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Proquest Dissertations Studies Towards the Total Synthesis of Colchicine A Thesis Presented by Man Tat Yu 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 January 1995 ProQuest Number: 10105668 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 10105668 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 This thesis is dedicated to my wife, Grace and written in memory of my father-in-law, Mr. P. Au, who passed away during the preparation of this work. Abstract This thesis is divided into three chapters. In the first chapter, brief accounts of the occurrence, isolation and structural determination, biological properties and biogenesis of colchicine are presented. Moreover, since one of the key structural features of colchicine is the tropolonyl ring C, significant preparative methods for tropones and tropolones are briefly reviewed. The general drawbacks of the previous syntheses of colchicine itself due to the tautomeric nature of the tropolonyl ring C are discussed and the key steps of each of the previous syntheses are also highlighted. In the second chapter, the general strategies of the total synthesis of (-)-colchicine employed in this project are discussed and two synthetic approaches are then described. The first approach, to which most of the work was directed, involves the cycloaromatisation of a 12-membered macrocycle containing an enediyne moiety via a Bergman cyclisation. The efforts made towards the synthesis of this macrocycle are divided into two areas, namely the investigations into the generation of the stereocentre and the construction of the macrocyclic framework. Although an advanced acyclic precursor for ring closure containing all of the requisite functionality was prepared, initial cyclisation studies were unsuccessful. The second approach involves a transition metal- mediated [2+2+2] cycloaddition of a tethered diyne and an appropriate cyclopropenone derivative. The synthesis of the diyne precursor and model studies of the [2+2+2] cycloaddition protocol are described. The third chapter provides a formal description of experimental results and procedures. Contents Page Abstract 3 Acknowledgements 6 Abbreviations and Denotations 7 Chapter One : Introduction 9 1.1. Occurrence, Isolation and Structural Determination 10 1.2. Biological Properties 13 1.3. Biogenesis 16 1.4. Preparation of Tropones and Tropolones 19 1.4.1. Preparation of Simple Tropone Derivatives 19 1.4.2. Preparation of Simple Tropolone Derivatives 26 1.5. Previous Syntheses 30 1.5.1. Category I : Syntheses involving desacetamido-precursors 32 1.5.2. Category II : Syntheses not involving desacetamido-precursors 39 Chapter Two : Results and Discussion 46 2.1. The Investigation of the Cycloaromatisation Approach 50 2.1.1. Strategy and Background 50 2.1.2. The Investigation of Generation of the C-7 Stereocentre 56 2.1.2.1. The L-Serine-Based Approach 56 2.1.2.2. The SAMP/RAMP-Based Approach 66 2.1.3. The Construction of the Macrocyclic Framework 73 2.1.4. Concluding Remarks on the Investigation of the Cycloaromatisation Approach 107 2.2. The Investigation of the [2+2+2] Cycloaddition Approach 110 2.2.1. Background and Strategy 110 2.2.2. Synthesis of the Diyne Precursor and Preliminary Studies of the Tethered [2+2+2] Cycloaddition 118 Chapter Three : Experimental 127 General Procedure 128 Preparation 129 References 202 Corrigenda 209 Acknowledgements I would like to express my deepest gratitude to my supervisor, Professor W.B. Motherwell, for his guidance, humour and immense patience over the past three years. I am grateful to my industrial supervisors, Drs David Corbett and David MacPherson, and other SKB staff for technical advice and other help during my stay in Great Burgh. I also thank all the members of the WBM 'research family', especially Lucilia, Sheena, Donogh and Lewis for the companionship they gave me during this sometimes difficult but mostly enjoyable period. Richard, Phil, Tim, Caroline, Nadine, Alvin, Adrian, Martin, Pete and Simon have hugely contributed to the existence of this thesis by their meticulous proof­ readings, which made my virtually unreadable English more presentable. I owe technical support from the staff in Imperial College and University College, especially Paul Hammerton (IC) and Jill Maxwell (UC) for the help in NMR; Geoff Tucker (IC), John Barton (IC), Margaret Mruzek (UC), John Hill (UC) and Suzan (UC) for the mass spectra; Hillary O'Callaghan (IC) and Alan Stones (UC) for the microanalyses. I am also indebted to the staff of SERC Mass Spectroscopy Centre, Swansea, and School of Pharmacy, London, for the high resolution mass spectra. I thank SmithKline Beecham, the Croucher Foundation and the Committee of Vice-Chancellors and Principals for their generous financial supports. Above all, I must thank affectionately Mum and Lil, who have shaped my life with great care and love, and Grace, with whom I delightfully share it. Abbreviations and Denotations A Heat hv Irradiation Ac Acetyl Ar Aryl Aq Aqueous Bn Benzyl Bu Butyl Bz Benzoyl c concentration Cl Chemical ionisation 1 ^C NMR Carbon-13 Nuclear Magnetic Resonance DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DIBAL-H Diisobutylaluminium Hydride DMAP 4-Dimethylaminopyridine DME Dimethoxyethane DMF MA^-Dimethylformamide DMSO Dimethylsulfoxide Et Ethyl El Electron ionisation Eq Equivalent FAB Fast Atom Bombardment HMDS 1,1,1,3,3,3-Hexamethyldisilazane 1H NMR Proton Nuclear Magnetic Resonance HPLC High Performance Liquid Chromatography i iso KHMDS Potassium Bis(trimethylsilyl)amide L Ligand LDA Lithium Diisopropylamide LG Leaving Group LiHMDS Lithium Bis(trimethylsilyl)amide m multiplet m meta Me Methyl Ms, Mesyl Methanesulfonyl n normal NaHMDS Sodium Bis(trimethylsilyl)amide P Protecting group p para Pr Propyl Ph Phenyl Pyr Pyridine q quartet r.t. room temperature s singlet s, sec secondary t triplet t, ten tertiary TBDMS r-Butyldimethylsilyl THF Tetrahydrofuran TIPS Triisopropylsilyl T.L.C. Thin Layer Chromatography TMS Trimethylsilyl Tf 2,2,2-Trifluoromethansulfonyl Ts, Tosyl p-Toluenesulfony 1 This arrow indicates an occurred reaction This arrow indicates a failed or envisaged reaction ^ _ ^ This arrow indicates a retrosynthetic operation These two bonds indicate the relative stereochemistry of atoms Theses two bonds indicate the absolute stereochemistry of atoms CHAPTER ONE : INTRODUCTION 1.1. Occurrence, Isolation and Structural Determination Judging from the number of relevant publications, colchicine can be described, without doubt, as one of the most interesting alkaloids existing in nature. Since its isolation by Pelletier and Caventou in 1820^ a constant stream of research related to colchicine has been reported in hundreds of publications, which have been duly reviewed^ on several occasions. This alkaloid is the toxic principle of Colchicum autumnale while it and its analogues also exist in a number of other Colchicum plants. The colchicinic alkaloids usually give a positive ferric chloride test after acid hydrolysis, indicating the presence of phenolic or tropolonic moieties. Moreover, colchicine was found in some other genera belonging to the liliaceae family, namely Merendera, Androcymbium, Gloriosa and Colchicum autumnale is a perennial meadow saffron which can be found over an extensive geographical area encompassing England, southern Europe and northern Africa. Colchicine can be extracted from all parts of the plant, with the highest concentration being in the flowers. However, due to the greater gross weight, the greatest amount of colchicine is found in the corms2(a).(b) The content of colchicine is season-dependent and the highest percentage with respect to dry weight of the plant occurs when fruiting begins in Spring. After Pelletier and Caventou^ had isolated an amorphous toxic principle from the alcoholic extracts of C. autumnale, Geiger^Ca) named a crystalline solid he obtained 2U) from a similar extraction 'colchicine'. However, in 1857 Oberlin found that the crystalline solid Geiger obtained was actually the hydrolysed product of the amorphous toxic principle. Therefore, he renamed the crystalline substance colchiceine and the initial amorphous material colchicine. More than 60 years later, in 1915, Clewer, Green and Tutin managed to acquire solvent-free, crystalline colchicine as pale yellow 10 needles. Elemental analysis indicated a formula of C22H24O6N for colchicine. After a series of investigations, the alkaloid was found to be a tricyclic compound containing a trimethoxybenzenoid ring A and a seven-membered ring B. Furthermore, although the aromatic nature of tropones was unknown at the time, Dewar correctly suggested a tautomeric structure for stipitatic acid (1)^ possessing an aromatic tropolonic ring and thus opened the investigations into a new class of aromatic compounds. He then MeO, MeO NHAc NHAc MeO MeO HO HO MeO MeO O' OMe OMe O 1 2a 2b proposed two isomeric structures, (2a) and (2b), containing tropolonic rings C for colchicine He also suggested that the high solubility of colchicine was due to an ionic resonance of the tropolonic ring, as shown in Scheme 1. O O- OMe OMe OMe + Scheme 1 MeO. NHAc MeO MeO CO2H. NHAc MeO MeO CO2H MeO O OMe It was later proven by both chemical deduction and by X-ray diffraction that natural colchicine (3) is indeed the a-isomer of (2a). The relative positions of the carbonyl and methoxy groups of ring C were confirmed by LoewenthaP by an unambiguous synthesis of (4), a reductive degradation product of colchicine^.
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