Studies Towards a Total Synthesis of Colchicine A Thesis Presented by Beatrice Angela Maltman In Partial Fulfilment of the Requirements for the Award of the Degree of DOCTOR OF PHILOSOPHY OF THE UNIVERSITY OF LONDON Department of Chemistry University College London 20 Gordon Street London WCIHOAJ January 2003 ProQuest Number: 10014465 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. uest. ProQuest 10014465 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract ABSTRACT This thesis describes a novel strategic approach towards the synthesis of colchicine which involves the use of the transition metal catalysed [5+2] cycloaddition reaction. The thesis is divided into three chapters. The first introductory chapter presents an overview of colchicine, with particular attention being focused on the isolation, structure, biological properties and biosynthesis of the natural product, together with a thorough account of previous synthetic approaches. Moreover, since the key reaction in our synthetic approach involves the exploitation of the transition metal catalysed [5+2] cycloaddition reaction, a detailed review into the recent developments and uses of this reaction is presented. In the second chapter, synthetic approaches are described for the preparation of two structurally different alkynyl-vinylcyclopropanes which are required for exploitation of the intramolecular variant of the transition metal mediated [5+2] cycloaddition, this strategy being selected to achieve concomitant formation of both seven-membered rings and also avoiding the problematic méthylation of a free tropolone unit. Detailed accounts of the successful synthetic routes to both of these potential cyclisation precursors are presented and discussed. In the event however, formation of the tricyclic skeleton by a variety of metal catalysed [5+2] cycloaddition protocols proved elusive. The third chapter provides a formal description of the experimental procedures and results obtained. Contents CONTENTS Abstract 1 Contents 2 Acknowledgements 4 Abbreviations 5 CHAPTER 1 : INTRODUCTION 8 1.0 General Remarks .........9 1.1 Colchicine .........9 1.1.1 Isolation 9 1.1.2 Structure 10 1.1.3 Structural Analogues 11 1.1.4 Biological Properties 12 1.1.5 Biosynthesis 14 1.1.6 Previous Syntheses 17 1.2 Transition M etal Catalysed [5+2] Cycloaddition Reaction .........34 1.2.1 Background 34 1.2.2 Mechanistic Approach 36 1.2.3 Alkyne Reactions 37 1.2.3.1 Wilkinson’s Catalyst 37 1.2.3.2 [Rh(CO) 2 Cl]2 Catalyst 41 1.2.3.3 Intermolecular Reactions 43 1.2.4 Alkene Reactions 45 1.2.5 Allene Reactions 47 1.2.6 1,2-Disubstituted Vinylcyclopropanes 49 1.2.7 Application to Total Synthesis 52 1.2.8 [CpRu(CH 3 CN)3 ]PFô Catalyst 54 1.2.9 Concluding Remarks 59 Contents CHAPTER 2: RESULTS AND DISCUSSION 61 2.1 Aims and Objectives ........62 2.2 Retrosynthetic Analysis in the Proposed [5+2] Cycloaddition Route for the Synthesis of Colchicine .........................................................62 2.3 Incorporation of the Chiral Centre at C -1 ........65 2.4 The Synthesis of Aldehyde (174) 67 2.5 The Synthesis of Alkynylcyclopropane (175) 69 2.6 Coupling of Aldehyde (174) and Alkynylcyclopropane (175) ........76 2.7 Cycloaddition Studies on Precursor (173) ........88 2.7.1 Wilkinson’s Catalyst in the [5+2] Cycloaddition Reaction ........88 2.7.2 Synthesis of [CpRu(CH 3 CN)3 ]PF6 90 2.7.3 [CpRu(CH3 CN)3]PF6 in the [5+2] Cycloaddition Reaction ... ........93 2.7.4 [Rh(CO) 2 Cl]2 Catalyst in the [5+2] Cycloaddition Reaction .........98 2.8 The Design of a New Cycloaddition Precursor 99 2.9 The Synthesis of Key Fragments 100 2.10 Coupling of the Aryl Iodide and Stannane Component ......108 2.11 Cycloaddition Studies on Precursor (250) ...... 119 2.11.1 [CpRu(CH3 CN)3 ]PF6 in the [5+2] Cycloaddition Reaction ... ......120 2.11.2 [Rh(CO) 2 Cl]2 Catalyst in the [5+2] Cycloaddition Reaction .... 121 2.12 Summary and Conclusions ......122 CHAPTER3: EXPERIMENTAL ....127 3.1 General Procedures ....128 3.2 Preparation of Individual Compounds ....130 References ....193 Appendix ....201 Acknowledgements ACKNOWLEDGEMENTS I would like to thank my supervisor Professor Willie Motherwell for giving me the opportunity to work in his group, and for his support and enthusiasm throughout my PhD. Many thanks also to Dr. Robyn Hay-Motherwell for keeping the lab in order and for her excellent training on Schlenk techniques. I am grateful to my second supervisor, Dr. Mike Porter for showing an interest in my project and for all his advice, especially during my first year. Dr. Abil Aliev deserves a huge ‘thank you’ for providing an excellent NMR service and for giving up so much of his time helping in the assignment of my compounds. Thanks also to Dr. Jorge Gonzales for NMR, John Hill for mass spectra and Dr. Howard Carless for kindly providing the photolysis equipment. I am indebted to Catherine, Camilla and Steve for taking their time to do an extremely thorough job in proof reading my thesis. In the lab I would like to thank Camilla, Catherine, Lynda and Oliver for their special friendship. Camilla for keeping me amused with all her little sayings, Catherine for always being available for a girly chat, Lynda for enlightening the lab with her cheekiness, and Oliver for being a never ending source of information. Thanks to Santi, Julien, Christoph and Rosa for making me feel so welcome in my first year and to everyone else in the lab, past and present, including Rehan, Guillaume, Ela, Charlotte, Marta, Geraldine, Steve and Karim. Finally, I would like to thank Kevin for always being there for me, and my family for their love and support. Abbreviations ABBREVIATIONS Ac Acetyl AIBN a-Azo wo-butyronitrile aq. Aqueous Ar Aromatic Bn Benzyl B og ^er^-Butyloxycarbonyl b.p. boiling point br broad Bu butyl CBS Corey-B akshi- Shibita Cl Chemical ionisation cm'^ Wavenumbers Cp ri^-Cyclopentadienyl d Doublet DCC A,A-Dicyclohexylcarbodiimide DCE Dichloroethane DCM Dichloromethane dd Double doublet ddd Double double doublets DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DEAD Diethyl azodicarboxylate dec. decomposes DIBALH Diwobutylaluminium hydride DIPEA Diwopropylethylamine DMA? 4-Dimethylaminopyridine DMF N, A-Dimethylformamide DMSO Dimethylsulfoxide dt Double triplet Et Ethyl Ether Diethyl ether Abbreviations FAB Fast atom bombardment FT-IR Fourier transform infra-red g Grams h Hour hv Irradiation of unspecified wavelength HMDS 1,1,1,3,3,3 -Hexamethyldisilazane HRMS High resolution mass spectrometry Im Imidazole 'Pr wo-Propyl JR Infra-red J Coupling constant LDA Lithium diwopropylamide LHMDS Lithium hexamethyldisilazane lit. Literature value LRMS Low resolution mass spectrometry m Meta M Molar concentration m Multiplet Me Methyl min minutes ml Millilitres mmHg Millimetres of mercury mol% Molar percentage mol moles mmol millimoles m.p. Melting point NBS A-Bromosuccinimide NMO A-Methylmorpholine-A-oxide NMR Nuclear magnetic resonance nOe Nuclear Overhauser effect o Ortho P Para Pd/C Palladium on carbon Abbreviations PE Petroleum ether Ph Phenyl ppm Parts per million py Pyridine q Quartet R/ Retention factor rt Room temperature s Singlet sat. Saturated t Triplet TBDMS ^er/-Butyldimethylsilyl TBDMSCl ^er/-Butyldimethylsilyl chloride TBDMSOTf ^er/-Butyldimethylsilyl triflate tert Tertiary Tf Trifluoromethanesulfbnyl TFA Trifluoroacetic acid TFE Trifluoroethanol THF Tetrahydrofuran tic Thin layer chromatography IMS Trimethylsilyl TMSA T rimethylsilylacetylene TMSOTf Trimethylsilyl triflate TPAP T etra-A-propylammonium perruthenate Ts p-T oluenesulphonyl Introduction CHAPTER ONE INTRODUCTION Introduction 1.0 General Rem arks The present thesis is concerned with synthetic approaches to the synthesis of the natural product, colchicine 1. The key objective in the synthetic strategy was to employ the transition metal catalysed [5+2] cycloaddition reaction to construct the two seven-membered rings in a single step. Accordingly, the introductory review is divided into two sections. The first part (section 1.1) describes the background to colchicine 1 and the previous synthetic approaches. The second part (section 1.2) consists of a review of the transition metal catalysed [5+2] cycloaddition reaction. 1.1 Colchicine 1.1.1 Isolation Colchicine 1 has attracted widespread interest over the years due to its potential as an anti-cancer agent. It is the major alkaloid constituent of the autumn crocus, Colchicum autumnale L., otherwise known as the common meadow saffron' and is found in all parts of the plant but its concentration is highest within the flowers.^ The plant can be found in many areas of the Northern Hemisphere, including England and Northern Africa. MeO ..... MeO MeO 12 OMe 1 Figure 1.1 Colchicine 1 was first isolated in 1820 by Pelletier and Caventou,^ but it was over a hundred years later before the unusual tropolone ring structure embedded within this molecule was predicted by Dewar"' in 1945, and finally confirmed using X- ray studies by King et al.^ in 1952. For over a decade after the discovery of colchicine 1, it was believed to be the only active principle of Colchicum Introduction autumnale. However, further studies resulted in the discovery of many new alkaloid constituents, with most of the structures now characterised and confirmed by partial synthesis.^ 1.1.2 Structure Colchicine 1 is a tricyclic compound with two mutually fused seven-membered rings (Figure 1.1).