STUDIES TOWARDS THE TOTAL SYNTHESIS OF THE NATURALLY-OCCURRING ANTICANCER AGENT HALICHOMYCIN b y Maxine Lai-Fun Cheung Me, OMe Me 'NH Me Me Me Me A thesis presented to the University of London in partial fulfilment of the requirements for the degree of Doctor of Philosophy June 2003 The Christopher Ingold Laboratories Department of Chemistry University College London ProQuest Number: 10015856 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 10015856 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. 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Box 1346 Ann Arbor, Ml 48106-1346 LIST OF ABBREVIATIONS Ac acetyl AIBN 2 ,2 -azoblsisobutyronjtrlle 9-BBN 9-borablcyclo[3.3.1]nonane Bn benzyl Bu^ f-butyl Cy cyclohexyl DBU 1,8-diazabicyclo[5.4.0]undec- DDQ 2,3-dlchloro-5,6-dicyano-1,4- DEAD diethyl azodicarboxylate DEIPS dlethylisopropylsllyl DET diethyl tartrate DIBAL diisobutylaluminium hydride DIPT diisopropyl tartrate DMAP 4-dimethylaminopyridine DMF A/,A/-dimethylformamide DMSO dimethyl sulfoxide EDCI 1 -(3-dimethylaminopropyl)-3- Et ethyl HMPA hexamethylphosphoramide LDA lithium diisopropylamide mCPBA 3-chloroperoxybenzoic acid Me methyl NMO 4-methylmorpholine A/-oxide PCC pyridinium chlorochromate PDC pyridinium dichromate Ph phenyl PMB 4-methoxybenzyl PPTS pyridinium 4-toluenesulfonate TBAF tetra-A7-butylammonium fluoride TBS fe/t-butyldimethylsilyl TES triethylsilyl Tf trifiuoromethanesulfonyl TFA trifluoroacetic acid TFAA trifluoroacetic anhydride THF tetrahydrofuran THP tetrahydropyranyl TMS trimethylsilyl TPAP tetra-n-propylammonium perruthenate TRIS tris(hydroxymethyl)aminomethane Ts 4-toluenesulfonyl Dedicated with love to Dean ACKNOWLEDGEMENTS I would like to thank Professor Karl J. Hale for his devoted and dedicated supervision over the last 3 years. I am grateful to him for giving me the opportunity to study such a remarkable molecule. I would especially like to thank all the people who helped me during my PhD, in particular Pascal for all his advice and guidance in the lab. To Soraya - Thanks for making me feel welcome and training me ‘from scratch’ when I arrived! Special thanks to all my friends in the lab who helped make my time at UCL enjoyable, especially Ying, Audrey, Sven, Marcus, Linos and Shahid - You will not be forgotten! Many thanks to all the technical staff for their excellent services, particularly Dr. Jorge Gonzalez Outereirino, Dr. Abil Aliev and Charles Willoughby for all their help and advice. I am thankful to Mike Cocksedge and staff at the London School of Pharmacy for HRMS, and to Jonathan Steed at King’s College London for performing the X-ray crystallography analysis. I am also grateful to the EPSRC and Pfizer for financial support. Finally, I am indebted to my parents for their love, support and help throughout my life, and especially to my boyfriend Dean for his never-ending patience, encouragement, devotion and invaluable advice, and it is to him that I dedicate this thesis. ABSTRACT This thesis is split into 4 sections, and is concerned with the development of a biomimetic total synthesis of the naturally-occurring antitumour agent, halichomycin. The first section describes a range of biomimetic natural product syntheses that have been devised since 1917, and shows the levels of complexity that have been transcended by various groups in these efforts. The second part of the thesis discusses the discovery and structure elucidation of halichomycin and Wood’s synthetic approach to a region of this compound. In addition to earlier ventures, our eventual biosynthetic proposal for tricyclic assembly in halichomycin is described in this thesis. Synthetic efforts towards halichomycin have so far resulted in the synthesis of an advanced AB-carbon backbone intermediate 252. In Chapter 3, our group’s original retrosynthetic analysis of halichomycin is described along with our attempts to implement this approach. A biosynthetic proposal for my assembly is then presented, and it will be shown how this served as a source of inspiration for a new synthetic strategy to halichomycin. Our progress towards this objective will then be reviewed. Specifically, the synthesis of an advanced precursor 252 of pre-halichomycin will be discussed. Noteworthy features of our synthesis include the Roush asymmetric crotylboration reaction between 210 and 211, en route to the anti-anti alcohol 212, and the face-selective enolate alkylation of 236 to give 237. Aldehyde 256 was converted to 254 via an Evans aldol reaction, followed by protection, then reduction. A Wittig-Stille sequence on 254 then completed the synthesis of 252. Evans Aldol, Wittig-Stille TE90 OTBS Protection Me sequence and Reduction 0PM B 254 OPMB Me C 02tt OPMB OMe 252 HO CHO B ''NH Me ,NH 2 Me . 24 i^e' 19 7 steps ^ Me Me Halichomycin Pre-Halichomycin 0 OTBOPS 250 210 Roush E n —/ Face-selective Asymmetric_ 3 steps^ i6\^y\Me Enolate Crotylboration Me Me Alkylation IPr02C ",/'''B Me iPiOgC IV CONTENTS List of Abbreviations I Acknowledgement ................................................................................................................... Ill Abstract ..................................................................................................................................... IV Contents .................................................................................................................................... V 1.0 INTRODUCTION 1.1 Biomimetic Syntheses 1 .1 . 1 Robinson’s Tropinone Synthesis ............................................................................... 2 1.1.2 O.L Chapman’s Biomimetic Synthesis of Carpanone ........................................... 6 1.1.3 W.S. Johnson’s Steroid Polyene Cyclisations ......................................................... 7 1.1.4 K.C. Nicolaou’s Biomimetic Approach to Endiandric Acids A-G ........................... 14 1.1.5 Heathcock’s Biomimetic Total Synthesis of Methyl Homosecodaphniphyllate .... 17 1 .1 . 6 W.S. Johnson’s Total Synthesis of d/-/?-Amyrin ...................................................... 28 1.1.7 Paterson’s Studies in Biomimetic Polyether Synthesis .......................................... 32 1.1.8 Baldwin’s Studies on the Biomimetic Synthesis of the Manzamine Alkaloids ....... 36 1.1.9 Sulikowski’s Progress toward a Biomimetic Synthesis of Phomoidride B ............ 44 1.1.10 Epilogue ....................................................................................................................... 48 2.0 BACKGROUND 2.1 The Discovery of the Antitumour Agent, Halichomycin .......................................... 49 2.2 The Yale Approach to the Synthesis of the C(1 )-C(7) Segment of Halichomycin: 52 The Wood Synthesis 3.0 RESULTS AND DISCUSSION 3.1 Original Retrosynthetic Analysis of Halichomycin and Preliminary Efforts to Implement a Conventional Synthetic Approach 3.1.1 Original Retrosynthetic Analysis of Halichomycin .................................................... 54 3.1.2 Attempted Implementation of the Original Retrosynthetic Strategy for Halichomycin 57 3.1.3 A Biogenetically-Modeiled Total Synthesis of Halichomycin ................................. 69 4.0 EXPERIMENTAL ........................................................................................................ 76 References V Chapter 1: Introduction 1.0 INTRODUCTION Numerous molecules have now been created by biomimetic approaches. A biomimetic synthesis is one that attempts to mimic the way Nature would biosynthesise the molecule. Given that much of this thesis will be spent discussing our attempts at implementing a biogenetically-modelled synthesis of the molecule halichomycin, we thought that it would be of interest to the reader to see what other types of biomimetic syntheses have been carried out during the 20*" Century. Below is a table outlining the biomimetic syntheses that will be discussed in this thesis by way of introduction to our own work in this field. Year Organic Chemist Work 1901 R. Willstatter First Synthesis of Tropinone via a long sequence of reactions 1917 R. Robinson Synthesis of Tropinone in one step 1923 R. Willstatter Synthesis of Cocaine 1971 O.L. Chapman Biomimetic Synthesis of Carpanone 1976 W.S.Johnson Biomimetic Approaches to Polyene Cyclisations 1982 K.C. Nicolaou Biomimetic Approaches to Endiandric Acids A-C: The Endiandric Acid Cascade 1992 C.H. Heathcock Biomimetic Studies on the Daphniphyllum Alkaloids: Total Synthesis of Homo secodaphniphyllate 1993 W.S.Johnson Total Synthesis of p-Amyrin 1993 1. Paterson Studies in Biomimetic Polyether Synthesis 1999 J.E. Baldwin Studies on the Biomimetic Synthesis of the Manzamine Alkaloids 2 0 0 2 C.A. Sulikowski Studies on the Biomimetic Synthesis of Phomoidride B Table 1: Overview of Biomimetic Synthetic Studies Covered in this Introduction Chapter 1: Introduction 1.1 BIOMIMETIC SYNTHESES 1.1.1 Robinson’s Tropinone Synthesis^ (1917) Me N COgMe OCOPh Fig. 1 : Structures of atropine 1, tropinone 2, and cocaine 3 Atropine (the racemate of structure 1) is an abundant alkaloid with remarkable physiological properties, its most