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Intramolecular Diels-Alder Reactions of Sulphonyl-Substituted Trienes

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Intramolecular Diels-Alder Reactions of Sulphonyl-Substituted Trienes INTRAMOLECULAR DIELS-ALDER REACTIONS OF SULPHONYL-SUBSTITUTED TRIENES A Thesis Presented by Andrew Marsh In Partial Fulfilment of the Requirements for the Award of the Degree of DOCTOR OF PHILOSOPHY OF THE UNIVERSITY OF LONDON Harwood Laboratory Department of Chemistry Imperial College of Science, Technology and Medicine London SW7 2AY September 1991 1 Abstract This thesis is divided into two parts. The first part describes the development of methodology for the intramolecular Diels-Alder (IMDA) reaction of sulphonyl-substituted trienes. A brief introduction to the the area of the IMDA reaction is provided. This provides the basis for the rational development of a new class of IMDA substrate. A series of E- and Z-sulphonyl substituted deca- and undecatrienes was synthesised and their cyclisation behaviour under thermal conditions examined. Cyclisation of (IE, 7E, 9E)-l-phenylsulphonyl-l,7,9-undecatriene gave a 6:1 mixture of cis- and trans-fused bicyclic sulphones. Contrastingly, cyclisation of the corresponding (Z, £, E)- sulphonyltriene yielded a 3:1 mixture of trans- and cis-fused isomers. These results added weight to the postulate that a suitable dienophile could exert a sereocontrolling influence over the outcome of the IMDA reaction. The lower homologues of these trienes were found to provide similar results. The reaction of a series of a-methylated trienes was carried out to examine the degree of stereocontrol exerted by the phenylsulphone group over the [4+2] cycloaddition. Characterisation of the bicyclic sulphones derived from these reactions is supported by X-ray crystallographic evidence and supplemented by chemical correlation. The second part begins with a review of approaches towards the total synthesis of the CD ring of vitamin D 3 and its analogues. This introduces the use of the IMDA reaction as a concise strategy towards the construction of a vitamin D 3 CD ring synthon in a stereocontrolled fashion. The synthesis of a suitable model substrate and its cyclisation via a novel IMDA route is described. With the success of this reaction, an enantiomerically pure triene was synthesised. Cyclisation under thermal conditions led to material suitable for elaboration to the natural product, vitamin D 3. The diastereomeric bicyclic tetrahydroindene adducts were epoxidised to allow their separation and characterisation using spectroscopic techniques. Contents Page Abstract 1 Acknowledgements 3 Abbreviations ^ Stereochemical Notation and Compound Numbering 8 PART I 1.0 Introduction 9 2 .0 Results and Discussion Part I 22 PART II 3 .0 Review: Approaches to the Total Synthesis of the CD Ring System of Vitamin D 3 and its Metabolites 57 4 .0 Results and Discussion Part II 112 5 .0 Experimental: Part I 149 PartE 211 6 .0 AppendixI: X-ray crystallographic data 263 Appendix II: Tables 277 Appendix III: nOe Experiments and nmr Spectra 280 7 .0 References 288 8.0 Corrigenda 298 3 Acknowledgements I would like to express my gratitude to Dr Donald Craig for his boundless enthusiasm in his support, help and friendship during my studies. The Old Building in the Chemistry Department has been a stimulating and enjoyable place to work and learn. The friendship of many colleagues in the Harwood, Whiffen, Barton and Perkin laboratories has made my time at Imperial College all the more enjoyable. Particular thanks are due to Jim Anderson, Steve Smith, Alison Smith and David Rainford for advice, entertainment and friendship. Thanks are due to the technical staff for providing the following services. Foremost, Mr Dick Sheppard and Mr Paul Hammerton for high-field nmr spectra; Dr D J Williams and Ms A M Z Slawin for X-ray structure determinations; Mr J N Bilton and Mr G P Tucker for mass spectroscopic measurements; Mr K Jones and Miss H O’Callaghan for elemental analyses. Mr E Poggiolli and colleagues are thanked for the sundry services that ensure a pleasant and efficient laboratory. The SERC Mass Spectroscopy Service at the University College of Swansea deserve special mention for such swift service. Many thanks are also due to Don, Jim, Smiffy, Biffa and Hartmuth for 500 MHz nmr spectra at a moments notice. Dr P Grice is gratefully acknowleged for help with molecular modelling as is Dr R Munasingh for my endeavours with the HPLC. Thanks to my proofreaders: Don, Martin Clasby, John Reader and Neil Press. I acknowledge the SERC for providing funding during this course of work. I would like to thank my parents for their love and support during my education. Finally my special thanks are reserved for Jill, for her patience and love which made this so enjoyable. 4 To Jill 5 Abbreviations Ac Acetyl At Aromatic Bn Benzyl br. Broad bp Boiling point n-Bu rt-Butyl f-Bu re/t-Butyl cat. Catalytic (amount) Cl Chemical ionisation CSA 10-Camphorsulphonic acid A Heat DCM Dichloromethane d. e. Diastereomeric excess DIBAL-H Diisobutylaluminium hydride DMAP 4-(Dimethylamino)pyridine DME Dimethoxyethane DMF Dimethylformamide DMPU Dimethylpropyleneurea (l,3-dimethyl-3,4,5,6-tetrahydro-2(l//)- pyrimidone DMSO Dimethylsulphoxide e. e. Enantiomeric excess El Electron impact eq Equivalent(s) Et Ethyl Ether Diethyl ether 6 FAB Fast atom bombardment hu Light hr Hour(s) HMPA Hexamethylphosphoramide HPLC High performance liquid chromatography IPA Isopropyl alcohol ir Infrared LDA Lithium diisopropylamide m Multiplet m Meta m-cbpa meta-Chloroperbenzoic acid min Minute(s) MoOPH Oxodiperoxymolybdenum(pyridine)hexamethylphosphoramide mp Melting point Me Methyl Ms Methanesulphonyl NaHMDS Sodium hexamethyldisilazide NMO N-Methylmorpholine-N-oxide nmr Nuclear magnetic resonance nOe Nuclear Overhauser effect 0 Ortho P Para PCC Pyridinium chlorochromate PDC Pyridinium dichromate Ph Phenyl iPr iso-Propyl Py Pyridine q Quartet rt Room temperature s Singlet t Triplet TBAF Tetra-rt-butylammonium fluoride TBS rm-Butyldimethylsilyl TBDPS tert-B utyldiphenylsilyl Tf Trifluoromethanesulphonyl THF Tetrahydrofuran THP T etrahydro-2//-pyran tic Thin layer chromatography TES Triethylsilyl TMS Trimethylsilyl TPAP Tetra-n-propylammonium perruthenate Ts p-Toluenesulphonyl UV ultraviolet 8 Stereochemical Notation and Compound Numbering. Throughout this thesis, the graphical representation of stereochemistry is in accord with the conventions proposed by Maehr .1 Thus, solid and broken wedges denote absolute configuration and solid and broken parallel-sided lines denote racemates. For the former, greater narrowing of both solid and broken wedges indicates increasing distance from the viewer.r°"i r0vi single enantiomer racemate In sections 1 ,2 ,4 and the experimental section, 6 , compounds adopt the systematic (IUPAC) numbering system. In section 3 however, compounds are named according to accepted steroid nomenclature since this is the convention used when describing fragments of vitamin D 3 and its homologues. In the experimental section nmr assignments follow the systematic numbering scheme for the compound. 9 1.0 Introduction. Our understanding of the intramolecular Diels-Alder reaction (IMDA) has advanced greatly since its discovery nearly thirty years ago .2 This powerful strategy has found application within the arena of synthetic organic chemistry largely due to the often predictable fashion in whch four or more (if linking chain substituents are present) stereocentres may be constructed. The reaction has been the subject of several books^ and reviews4 within the past ten years, which has resulted in extensive coverage of the literature and the ideas developed in it. Whilst much research has been reported on the IMDA reaction, there are still areas which remain poorly understood. One such fundamental area is the relationship between dienophile substitution and stereoselection exhibited by the cyclisation reaction. These factors may be expected to be closely linked. Relevant research however, has often led to the conclusion that dienophile geometry plays a secondary role in determining stereochemical preferences in intramolecular cycloadditions .5 For thermal processes, the development of a reaction whose stereochemical outcome is a direct and predictable consequence of dienophile geometry is an important and attractive goal. In order to understand the concepts that lie behind achievement of this goal, it is necessary to consider previous research. Many natural products contain bicyclo[4.3.0]- or bicyclo[4.4.0]-fused rings and as a result, the construction of these systems in a controlled manner has been the subject of frequent investigations utilising this reaction. 1.1. Background: Thermal IMDA Cyclisations of Simple Trienes. The study of simple trienes without substituents in the linking chain has emerged as a powerful tool in learning about the stereochemical outcome of the IMDA reaction. 10 Useful insight into the origins of stereocontrol in the cycloaddition process has undoubtedly been gained from work carried out towards natural product synthesis; however, attendant functionality may obscure underlying trends. It is more instructive to consider simple trienes which have been designed to elucidate information about cycloadduct stereochemistry. 1.1.1 The thermal and Lewis-acid catalysed cycloadditions of a number of representative trienes have been studied. Substrates leading to both bicyclo[4.3.0]^ and bicyclo[4.4.0 ]7 systems were considered (Scheme 1). R1 1 r ' s CO2CH3, R2 = H 94% 49 : 51 2 R1 = H, R2 = CO2CH3 90% 49 : 51 55 : 45 Scheme 1 11 The conclusions drawn from these studies were: (i) product selectivity is independent of dienophile stereochemistry; (ii) secondary
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