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Applications of Imino-Diels–Alder Reactions in Synthesis

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Applications of Imino-Diels–Alder Reactions in Synthesis Applications of Imino-Diels–Alder Reactions in Synthesis A thesis presented by Jasprit Kaur Chahal As partial fulfilment of the requirements for the award of the degree of Doctor Philosophy of Imperial College London Thorpe Laboratory Department of Chemistry Imperial College London South Kensington Campus London SW7 2AZ 1 Declaration of Originality The work reported in this thesis is my own and information derived from the published and unpublished work of others has been appropriately referenced. 2 Abstract The aim of the project was to synthesise (−)-morphine utilising a tethered intramolecular imino-Diels–Alder reaction. This thesis begins by providing brief reviews on the subjects of total synthesis of morphine and asymmetric imino-Diels–Alder reaction. The major section focuses on the research findings in the past four years. Starting with investigations in the development of a novel stereoselective imino-Diels–Alder reaction of methyl propargyl ether derived (1 E, 3Z)-1-silyloxy-3-(phenylthio)-1,3- dienes with trans -2-phenylcyclohexyl glyoxylate derived N-tosylimine. Following with the progress made so far to synthesise triene II; this was envisaged to be prepared from the enantiomerically pure alcohol III and allylic halide IV. The alcohol III was prepared in a five-step sequence from p-anisaldehyde. However, the synthesis of the allylic halide IV from D-lyxose was more challenging and problematic. Initial efforts for its synthesis via a route incorporating the Ohira–Bestmann reaction caused an unwanted epimerisation. Further efforts, through an eleven-step sequence including Wittig dibromomethylenation and intramolecular ene–yne metathesis gave V or VI . However, the reductive eliminations to give the alcohol precursor to IV were unsuccessful. O HO O H O NMe O HH N TsH I HO (−)-morphine I OMe O O O OH I O R O O TBDPSO + O O I OMe Br II NTs III IV V R = SPh OMe VI R = SO2Ph Experimental details and characterisation data are provided at the end of the thesis. 3 Contents 1 Acknowledgements ................................................................................................ 5 2 Abbreviations ......................................................................................................... 7 3 Stereochemical Notation ...................................................................................... 10 4 Morphine Numbering ........................................................................................... 10 5 Introduction .......................................................................................................... 11 5.1 Biosynthesis of Morphine ............................................................................ 12 5.2 Total Syntheses of Morphine ....................................................................... 14 5.2.1 Rice’s synthesis ........................................................................................ 14 5.2.2 Overman’s synthesis ................................................................................ 15 5.2.3 Mulzer’s synthesis ................................................................................... 16 5.2.4 Magnus’ synthesis .................................................................................... 18 5.3 Our Proposed Synthesis of (−)-morphine .................................................... 21 5.4 Asymmetric Imino-Diels–Alder Reactions .................................................. 22 5.4.1 Imine dienophile ...................................................................................... 24 5.4.2 1-Azadiene ............................................................................................... 34 5.4.3 2-Azadiene ............................................................................................... 36 5.5 Conclusion ................................................................................................... 39 6 Results and Discussion ........................................................................................ 40 6.1 Stereoselective Diels–Alder Reactions for Piperidine Synthesis ................. 40 6.1.1 Diene synthesis ........................................................................................ 42 6.1.2 Synthesis of N-tosylimine dienophiles ..................................................... 50 6.1.3 Imino-Diels–Alder reaction ..................................................................... 57 6.1.4 Future work .............................................................................................. 59 6.1.5 Conclusion ............................................................................................... 60 6.2 Diastereoselective Intramolecular Diels–Alder Reactions for an Approach to (−)-morphine ............................................................................................................ 61 6.2.1 Synthesis of the enantiomerically pure alcohol ....................................... 64 6.2.2 Progress toward the synthesis of the allylic halide .................................. 65 6.2.3 Future work .............................................................................................. 87 6.2.4 Conclusion ............................................................................................... 88 7 Experimental ........................................................................................................ 89 8 Appendices ......................................................................................................... 163 8.1 Appendix I ................................................................................................. 163 8.2 Appendix II ................................................................................................ 166 8.3 Appendix III ............................................................................................... 171 9 References .......................................................................................................... 175 4 1 Acknowledgements First of all, I would like to thank Professor Donald Craig for his endless support, enthusiasm and encouragement over the past four years, and for giving me the opportunity to undertake my postgraduate research under his guidance. Secondly, I would like to express my thanks to my industrial supervisors at GlaxoSmithKline, Dr Andrew Payne and Dr Chris Smethurst, for their continual assistance during the past few years. Both supervisors have been an immense source of ideas, inspiration and motivation. I would also like to acknowledge and express my gratitude to the past and present members of the Craig group for their professional support and for providing a great working atmosphere. Special thanks go to all the members of the Thorpe laboratory; Alex, Kiyo, Darryl, Elliott, Diane, Shu, James, Rich, Albert, Prathap and Sky for maintaining a clean and smooth-running laboratory. I would also like to take this opportunity to mention and again thank Jason, Federica, Steve, Sophie, Pengfei, Niels, Claire, Jamie, Rik, Simon, Phin, Shan Shan, Marc, Clarice, Alpha, Joe, Tom, Marcus and Almuth for all of their help and support. In addition, I would like to thank all the technical staff in the chemistry department at Imperial College London; especially John Barton, Dick Sheppard, Peter Haycock and Dr Andrew White for their analytical support. Special thanks to all my friends in the chemistry department and at Imperial; particularly Claire, Bingli and Laura, with whom I have spent the last nine or so years at Imperial enjoying and moaning about our undergraduate and postgraduate studies in chemistry. I must also thank Paul and Jame from the VWR stores, the Craig group and all the fabulous members of the postgraduate chemistry society committee, for the eventful and memorable times in the Holland Club and Eastside. 5 I would like to express my gratefulness to my family for their unconditional support and encouragement during the last four years. Finally, I am very grateful to the EPSRC and GlaxoSmithKline for providing the financial support for my postgraduate studies. 6 2 Abbreviations Ac acetyl ADDP 1,1’-(azodicarbonyl)dipiperidine atm atmosphere br broad brsm based on recovered starting material bp boiling point BHT 2,6-bis(1,1-dimethylethyl)-4-methylphenol n-Bu normal -butyl cat. catalytic CI chemical ionisation CSA camphorsulfonic acid d doublet DABCO 1,4-diazabicyclo[2.2.2]octane DBDMH 1,3-dibromo-5,5-dimethylhydantoin DBU 1,8-diazobicyclo[5.4.0]undec-7-ene DBS dibenzosuberyl DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethylsulfoxide dr diastereomeric ratio EDG electron donating group ee enantiomeric excess equiv equivalents ESI electrospray ionisation Et ethyl EtOAc ethyl acetate EtOH ethanol EWG electron withdrawing group h hours HMDS hexamethyl disilazide HOMO highest occupied molecular orbital 7 IMDA intramolecular Diels–Alder IR infra-red KHMDS potassium bis(trimethylsilyl)amide LDA lithium diisopropylamide LiHMDS lithium bis(trimethylsilyl)amide LUMO lowest occupied molecular orbital m multiplet m-CPBA meta -chloroperbenzoic acid Me methyl MeOH methanol min minutes MMPP magnesium monoperoxyphthalate mp melting point Ms methanesulfonyl NBS N-bromosuccinimide NCS N-chlorosuccinimide NMR nuclear magnetic resonance nOe nuclear Overhauser effect o- ortho - p- para - PCC pyridinium chlorochromate Ph phenyl Pht phthalimidyl PMP 1,2,2,6,6-pentamethylpiperidine i-PrOH isopropyl alcohol q quartet Rf retention factor rt room temperature s singlet s- sec - t triplet t-
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