Radical Approaches to Alangium and Mitragyna Alkaloids A Thesis Submitted for a PhD University of York Department of Chemistry 2010 Matthew James Palframan Abstract The work presented in this thesis has focused on the development of novel and concise syntheses of Alangium and Mitragyna alkaloids, and especial approaches towards (±)-protoemetinol (a), which is a key precursor of a range of Alangium alkaloids such as psychotrine (b) and deoxytubulosine (c). The approaches include the use of a key radical cyclisation to form the tri-cyclic core. O O O N N N O O O H H H H H H O N NH N Protoemetinol OH HO a Psychotrine Deoxytubulosine b c Chapter 1 gives a general overview of radical chemistry and it focuses on the application of radical intermolecular and intramolecular reactions in synthesis. Consideration is given to the mediator of radical reactions from the classic organotin reagents, to more recently developed alternative hydrides. An overview of previous synthetic approaches to a range of Alangium and Mitragyna alkaloids is then explored. Chapter 2 follows on from previous work within our group, involving the use of phosphorus hydride radical addition reactions, to alkenes or dienes, followed by a subsequent Horner-Wadsworth-Emmons reaction. It was expected that the tri-cyclic core of the Alangium alkaloids could be prepared by cyclisation of a 1,7-diene, using a phosphorus hydride to afford the phosphonate or phosphonothioate, however this approach was unsuccessful and it highlighted some limitations of the methodology. Chapter 3 explores the radical and ionic chemistry of a range of silanes. Initial studies explored the radical addition of a range of silicon hydrides to alkenes to afford the corresponding hydrosilylation products. The chemistry of the hydrosilylation products was then explored – it was hoped that a subsequent Peterson olefination or Fleming-Tamao oxidation would afford the corresponding alkene or alcohol. Subsequent investigations looked into the possibility of combining the radical and ionic reactions, to afford alkenes or alcohols, in a one-pot transformation. i Chapter 4 explores the radical cyclisation of various compounds, including unsaturated alpha-haloamides (d and e), xanthates (f), vinyl bromides (g and h). For this, a robust and efficient synthesis of an allyl tetrahydroisoquinoline core (i and j) was developed, following conversion into the desired radical precursors these compounds were treated with tributyltin hydride and a radical initiator. Finally, Chapter 4 investigates the radical cyclisation of some unsaturated phenylselenides (k and l), which resulted in the isolation of the desired target alkaloid (±)-protoemetinol (a) in 4 steps and in 2% overall yield. O O O N O N NH O O O Br X X X X=Cl,d X=Me,g X=H,i X=Br,e X=COCH , h X=Br,j X=SC(S)OEt,f 2 3 O O N R N O O SePh R O R=H,k R=H,m R=Me,l R=Me,a O OH Chapter 5, which builds on previous work within Chapter 4, discusses the cyclisation of vinyl bromides bearing an α,β-unsaturated ester (n and o). This resulted in short 4-step syntheses of both (±)-des-methyl-protoemetinol (m) and (±)-protoemetinol (a) (along with some epimers). Subsequent studies then expanded the synthetic strategy to include the synthesis of a structurally simpler analogue of mitragynine (p). OMe O O Br N N O O N R N H H R=H,n O R=H,m R Mitragynine R=Me,o R=Me,a p OMe O OH MeO2C ii Contents Abstract i Contents iii Acknowledgements vii Declaration viii Abbreviations ix Chapter 1 Introduction 1.1 Radical chemistry 1 1.1.1 - Overview of radical chemistry 1 1.1.2 - General considerations of radical reactions 1 1.1.3 - Overview of intermolecular additions 3 1.1.4 - Overview of radical cyclisations 4 1.1.5 –Organotin radicals in synthesis 7 1.1.5.1 - Additions to carbon-carbon multiple bonds 7 1.1.5.2 - Addition to a carbon–heteroatom double bond 8 1.1.5.3 - Problems associated with tributyltin hydrides 10 1.1.6 - Single Electron Transfer Reactions 11 1.1.6.1 - Nickel mediated reactions 11 1.1.6.2 - Manganese(III) acetate mediated reactions 12 1.1.6.3 - Samarium(II) mediated reactions 13 1.1.6.4 Tetrathiofulvalenes 14 1.1.7 - Alternative hydrides 15 1.1.7.1 - Germanium hydrides 15 1.1.7.2 – Thiols 16 1.1.7.3 – Silanes 17 1.1.7.4 - Silylated cyclohexadienes 18 1.1.7.5 - Tris(trimethylsilyl)silane 19 1.1.7.6 - Organophosphorus hydrides 21 1.2 Alkaloids 25 1.2.1 –Overview of Alangium and Mitragyna alkaloids 25 1.2.2 - Alangium alkaloids 26 1.2.2.1 - Synthesis of Alangium alkaloids and related compounds 26 iii 1.2.2.2 - Iron catalysed cyclisation 27 1.2.2.3 A domino hetero-Diels-Alder reaction 28 1.2.2.4 Catalytic asymmetric allylation 31 1.2.2.5 - [3+3] Annulation followed by acid-catalysed cyclisation 32 1.2.2.6 - Pictet-Spengler and subsequent Strecker reaction 34 1.2.3 The Mitragyna alkaloid mitragynine (86) 35 1.2.3.1 - Synthesis of mitragynine (86) and related compounds 36 1.2.3.2 - First total synthesis of mitragynine (86) 36 1.2.3.3 - Second total synthesis of mitragynine (86) 39 1.2.3.4 - Synthesis of related alkaloids 41 1.2.3.4.1 - Synthesis of (-)-9-methoxymitralactonine (167) 41 1.2.3.4.2 - Synthesis of enantiomer of corynantheidol (183) 43 1.3 Project Aims 44 Chapter 2 - Reactions of phosphorus-centred radicals 2.1 Introduction 46 2.2 Synthesis of 1,7-dienes 48 2.2.1 Synthesis of imines by oxidation 48 2.2.2 Addition of organometallic reagents to imines 49 2.2.3 Addition of organometallic reagents to imine salts 50 2.3 Reaction of phosphorus hydrides 50 2.3.1 Reaction of phosphorus hydrides with 1,7-diene 188 50 2.3.2 Reaction of phosphorus hydrides with a model system 51 2.3.3 Reaction of phosphorus hydrides with test systems 51 2.4 Chemistry of enamines with phosphorus hydrides 53 2.4.1 Preparation of enamines 53 2.4.2 Reactions of enamines with phosphorus hydrides 54 2.5 Preparation and reactions of amide based 1,7-dienes 56 2.6 Conclusions 59 Chapter 3 - Addition Reactions of Silicon-centred Radicals 3.1 Introduction 60 3.2 Reactions of tris(trimethylsilyl)silane 61 3.3 Reactions of alkyl- and aryl-silanes 62 3.3.1 Addition of alkyl- and aryl-silanes at elevated temperature 62 iv 3.3.2 Addition of alkyl- and aryl-silanes at room temperature 64 3.3.3 – Ionic reactions of alkyl- and aryl-silanes 66 3.4 – Reactions of alkoxysilanes 67 3.5 – Reactions of chlorosilanes 67 3.5.1 – Addition of chlorophenylsilane 67 3.5.2 – Addition of trichlorosilane 68 3.6 Conclusion 70 Chapter 4 - Tributyltin hydride mediated cyclisation 4.1 - Synthesis of the allyl-tetrahydroisoquinoline core 72 4.1.1 – Myers approach to an allyl-tetrahydroisoquinoline core 72 4.1.2 – Methylsulfonyl approach to an allyl-tetrahydroisoquinoline core 73 4.1.3 – Phenylsulfonyl approach to an allyl-tetrahydroisoquinoline core 74 4.1.4 – N-Pivaloyl approach to an allyl-tetrahydroisoquinoline core 75 4.1.5 – N-Boc approach to an allyl-tetrahydroisoquinoline core 76 4.2 - Synthesis and reaction of a xanthate or alpha-halo amides 76 4.2.1 - Synthesis of xanthate and alpha-halo amides 77 4.2.2 – Radical reactions of xanthate (294) 79 4.2.3 – Radical reactions of alpha-halo amides (295) and (296) 79 4.3 - Cyclisation of vinyl bromides onto an N-allyl fragment 80 4.3.1 – Synthesis of vinyl bromide (307) 81 4.3.2 – Radical reaction of vinyl bromide (307) 81 4.3.3 – Synthesis of vinyl bromide (317) 83 4.3.4 – Radical reaction of vinyl bromide (307) 84 4.3.5 – Approaches to protoemtinol (88) from ester (318-a) 85 4.4 Formation and reaction of phenylselenides 87 4.4.1 Synthesis of phenylselenides (331) and (332) 87 4.4.2 Radical cyclisation of phenylselenides (331) and (332) 88 4.4.3 Synthesis and cyclisation of phenylselenide (343) 90 4.4.4 Synthesis of an α,β-unsaturated ester with a phenylselenide (349) 92 4.5 Conclusion 93 Chapter 5 - Vinyl bromide approaches to Alangium and Mitragynine alkaloids 5.1 - Approaches to (±)-protoemetinol (88-a) 95 v 5.1.1 – Synthesis and cyclisation of a model vinyl bromide (352) 95 5.1.2 - Synthesis of (±)-des-methyl protoemetinol (342-a) 97 5.1.3 - Synthesis of protoemetinol (88-a) 100 5.1.4 - Conversion of (±)-des-methyl protoemetinol (343-a) into (±)- protoemetinol (88-a) 103 5.1.5 - Alternative conditions for the cyclisation of the vinyl bromides 104 5.2 - Approaches to mitragynine (86) starting from a vinyl bromide 107 5.2.1 - Synthesis of vinyl bromide 395 107 5.2.2 – Radical reactions of vinyl bromide 395 109 5.2.3 –Functionalisation of ester 397 110 5.3 – Conclusion 112 Chapter 6 - Conclusions, Summary and Future Work 6.1 Chapter 2 - Summary, Conclusions and Future Work 114 6.2 Chapter 3 - Summary, Conclusions and Future Work 114 6.3 Chapter 4 – Summary, Conclusions and Future Work 115 6.4 Chapter 5 - Summary, Conclusions and Future Work 117 6.5 Summary of routes to (±)-des-methyl-protoemetinol (342-a) and (±)- protoemetinol (88-a) 120 Chapter 7 - Experimental 7.1 General Experimental 122 7.2 Experimental for chapter 2 124 7.3 Experimental for chapter 3 139 7.4 Experimental for chapter 4 163 7.5 Experimental for chapter 5 201 Chapter 8 – Appendix 226 Appendix - NMRs Appendix - X-ray crystal structure for the dichloromethane salt, 363 Chapter 9 - References 253 vi Acknowledgements Many people have contributed to my years of research at York, all deserve much thanks for their help.