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Synthesis of Substituted Azetidines and Spirocyclic

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Synthesis of Substituted Azetidines and Spirocyclic 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
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