CYCLOPENTANE ANNULATION STUDIES AND THEIR APPLICATION IN THE POLYQUINANE AREA a thesis presented by RICHARD THOMAS LEWIS in partial fulfilment of the requirements for the DOCTOR OF PHILOSOPHY of the UNIVERSITY OF LONDON BARTON LABORATORY CHEMISTRY DEPARTMENT IMPERIAL COLLEGE LONDON SW7 2AY NOVEMBER, 1987 2 ABSTRACT This thesis is divided into two parts. In the initial review section, the preparation and selected reactions of alkylidene- and vinylidene- cyclopropanes are surveyed. The second section describes endeavours directed towards the development of new approaches to the construction of five membered carbocycles, with a view to their application to polyquinane sesquiterpenoid synthesis. The first approaches explored utillised addition of an unsaturated three carbon atom unit to an olefin, followed by elaboration to a penultimate 1-vinyl-l-cyclopropanol precursor for thermal rearrangement. As anticipated, a-alkoxy allylic carbenes were insufficiently reactive to provide convenient access to the required cyclopropanols. Methods for oxidative allylic transposition of readily available alkylidenecyclopropanes were studied. Thus, three component condensation of cyclohexene with 2-phenylseleno-cyclohexanone and diethyl diazomethyl phosphonate under basic conditions furnished a suitable precursor for [2,3] sigmatropic rearrangement of the derrived selenoxide. The scope and generality of this strategy was investigated with a range of substrates, and found to suffer from disadvantages of competing ketone enolisation,facile allylic phenylselenide rearrangement,and over-oxidation to afford oxaspiropentanes. Alternative strategies employing singlet oxygen gave products of radical cleavage. In an alternative approach cyclopropyl phosphonate s, prepared by efficient copper(I) catalysed decomposition of diethyl diazomethyl phosphonate in the presence of electron rich olefins, were used in a Wadsworth-Emmons reaction to give (diphenylmethylene)cyclopropanes of diverse substitution pattern.Further elaboration provided precursors for the first intramolecular variant of a palladium(0) catalysed [2% + 2o] cyclisation to afford substituted bicyclo[3.3.0]octanes in high yield. Nickel(0) catalysed reaction gave different products including a low yield of a novel intramolecular Diels-Alder adduct. ACKNOWLEDGEMENTS These last three years would have been neither as productive nor as enjoyable but for the assistance of a number of people, whose contributions I gratefully acknowledge. Primarily I thank Dr Willie Motherwell for inspiration, friendship, unstinting and invaluable support, advice and encouragement during the course of this work. Thanks are also due to Dr H Broughton for his help with the molecular mechanics studies, to Mr K I Jones and his staff for performing the microanalyses, and to Mr J N Bilton and Drs. J A Challis and E S Waight for mass spectroscopic measurements. I salute Chris, Fred and the other technicians for their specialist support. Mr R N Sheppard and his assistants deserve special thanks for advice and uniquely valuable help with obtaining high field n.m.r. data, and for performing the n.O.e experiments. Special thanks are also due to Dr D J Williams and Ms. A M Z Slawin for performing X-ray structural determinations. I also applaud the contributions, of incalculable value, made by my proof readers Willie, Dennis, Jerry, Tony. Matt and John, and praise their patience, stamina and thoroughness, and by Miss D S Dobson whose sterling efforts transformed my hieroglyphics into type. I am particularly indebted to colleagues past and present in the Barton, Whiffen, Harwood and Perkin Laboratories for their friendship, wit and erudition which have made these years all the more enjoyable. TO MY PARENTS 6 ABBREVIATIONS AN — Acrylonitrile Il-BuLi - n-Buty11ithium Bu - n-butyl £-BuLi - t-Butyllithium Bz - Benzyl COD - Cyclooctadienyl- DBA - Dibenzylideneacetone DBU - Diazobicyclo[5.4.0]undec-7-ene DCM - D i chioromethane DHP - 3,4-Dihydro-2H-pyran DAMP - Diethyl Diazomethyl Phosphonate DMAP - N, N-Dimethyl-4-aminopyridine DME - 1,2-Dimethoxyethane DMF - N,N-Dimethylformamide DMSO - Dimethylsulphoxide Et - Ethyl EtO - Ethoxy eq - Equivalents H.P.L.C - High performance liquid chromatography 7 KOBu*1 — Potassium t-Butoxide LDA - Lithium diisopropylamide mCPBA - m-Chloroperbenzoic acid Me - Methyl MeO - Methoxy Ms - Methane sulphonyl (me sy1) n.m.r - Nuclear magnetic resonance n.O.e - Nuclear Overhauser effect Ph - Phenyl PLC - Preparative layer chromatography PPTS - Pyridinium p-toluenesulphonate iPr - isopropyl r.t - room temperature TBAF - Tetra-n-butylammonium fluoride TMEDA - N,N, N *,N *-Tetramethylethylenediamine Tf - Trifluoromethanesulphonate (triflate) THF - Tetrahydrofuran t.l .C - Thin layer chromatography TMS - Trimethylsily1 Trisyl - 2,4,6-Triisopropylbenzenesulphonyl Ts - p-Toluenesulphonyl- (tosyl) CONTENTS ABSTRACT 2 ACKNOWLEDGEMENTS 4 ABBREVIATIONS 6 A REVIEW OF THE PREPARATION AND REACTIONS OF ALKYLIDENE CYCLOPROPANES 10 REVIEW REFERENCES 110 RESULTS AND DISCUSSION 123 INTRODUCTION 124 1.0 1-VINYL- 1-CYCLOPROPANOLS AS IMPORTANT PRECURSORS TO CYCLOPENTANOIDS; A DIRECT APPROACH 126 2.0 REARRANGEMENT OF ALLYL SELENOXIDES 137 2.1 Preparation of Diethyl diazomethyl phosphonate 139 2.2 Preparation and reaction of (Phenylselenoalkylidene)cyclopropanes 141 3.0 SINGLET OXYGEN ENE REACTIONS 157 Radical allylic oxidation 162 4.0 THE SYNTHESIS OF POLYQUINANE SKELETONS BY APPLICATION OF [2a + 2k ] TRANSITION METAL CATALYSED C Y CLOCODIMERIS ATION OF ALK YLIDENEC YCLOPROPANE S WITH OLEFINS AND ACETYLENES 165 4.1 A Wadsworth-Emmons approach to (Diphenylmethylene)cyclopropanes 167 4.2 A model approach to linear triquinanes 174 9 4.2.1 Synthesis of the (Diphenylmethylene)cyclopropane precursor (82) 174 4.2.2 The palladium(0) promoted cyclisation reaction 185 4.2.3 The nickel(0) promoted reaction 200 4.3. An approach to angular triquinanes 203 4.3.1 Synthesis of the (Diphenylmethylene)cyclopropane precursor (92) 206 4.3.2 Synthesis of methylenecyclopropane precursor (93) 212 PERSPECTIVES AND CONCLUSION 215 APPENDIX X- ray data and selected n.mi spectra 218 EXPERIMENTAL 223 REFERENCES 309 PREPARATION AND REACTIONS OF ALKYLBDENE CYCLOPROPANES REVIEW CONTENTS INTRODUCTION 14 PART 1 j_ METHODS OF PREPARATION 15 Wittig reaction 15 Wadsworth-Emmons reaction 17 Petersen olefination 18 From a-halo-a-lithiocyclopropanes 19 From a-lithio-a-phenylthiocyclopropanes 20 From a-lithio-a-selenocyclopropanes 21 1-Seleno-1-vinyl-cyclopropanes 22 Singlet oxygen ene reaction 24 0-Elimination strategies 25 1,4-Elimination strategies 30 Rearrangement of cyclopropenes 31 Ring closure as the final step 35 Enamines and enol ethers 39 Cyclobutylidene rearrangement 41 Carbene addition to allenes 41 Simmons Smith reagents 41 Diazoalkanes 45 Dihalocarbenes 46 Decomposition of alkylidene pyrazolines 47 Alkylidene carbene insertions 49 N-Nitroso-oxazolidones 51 Vinylamines 51 Diazoethenes (Diazomethyl phosphonates) 51 12 1.17.4 Tosylazo alkenes 52 1.17.5 a-Bromo-vinylmercury bromides 52 1.17.6 a-Halo-vinylsilanes 53 1.17.7 Vinyl-trifluoromethane sulphonates 55 1.17.8 Halides 56 1.17.8a Acetylenic 56 1.17.8b Primary vinyl halides 57 1.18 Alkylidene cyclopropane rearrangement 58 2.0 PART 2 : REACTIONS 59 2.1 Palladium(O) & Nickel(O) catalysed [2ir + 2a] & [2a ♦ 2o] reactions 59 2.1.1 Nickel catalysed [2a + 2o] reactions 59 2.1.2 Palladium catalysed [2a ♦ 2o] reactions 67 2.1.3 C2tt + 2a] reactions S> cyclodimerisation 70 2.2 Chloropalladation of methylenecyclopropanes 73 2.3 Some other transition metal chemistry 79 2.4 Electrocyclic reactions 84 2.4.1 [4a + 2a] reactions 84 2.4.1a as dienes 84 2.4.1b as dienophiles 86 2.4.2 [2a + 2a] reactions 87 2.4.2a Dimerisation 87 2.4.2b Cross dimerisation 89 2.4.3 [3 + 2] cycloadditions 90 2.4.4 Cope rearangements 92 2.5 Intramolecular nucleophilic attack 93 2.5.1 Alkylidenecyclopropanes 93 13 2.5.2 Alkenylidenecyclopropanes 95 2.6 Electrophilic additions 98 2.6.1 Epoxidation 98 2.6.2 Carbene insertion 99 2.7 Singlet oxygen ene reactions 100 2.8 Nucleophilic attack on the olefin 102 2.9 Reducing agents 103 2.9.1 Alkene reduction 103 2.9.1a catalytic hydrogenation 103 2.9.1b metal hydrides 104 2.9.1c boranes 105 2.9.1d dissolving metal systems 106 2.9.2 Hydrodehalogenation 106 2.10 Metallation 107 2.11 Rearrangements 108 CONCLUSION 109 14 fJEP_ARATI0H_AWP_REAC110HS OF ALKYLIDENE -CY.ClQP&fiEANES INTRODUCTION Since 1893 when Feist's Acid (2).arising from the alkaline hydrolysis of pyrone (1) was first isolated,1 there has been active interest in the preparation and reactions of alkylidene cyclopropanes. C02H The novel rearrangements which occur in such systems have stimulated considerable research efforts amongst physical organic chemists. 2 The presence of the structure in a variety of 3-5 compounds possessing important biological activity has spurred development of new synthetic strategies to this structural unit.The utility of these versatile synthetic 6a.7-16.17d intermediates has recently been explored. This review covers the synthetic approaches to these systems, and some of their more synthetically useful transformations. Detailed consideration of theoretical aspects associated with the reactions is necessarily beyond its scope; many of the mechanistic aspects are not as yet fully understood. 1.0 PART 1 : METHODS OF PREPARATION 1-D BgasUftfl Wittig methodology has been extensively employed, due to the 1 8 ready availability of cyclopropyltriphenylphosphorane (3), (Scheme 2a). c) Ph4PBr HBr -PhH ^ *Y -L IB r PPh3 +