................................... 35 1.5.3 Direct Synthesis of 2-Substituted Azetidin-3-ones .................................. 37 1.5.4 Asymmetric Synthesis of 2-Substituted Azetidin-3-ones ........................ 39 1.6 Research Aims ................................................................................................ 42 1.7 Results and Discussion .................................................................................... 44 1.7.1 Formation of Hydrazone from Azetidin-3-one ........................................ 45 2 1.7.2 Metalation and Alkylation of Azetidine SAMP Hydrazone .................... 46 1.7.3 Hydrazone Cleavage ................................................................................ 48 1.7.4 One-pot Synthesis of 2-Substituted Azetidin-3-ones ............................... 49 1.7.5 Variation of the N-Protecting Group ....................................................... 51 1.7.6 Optimising Enantioselectivity.................................................................. 53 1.7.7 Establishing Scope of the Reaction ......................................................... 54 1.7.8 Determination of Sense of Asymmetric Induction .................................. 58 1.7.9 Attempted Synthesis of Disubstituted Derivatives .................................. 63 1.7.10 Mechanistic Insights ................................................................................ 67 1.7.11 Attempted Synthesis of 2-Substituted Thietan-3-ones ............................ 69 1.8 Application to Fused Heterocyclic Systems ................................................... 69 1.9 Conclusions ..................................................................................................... 73 1.10 Future Work .................................................................................................... 74 Chapter 2: Synthesis of Spirocyclic 1,2-Diazetidines ................................................ 76 2.1 Introduction to 1,2-Diazetidines ..................................................................... 77 2.1.1 Background & Application of 1,2-Diazetidines ...................................... 78 2.1.2 Structure and Properties of 1,2-Diazetidines ........................................... 79 2.2 Synthetic Routes to 1,2-Diazetidines .............................................................. 81 2.2.1 Synthesis by [2+2] Cycloaddition Reactions ........................................... 81 2.2.2 Intramolecular Ring Closure of Hydrazine Derivatives .......................... 86 2.2.3 Metal Catalysed Synthesis of Substituted 1,2-Diazetidines .................... 87 2.3 Spirocyclic 1,2-Diazetidines ........................................................................... 90 2.3.1 Introduction to Spirocyclic Rings ............................................................ 90 2.4 Research Aims ..................................................................................................... 92 2.5 Synthesis of Spirocyclic 1,2-Diazetidines by Ring Closure ................................ 93 2.5.1 Synthesis of Hydrazine Substrates ................................................................ 94 2.5.2 Attempted Iodination of the Alcohol ............................................................. 96 3 2.5.3 Attempted Cyclisation to Spirocyclic 1,2-Diazetidin-3-ones ...................... 100 2.6 Synthesis of Spirocyclic 1,2-Diazetidines by Alkene Addition ......................... 103 2.6.1 Background to 3-Methylene-1,2-Diazetidines ............................................ 103 2.6.2 Synthesis of 3-Methylene-1,2-Diazetidines ................................................ 106 2.6.2.1 Synthesis of Hydrazodicarboxylates ..................................................... 106 2.6.2.2 Cyclisation to 3-Methylene-1,2-Diazetidines ....................................... 110 2.7 Synthesis of 4,5-Diazaspiro[2.3]hexanes ........................................................... 113 2.7.1 Cyclopropanation by Difluorocarbenes ....................................................... 113 2.7.2 Cyclopropanation by Dichlorocarbenes ...................................................... 116 2.7.2.1 Scope of Dichlorocyclopropanation ..................................................... 119 2.7.2.2 Mechanistic Proposal for Formation of Ring Expanded Product ......... 122 2.7.3 Attempted Cyclopropanation by Dibromocarbenes .................................... 123 2.7.4 Asymmetric Cyclopropanations of 1,2-Diazetidines .................................. 124 2.7.5 Manipulations of 4,5-Diazaspiro[2.3]hexanes ............................................ 126 2.7.5.1 Attempted Dechlorination..................................................................... 126 2.7.5.2 Deprotection of Spirocyclic 1,2-Diazetidines ....................................... 126 2.8 Synthesis of 1,2-Diazaspiro Compounds ........................................................... 128 2.8.1 Synthesis of 1,2-Diazaspiro[3.3]heptanes ................................................... 128 2.8.2 Attempted Synthesis of 1,2-Diazaspiro[3.5]nonanes .................................. 131 2.9 Conclusions ........................................................................................................ 132 2.10 Future Work ..................................................................................................... 134 Chapter 3: Experimental .......................................................................................... 135 3.1 General Information ........................................................................................... 136 References ................................................................................................................ 195 Appendix I – Chiral GC analysis of (S)-159, (R)-159 and Racemic 159 ................. 208 Appendix II – Chiral HPLC analysis of (S)-170 ...................................................... 209 Appendix III – NOESY spectra of (R,S)-363a ........................................................ 210 4 Acknowledgements First and foremost, I would like to thank my supervisor Professor Mike Shipman for not only the project, but for all of the help, guidance and support over the years. It has been very much appreciated and this thesis would not have been possible without it. I would also like to thank the University of Warwick and EPSRC for the financial support. Thank you to Guy Clarkson for his expertise on X-ray crystallography. Many thanks
Recommended publications
  • Modular, Stereocontrolled Cβ–H/Cα–C Activation of Alkyl Carboxylic Acids Ming Shang,⊥,† Karla S

    Modular, Stereocontrolled Cβ–H/Cα–C Activation of Alkyl Carboxylic Acids Ming Shang,⊥,† Karla S

    Modular, Stereocontrolled Cβ–H/Cα–C Activation of Alkyl Carboxylic Acids Ming Shang,⊥,† Karla S. Feu,⊥,† Julien C. Vantourout,† Lisa M. Barton,† Heather L. Osswald,† Nobutaka Kato,§ Kerstin Gagaring,‡ Case W. McNamara,‡ Gang Chen,† Liang Hu,† Shengyang Ni,† Paula Fernández-Canelas,† Miao Chen,† Rohan R. Merchant,† Tian Qin,† Stuart L. Schreiber,ǁ,§ Bruno Melillo,*,†,§ Jin-Quan Yu,*,† Phil S. Baran*,† †Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037 ‡Calibr at The Scripps Research Institute, La Jolla, California 92037 §Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, Massachusetts 02142 ǁDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138 ABSTRACT: The union of two powerful transformations, directed C–H activation and decarboxylative cross-coupling, for the enantioselective synthesis of vicinally functionalized alkyl, carbocyclic, and heterocyclic compounds is described. Starting from simple carboxylic acid building blocks, this modular sequence exploits the residual directing group to access more than 50 scaffolds that would be otherwise extremely difficult to prepare. The tactical use of these two transformations accomplishes a formal vicinal difunctionalization of carbon centers in a way that is modular and thus amenable to rapid diversity incorporation. A simplification of routes to known preclinical drug candidates is presented along with the rapid diversification of an antimalarial compound series. Introduction block like 3-(3-bromophenyl) propanoic acid (4) could be It is becoming increasingly clear that practitioners are no longer employed as its precursor (Figure 1b). Within the privileged bound by notion that the pervasive C–H bond is unresponsive realm of saturated cyclic heterocycles, such logic could be to manipulation.
  • A Straightforward Synthesis of Enantiopure 2-Cyano Azetidines from B-Amino Alcohols

    A Straightforward Synthesis of Enantiopure 2-Cyano Azetidines from B-Amino Alcohols

    Issue in Honor of Prof. Alain Krief ARKIVOC 2007 (x) 71-93 A straightforward synthesis of 3-substituted azetidinic amino acids Mangaleswaran Sivaprakasham,a François Couty,a,* Gwilherm Evano,a B. Srinivas,b R. Sridhar,b and K. Rama Raob a Institut Lavoisier, UMR 8180, Université de Versailles, 45, avenue des Etats-Unis, 78035, Versailles Cedex, France b Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad-500 007, India E-Mail: [email protected] Dedicated to Professor A. Krief on the occasion of his 65th anniversary Abstract A series of enantiomerically pure N,N-disubstituted β-amino alcohols were chlorinated by treatment with thionyl chloride. This reaction afforded a mixture of regioisomeric β-amino chlorides that could be equilibrated to the more stable regioisomer by heating in DMF. The secondary chlorides thus obtained were engaged in an intramolecular anionic ring-closure to give access to fully protected enantio- and diastereoisomerically pure 2,3-cis-disubstituted azetidinic amino acid. One of the latter was deprotected for inclusion in a tripeptide sequence. This synthetic methodology was applied for N,N-disubstituted γ-amino alcohols, leading to 3- or 5- substituted proline derivatives but with a low 2,3- or 2,5- diastereoselectivity. Keywords: Azetidines, amino-acids, amino-alcohols Introduction Conformationally constrained amino acids have been the subject of growing interests within past years in peptide chemistry. These modified amino acids can be used as tools for the modification of the secondary
  • Development of New Methodologies in Organic Synthesis for the Preparation of Bioactive Molecules Marwa Hussein

    Development of New Methodologies in Organic Synthesis for the Preparation of Bioactive Molecules Marwa Hussein

    Development of new methodologies in organic synthesis for the preparation of bioactive molecules Marwa Hussein To cite this version: Marwa Hussein. Development of new methodologies in organic synthesis for the preparation of bioac- tive molecules. Organic chemistry. Université Rennes 1; Université Libanaise, 2017. English. NNT : 2017REN1S046. tel-01682268 HAL Id: tel-01682268 https://tel.archives-ouvertes.fr/tel-01682268 Submitted on 12 Jan 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. ANNÉE 2017 THÈSE / UNIVERSITÉ DE RENNES 1 sous le sceau de l’Université Bretagne Loire avec Université Libanaise pour le grade de DOCTEUR DE L’UNIVERSITÉ DE RENNES 1 Mention : Chimie Ecole doctorale Sciences de la Matière, Rennes présentée par Marwa Hussein préparée à l’unité de recherche UMR 6226 CNRS / Institut des Sciences Chimiques de Rennes / Equipe PNSCM Composante universitaire : S. P. M. Thèse soutenue à Beyrouth Development of new le 20 Mars 2017 devant le jury composé de : methodologies in Thierry DURAND Directeur de Recherche CNRS, Université de organic synthesis to Montpellier /rapporteur Kamal H. BOUHADIR prepare bioactive Professeur, Université Américaine Beyrouth / rapporteur compounds Jean-Pierre BAZUREAU Professeur, Université de Rennes1 /examinateur Fares FARES Professeur, Université Libanaise Beyrouth / examinateur Ali HACHEM Professeur, Université Libanaise Beyrouth / co- directeur de thèse René GREE Directeur de Recherche CNRS (Em.), Université de Rennes 1 / co-directeur de thèse i i Table of Schemes Scheme I.
  • Synthesis of Azetidines, Γ-Lactams, Fused Furan Bispyrrolidines and 2-Pyrazolines: Towards Medical Application

    Synthesis of Azetidines, Γ-Lactams, Fused Furan Bispyrrolidines and 2-Pyrazolines: Towards Medical Application

    School of Chemistry Synthesis of azetidines, γ-lactams, fused furan bispyrrolidines and 2-pyrazolines: Towards medical application By Mariwan A. Hama Salih A thesis submitted to the University of Birmingham for the degree of DOCTOR OF PHILOSOPHY Project supervisor: John S. Fossey Co-Supervisor: Ferenc Mueller September 2015 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Contents Abstract ......................................................................................................................................................... ix Aim of the project .......................................................................................................................................... x Chapter One .................................................................................................................................................. xi 1. Introduction ...............................................................................................................................................
  • Naming and Indexing of Chemical Substances for Chemical Abstractstm

    Naming and Indexing of Chemical Substances for Chemical Abstractstm

    Naming and Indexing of Chemical Substances for Chemical AbstractsTM 2007 Edition A publication of Chemical Abstracts Service Published by the American Chemical Society Naming and Indexing of Chemical Substances for Chemical AbstractsTM A publication of Chemical Abstracts Service Published by the American Chemical Society Copyright © 2008 American Chemical Society All Rights Reserved. Printed in the USA Inquiries concerning editorial content should be sent to: Editorial Office, Chemical Abstracts Service, 2540 Olentangy River Road, P.O. Box 3012, Columbus, Ohio 43210-0012 USA SUBSCRIPTION INFORMATION Questions about CAS products and services should be directed to: United States and Canada: CAS Customer Care Phone: 800-753-4227 (North America) 2540 Olentangy River Road 614-447-3700 (worldwide) P.O. Box 3012 Fax: 614-447-3751 Columbus, Ohio 43210-0012 USA E-mail: [email protected] Japan: JAICI (Japan Association for International Phone: 81-3-5978-3621 Chemical Information) Fax: 81-3-5978-3600 6-25-4 Honkomagome E-mail: [email protected] Bunkyo-ku, Tokyo Japan, 113-0021 Countries not named above: Contact CAS Customer Care, 2540 Olentangy River Road, P.O. Box 3012, Columbus, Ohio 43210-0012 USA; Telephone 614-447-3700; Fax 614-447-3751; E-mail [email protected]. For a list of toll-free numbers from outside North America, visit www.cas.org. 1 Naming and Indexing of Chemical Substances for Chemical Abstracts 2007 ¶ 102 NAMING AND INDEXING OF CHEMICAL SUBSTANCES 101. Foreword. Although the account which follows describes in consid- zwitterions (inner salts, sydnones). The changes for the Fourteenth (1997- erable detail the selection of substance names for Chemical Abstracts (CA) in- 2001) Collective Index period affect coordination nomenclature, stereochemi- dexes, it is not a nomenclature manual.