ew Routes to Indolizidine Alkaloids: The Total Synthesis of (−)-Grandisine B James David Cuthbertson Thesis submitted in partial fulfilment of the requirements for the Degree of Doctor of Philosophy The University of York Department of Chemistry September 2011 Abstract The plant family Elaeocarpaceae has been the source of a plethora of structurally related alkaloids isolated over the last 50 years. This Thesis describes our synthetic approaches to (−)-grandisine B I, a bioactive indolizidine alkaloid isolated from Elaocarpus grandis in 2005. An overview of alkaloids isolated from the family Elaeocarpaceae is provided and preliminary studies into the synthesis of grandisine B I are described (Chapters 1 and 2). Novel routes to bicyclic lactams II and isoquinuclidinone frameworks III have been developed using aqueous ammonia in a one-pot amination/cyclisation sequence (Chapters 3 and 4). The scope of the developed methodology was initially demonstrated with a concise synthesis of the alkaloid (−)-mearsine V. A biomimetic synthesis of (±)- grandisine B I, using the alkaloid grandisine D IV as a synthetic precursor, is then described in Chapter 5. The development of a formic acid mediated alkyne/acetal cyclisation for the synthesis of heterocyclic scaffolds is also reported. The scope and limitations of the methodology are discussed and applications of the methodology in the synthesis of (−)-grandisine B I and structurally related Elaeocarpus alkaloids are described (Chapter 6). I Contents Abstract ............................................................................................................................ I Contents .......................................................................................................................... II List of Figures ............................................................................................................ VIII List of Tables .................................................................................................................. X Acknowledgements ....................................................................................................... XI Declaration ................................................................................................................... XII Chapter 1. Introduction ................................................................................................. 1 1.1 Alkaloids of Elaeocarpus sp. .................................................................................. 1 1.1.1 E. polydactylus ................................................................................................ 1 1.1.2 E. dolichostylis ................................................................................................ 2 1.1.3 E. sphaericus ................................................................................................... 3 1.1.4 E. grandis ........................................................................................................ 4 1.1.5 E. habbemensis ................................................................................................ 5 1.1.6 E. fuscoides ..................................................................................................... 6 1.2 Alkaloids of Peripentadenia mearsii ...................................................................... 6 1.3 Biological Activity .................................................................................................. 8 1.3.1 Opioid Receptor Agonists ............................................................................... 8 1.3.2 Biological Activity ........................................................................................ 10 1.3.3 SAR Studies .................................................................................................. 10 1.4 Grandisine B (15) – Structure Elucidation ........................................................... 11 1.5 Elaeocarpus Alkaloid Biosynthesis ...................................................................... 12 1.5.1 Biosynthesis of Mearsine (27) ...................................................................... 14 1.6 Indolizidine Alkaloids .......................................................................................... 15 1.6.1 Elaeokanine A (57) ....................................................................................... 15 1.6.2 Elaeokanine B (58) ........................................................................................ 19 1.6.3 Indolizidine 209D (83) .................................................................................. 20 II 1.7 Isoquinuclidinones ............................................................................................... 20 1.7.1. Diels-Alder Approaches to Isoquinuclidinones ........................................... 22 1.7.3. Asymmetric Syntheses of Isoquinuclidinones .............................................. 24 1.8 Previous Syntheses of Grandisine Alkaloids ........................................................ 27 1.8.1 Grandisine A (14) .......................................................................................... 27 1.8.2 Grandisine D (17) .......................................................................................... 28 1.8.3 Grandisine B (15) and F (19) ........................................................................ 30 1.9 Aims and Objectives: Retrosynthetic Analysis .................................................... 30 Chapter 2. A Potential Cross-Coupling Approach to Grandisine B (15) ............... 34 2.1 Synthesis of 8-Bromo-1,2,3,5,6,8a-hexahydroindolizidine (74) .......................... 34 2.1.1 Proposed Mechanism for the N-Acyliminium Ion Cyclisation ...................... 35 2.1.2 Challenges of Overman's Route .................................................................... 36 2.1.3 Halogen-Lithium Exchange .......................................................................... 38 2.2 Synthesis of a Model Bicyclic Lactam (154) ........................................................ 39 2.3 Synthesis of a Bicyclic Imidoyl Chloride/Triflate Cross-Coupling Partner ........ 40 2.4 Nitrone Chemistry ................................................................................................ 41 2.4.1 Addition of Organolithium Reagents to Cyclic Nitrones ............................... 42 2.5 Addition of Organolithium Reagents to N-Silylated Lactams .............................. 43 2.6 Addition of Organometallic Reagent to Amides .................................................. 45 2.7 Grignard Addition to Thioimidates ...................................................................... 47 2.8 A Liebeskind-Srogl Cross-Coupling Strategy ...................................................... 48 2.9 Summary ............................................................................................................... 49 Chapter 3. Synthesis of a Functionalised Bicyclic Lactam ....................................... 50 3.1 Introduction .......................................................................................................... 50 3.2 A Nitrile Diels-Alder Approach ........................................................................... 50 3.3 Cordova Diels-Alder Chemistry ........................................................................... 51 3.3.1 PMP Deprotection ......................................................................................... 53 3.4 Oxidation of Isoquinuclidinones .......................................................................... 55 III 3.5 Synthesis of 5-Methylcyclohexenone (87) ............................................................ 58 3.6 An Alternative Strategy for the Synthesis of Isoquinuclidinones ......................... 60 3.6.1 Initial Studies ................................................................................................ 62 3.6.2 Structure Elucidation ..................................................................................... 63 3.6.3 Mechanism of the Amination/Cyclisation Sequence .................................... 64 3.6.4 Scope of the Amination/Cyclisation Sequence ............................................. 65 3.6.5 Synthesis of Bridgehead Substituted Isoquinuclidinones ............................. 68 3.7 Synthesis of N-Substituted Bicyclic Lactams........................................................ 71 3.8 Synthesis of a Thiolactam Cross-Coupling Partner ............................................ 73 3.9 Summary ............................................................................................................... 73 Chapter 4. An Amination/Cyclisation Approach to Isoquinuclidinones ................ 74 4.1 Initial Cyclisation Studies .................................................................................... 74 4.1.2 A Phenyl-Substituted Model Substrate ......................................................... 75 4.1.2 A Cyclohexyl-Substituted Model Substrate .................................................. 77 4.2 Synthesis of Substituted Isoquinuclidinones......................................................... 78 4.2.1 Structure Elucidation ..................................................................................... 79 4.3 Scope of the Amination/Imination Sequence ........................................................ 79 4.4 Bridgehead Substituted Isoquinuclidinones ......................................................... 82 4.5 Attempted