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Guerot, Carine (2009) Construction of Carbocycles Via Oxonium Ylides Generation and Rearrangement: Towards the Synthesis of Taxol

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Guerot, Carine (2009) Construction of Carbocycles Via Oxonium Ylides Generation and Rearrangement: Towards the Synthesis of Taxol Guerot, Carine (2009) Construction of carbocycles via oxonium ylides generation and rearrangement: towards the synthesis of taxol. PhD thesis. http://theses.gla.ac.uk/645/ Copyright and moral rights for this thesis are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the Author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the Author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Glasgow Theses Service http://theses.gla.ac.uk/ [email protected] Construction of Carbocycles via Oxonium Ylides Generation and Rearrangement: Towards the Synthesis of Taxol Carine Guérot Thesis submitted to the University of Glasgow for the degree of Doctor of Philosophy Department of Chemistry February 2009 © Carine Guérot, 2009 Abstract The diterpenoid natural product Taxol, first discovered in the late 1960’s, is one of the most important current drugs for the treatment of several cancers including breast and ovarian cancers. Although tremendous efforts towards its synthesis have been made in the last two decades, resulting in six elegant total syntheses, Taxol still constitutes a remarkable challenge for organic chemists due to its unique structural framework. NHBz OAc Ph O O OH HO O Taxol HO H O BzO AcO The high level of interest has spilled over to our laboratory, the purpose of this thesis was to develop an approach for the construction of medium-ring fused polycarbocyclic systems, which would then be applied to the synthesis of the sterically hindered eight-membered ring of the tricyclic core system of Taxol. Described herein is the continuation of efforts focused towards the access of fused medium-ring carbocycles by tandem catalytic oxonium ylide generation and rearrangement. The novel method in which intramolecular reaction of metal carbenoids with α-vinyl ethers and subsequent [2,3]- rearrangement of the cyclic oxonium ylide intermediates has been used as a powerful strategy to produce linearly fused bicyclic and tricyclic systems. 2 2 R 1 R 1 R 1 1 R H R H R H Rh or Cu 2 H Rh or Cu R R2 OR OR H OR H OR N O N O H 2 H 2 O O Up to 33% Up to 90% ii Following the success of our methodology, a key diazoketone intermediate was chosen to establish the viability of our strategy, before embarking on the total synthesis of Taxol. The efficient synthesis of the required diazoketone is discussed in detail, after the exploration of many different approaches. Finally, studies concerning the catalytic decomposition of the diazoketone towards the tricyclic core system of Taxol are presented. O N2 H O O H O H OMe O OH Me Rh or Cu O H O Me R O HOO HO H MeO OH iii Declaration I hereby declare that the substance of this thesis has not been submitted, nor is currently submitted, in candidature for any other degree. Portions of the work described herein have been published elsewhere as listed below. I also declare that the work presented in this thesis is the result of my own investigations and where the work of other investigators has been used, this has been fully acknowledged in the text. Rapid synthesis of medium-ring fused polycarbocyclic systems by rearrangement of carbenoid-derived oxonium ylides – J. Stephen Clark, Carine Guérot, Claire Wilson, Alexander J. Blake Chem. Comm. 2007 , 4134. Carine Guérot Prof. J. Stephen Clark iv Acknowledgements I would first like to express my sincere gratitude to my supervisor, Prof. J. Stephen Clark, for all his help, advice and support over the last three years. I would like to thank him for giving me the opportunity to work on a such challenging and exciting project. It has been a pleasure and an honour to be a member of his great research group. I acknowledge the financial support of the University of Glasgow and the University of Nottingham. I also would like to thank the technical staff at the University of Glasgow and the University of Nottingham who provided excellent advices and supports. I am very grateful to the X-ray crystallography teams of the University of Glasgow and the University of Nottingham for their contributions. I would also like to extend an enormous thank you to all the past and present members of the Clark Group. There are far too many people to list all of them, but all of them have largely contributed to the success of this thesis through advice, friendship and making the lab a very enjoyable place to carry out my research. I would especially like to thank David, Delphine and Jéjé (alias Jérôme) who, as me, moved from Nottingham to Glasgow not without difficulties, but the support to each other made the event achievable and even full of surprises and funs. Thanks to Flo and Raph for the many hours of amusement, laughter and gossip in and out of the lab, at the gym and obviously around a beer, not forgetting Alex, Bora and Fred. Thanks to the Moody Group and the Simpkins Group from the University of Nottingham and the Marquez Group from the University of Glasgow for the many great night-outs in the Johno’s and the Ruby our favourite pubs which often brought us to the Irish and the Viper. Finally, I wish to thank my family and friends, they constantly supported me from distance and without their encouragement this thesis wouldn’t be complete. Many Thanks to all, you made these three years unforgettable and enjoyable, both in the storm and the sunshine of this fulfilling journey. v Abbreviations p-ASBA p-acetamidobenzenesulfonyl azide Ac acetyl acac acetylacetonate acam acetamidate AIBN 2,2’-azobis(2-methylpropionitrile) Ar aromatic BHT 2,6-di-tert -butyl-p-tolyl Bn benzyl BOM benzyloxymethyl BRSM based on recovered starting material Bu butyl Bz benzoyl CAN ceric ammonium nitrate CM cross-metathesis COD 1,5-cyclooctadienyl Cp cyclopentadienyl m-CPBA m-chloroperbenzoic acid DABCO 1,4-diazabicyclo[2.2.2]octane dba dibenzylideneacetone DBB 4,4’-di(tert-butyl)-1,1’-biphenyl DBU 1,8-diazobicyclo-[5,4,0]-undec-7-ene DCC dicyclohexylcarbodiimide DCE 1,2-dichloroethane DCHMS dicyclohexylmethylsilyl DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DEAD diethyl azodicarboxylate DHQ-PHN dihydroquinine-9-O-(9’-phenanthryl) ether DIAD diisopropyl azodicarboxylate DIBAL-H diisobutylaluminium hydride vi DIPEA diisopropylethylamine DMA , -dimethylacetamide DMAP 4-dimethylaminopyridine DME 1,2-dimethoxyethane (ethylene glycol dimethyl ether) DMF , -dimethylformamide DMP Dess-Martin periodinane DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone DMSO dimethylsulfoxide DOSP (-dodecylbenzenesulfonyl)prolinate d.r. diastereomeric ratio EDG electron-donating group ee enantiomeric excess Et ethyl EWG electron-withdrawing group hfacac hexafluoroacetylacetonate HMDS hexamethyldisilazide HMPA hexamethylphosphoramide LDA lithium diisopropylamide LTMP lithium tetramethylpiperidide MABR methylaluminium bis(4-bromo-2,6-di-tert -butylphenoxide) MAD methylaluminium bis(2,6-di-tert -butyl-4-methylphenoxide) Me methyl MEM methoxyethoxymethyl MEOX oxazolidine-4-carboxylic acid methyl ester MEPY pyrrolidine-4-carboxylic acid methyl ester ML n transition metal with ligands MOM methoxymethyl Ms methanesulfonyl MS molecular sieves NBS -bromosuccinimide NCS -chlorosuccinimide NMO -methylmorpholine--oxide NMR nuclear magnetic resonance nOe nuclear Overhauser effect PCC pyridinium chlorochromate vii PDC pyridinium dichromate pfb perfluorobutyrate Ph phenyl piv pivaloyl PMB p-methoxybenzyl PPTS pyridinium-p-toleuenesulfonate Pr propyl PTSA p-toluenesulfonic acid pttl -phtaloyl-tert -leucinate py pyridine RCM ring-closing metathesis Red-Al sodium bis(2-methoxyethoxy)aluminium hydride ROM ring-opening metathesis r.t. room temperature TBAF tetra-n-butylammonium fluoride TBAI tetra-n butylammonium iodide TBDPS tert -butyldiphenylsilyl TBS tert -butyldimethylsilyl TES triethylsilyl Tf trifluromethanesulfonyl (triflyl) tfa trifluoroacetate tfacac trifluoroacetylacetonate tfacam trifluoroacetamide THF tetrahydrofuran THP tetrahydropyran TIPS triisopropylsilyl TMEDA ,,’,’ -tetramethyl-1,2-ethylenediamine TMS trimethylsilyl Tol p-methylphenyl Tos, Ts p-toluenesulfonyl (tosyl) tpa triphenylacetate TPAP tetra-n-propylammonium perruthenate Tr trityl Tris 2,4,6-triisopropylbenzenesulfonyl (trisyl) Troc trichloroethoxycarbonyl viii Table of contents Abstract .......................................................................................................................... ii Declaration ................................................................................................................. iv Acknowledgements .................................................................................................. v Abbreviations ............................................................................................................ vi Table of contents ..................................................................................................... ix Chapter 1: Introduction .......................................................................... 1 1. The chemistry of α-diazocarbonyl compounds ....................... 1 1.1. Synthesis of α-diazocarbonyl compounds ...................................... 1 1.2. Generation of metal carbenoids from diazo compounds .......... 3 1.3. Reactions of metal carbenoids ............................................................
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