Intramolecular Cycloaddition Strategies For

INTRAMOLECULAR CYCLOADDITION STRATEGIES FOR THE CONSTRUCTION OF POLYCYCLIC CYCLOPENTANOIDS a thesis presented by SORAB ANTONY BAPUJI in partial fulfilment of the requirements for the award of the degree of DOCTOR OF PHILOSOPHY OF THE UNIVERSITY OF LONDON BARTON LABORATORY CHEMISTRY DEPARTMENT IMPERIAL COLLEGE LONDON SW72AY MAY 1989 Abstract This thesis comprises three major sections. Firstly, a review of the syntheses of triquinane sesquiterpenoids is presented. Particular emphasis has been placed upon recent synthetic strategies and methodology developed. The second section outlines a synthetic strategy for construction of the p-isocomene skeleton which features an intramolecular [jc2 s +ji2 s ] cycloaddition of an olefin and an in situ generated ketene or keteniminium salt as the key step. Contemporaneous model studies conducted while the precursor was in the assembly stage indicated that such an approach was experimentally very demanding. The third section deals with a fundamental study designed to achieve the equivalent of a Diels-Alder type synthesis for five-membered rings and involves a novel intramolecular application of the palladium (0) or nickel (0) catalysed [2te+2<t] cycloaddition of an olefinic or acetylenic component with a suitably constructed alkylidene cyclopropane. The nature of the metal and ancillary ligands on the catalyst and the resulting control of regiochemistry are discussed in terms of a probable mechanism for this reaction. Approaches towards the elaboration of the carbocyclic skeleton of p-isocomene using this methodology are discussed. » (i) Acknowledgements I would like to take this opportunity to thank my supervisor and friend, Dr. Willie Motherwell, for his relentless support, strong encouragement and kindness throughout the course of my work. I am indebted to the technical staff at Imperial College, who include John Bilton and Geoff Tucker for mass spectra, Ken Jones and his staff for microanalyses and Dr. Dick Sheppard for his advice and work on the high-field n.m.r. experiments. I would also like to thank my colleagues in the Barton, Whiffen and Perkin labs. - both past and present - for their help, friendship and knowledge. I am particularly grateful to my proof readers for their meticulous efforts: Dennis, Gavin, John, Matt, Andy, Mike, Dave and Rob. I wish to express a special thank you to Dr. Richard Lewis, who has given me much time and invaluable guidance. I am grateful to Prof. Steve Ley whose equipment I have frequently used. And lastly, thanks are also due to Prof. S. M. Roberts and Dr. P. Myers for their help throughout this research, and also to Glaxo for providing financial support. To my family, for their love and support. Abbreviations Ac - Acyl AIBN - Azobisisobutyronitrile aq- - aqueous IL-BuLi - a-Butyllithium I-B u L i - 1-Butyllithium COD - Cycloocta-1,5-diene Cp - Cyclopentadienyl DAMP - Diethyl diazomethyl phosphonate d b a - Dibenzylideneacetone DBU - Diazobicyclo[5.4.0]undec-7-ene DMAP - N,N-Dimethyl-4-aminopyridine DM90 - Dimethyl sulphoxide eq. - equivalent h - hour HMPA - Hexamethylphosphoric triamide iP r - isopropyl LDA - Lithium diisopropylamide mcpba - m-Chloroperbenzoic acid min - minute Ms - Methanesulphonyl n.m.r. - Nuclear magnetic resonance n.0.e. - Nuclear Overhauser effect PCC - Pyridinium chlorochromate PPTS - Pyridinium p-toluenesulphonate py - Pyridine RT - room temperature TBAF - Tetra-a-butylammonium fluoride (iv) TBDMS t-Butyldimethylsilyl THF Tetrahydrofuran THP Tetrahydro-2H-pyran-2-yl TMS Trimethylsilyl Tol Tolyl Ts p-Toluenesulphonyl (V) Conlenls Abstract ( i ) Acknowledgements (ii) List of Abbreviations (iv) Chapter One A Review of Recent Synthetic Strategies and Methodology of Selected Polyquinane Sesquiterpenoids 1.1 Introduction 1 1.2 Linear Triquinanes 2 1.2.1 Hirsutene 2 1 .2 .2 The Capnellene Group 7 1 .2 .3 Coriolin 1 1 1 .2 .4 Hirsutic Acid 1 4 1.3 Angular Triquinanes 1 5 1.3.1 Isocomene Sesquiterpenes 1 5 1.3.2 Silphinene 3 6 1 .3 .3 Pentalenene 4 2 1 .3 .4 Pentalenic Acid 5 0 1 .3 .5 Senoxydene 5 4 1 .3 .6 Silphiperfolene and Related Congeners 5 5 1 .3 .7 Subergorgic Acid 6 0 1 .3 .8 Conclusions 6 2 References 6 4 Chapter Two The Intramolecular Ketene-Olefin Approach to Polyquinanes 2.1 Historical Background 68 2 .2 A Model Study 74 2 .3 Construction of the Monocyclic Precursor 7 7 Chapter Three The Intramolecular Transition Metal Catalysed [2jc+2 ct] Approach to Polyquinanes 3.1 Introduction 8 3 3 .2 Strategy Towards Construction of an Acyclic Precursor for a Bicyclo[3.3.0]octane Framework 8 9 3 .3 Construction of Acyclic Precursors for Bicyclo[4.3.0]nonane Frameworks 9 4 3 .4 The Palladium (0) Catalysed Reaction 9 5 3 .5 The Nickel (0) Catalysed Reaction 11 0 3 .6 An Approach to a Precursor Biased Towards Proximal Cleavage 11 7 3 .7 Initial Synthetic Strategies in the Direction of the Isocomene Framework and Perspectives 1 21 Experimental 128 References 1 7 2 Chapter One A Review of Recent Synthetic Strategies and Methodology of Selected Polyquinane Sesquiterpenoids 1.1 Introduction Traditionally the chemistry and stereochemistry associated with six-membered ring systems has played a dominant role in synthetic organic chemistry, no doubt in part, because of the widespread occurence of this structural feature in many biologically important natural products. By way of contrast, prior to the early nineteen-sixties, polycondensed cyclopentanoid natural products were relatively rare, and hence developement of synthetic strategy to such systems was understandably overshadowed by a pre-occupation with their six-membered ring counterparts.1 By the mid seventies, however, the area of polyquinane chemistry was on the verge of an explosive growth period. There were several underlying reasons for this surge of interest in molecules whose frameworks featured mutually fused cyclopentane rings.2 In the first instance, comparatively little attention had been paid to methodology for annulation of one five-membered ring to another. The intellectual challenge of developing suitable protocols of this type was reinforced by a need arising throughout organic synthesis. Thus, the isolation of new substances in classical natural product chemistry possessing the di- or triquinane skeletons was of considerable interest to the synthetic chemist as was their biosynthesis from farnesyl pyrophosphate or related precursors. In the realms of non-natural product synthesis, there was a growing fascination for the possibly unusual physical and chemical properties of then unknown spherical compounds such as dodecahedrane. In addition, many novel polycyclopentanoid allylic systems of theoretical interest were yet to be synthesized. 1 The proliferation of review literature in this area, even with the lifespan of the present thesis, has been considerable, and it would be unrealistic to attempt to reproduce it here. Therefore, in order to place the studies described herein in their proper context, we have elected to highlight the key features relating to cyclopentanoid construction in several natural product systems. 1.2 LiQ£2I__ Triauinanes 1.2.1 Hirsutene Scheme 1 ?— O n OH ( 1) (3) Hirsutene (1) is the simplest member of a group of fungal metabolites possessing the linearly fused cis-anti-cis-tricvclo [6.3.0.02’6] undecane carbon skeleton.3 Other members with this framework include capnellene (2)16 and coriolin (3).25 As a result of the antibiotic and antitumour properties displayed by some of these triquinanes, new methods of annulation are constantly being devised for their construction. A formal [3+2] cyclisation was used by Magnus and Quagliato4 to produce bicyclic enone (4), although the yield was poor (38%). Stepwise methylene cyclopentane annulation followed by reduction produced (±)-hirsutene (Scheme 2). 2 o AgBF4 H --------------------- ► / (4) H SPh 1. MeLi 1 2. H g C l^ Thus the key step in Little's synthesis5 involved an ingenious intramolecular 1,3- diyl trapping reaction of an activated biradical diylophile (Scheme 3). 3 In terms of synthetic efficiency, reactions in which two or more C-C a bonds can be created in the same reaction are most attractive. This method has also been applied to coriolin synthesis.6,7 The intramolecular [3+2] nitrone-olefin cycloaddition by Funk,8,9 employed in the stereospecific construction of the hirsutene framework, was of interest in that heating the mixture of nitrone isomers resulted in only one adduct. With regard to cyclopentanoid formation, however, only one carbon-carbon bond is formed in this ring closure reaction (Scheme 4). o - Schem e 4 In contrast, the increasingly predictable behaviour of kinetically controlled radical cyclisation reactions was elegantly extended by Curran to tandem cyclisation reactions.10 The overall result is that the tricyclic skeleton is assembled in a single step from a monocyclic precursor (Scheme 5). However, the cis-anti-cis geometry can only be controlled by the non-trivial task of setting up the requisite 3.5-trans disposition of the starting cyclopentane. 4 *fcu£nH AffiN 8 3 % Schem e 5 In addressing the problem of entering the optically active series Hua employed condensation of a chiral sulphoxide with an enone during an asymmetric synthesis of (+)-hirsutene.11,12 At the time, its absolute configuration was not known; thus the synthesis enabled this to be established. Oxidation and selenoxide elimination followed by chromic oxidation and a cuprate addition to the resulting enone provided a side chain. This was elaborated to the tricyclic framework (Scheme 6). Scheme 6 OCOMe TnIS OH 4 : 1 86% yield 94% ee Tor OH H 5 Ley employed an organoselenium-mediated cyclisation reaction using N- phenylselenophthalimide (NPSP) and tin tetrachloride (Scheme 7).13,14 Since both the cis-anti-cis (6) and the unwanted cis-syn-cis (7) isomer were produced methods for elaborating the cis-svn-cis isomer were investigated in order to increase the overall yield of hirsutene. Ultimately, oxidation of the cis-syn-cis isomer to the selenoxide followed by elimination gave (8), which was hydrogenated under reductive rearrangement conditions to give (6).

Load more