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Studies towards the enantioselective synthesis of aspidosperma natural products
thesisposted on 15.02.2017, 23:35 by Gartshore, Christopher
The indole alkaloid (–)-aspidophytine was isolated from Haplophyton cimicidium, a plant traditionally known throughout Mexico for its insecticidal properties. The structural complexity of (–)-aspidophytine, characterized by the presence of a bridging lactone and unsaturation in the C ring appended to the characteristic aspidosperma [22.214.171.124.5] ABCDE ring system, has made it an appealing target for total synthesis. This thesis details studies focused on the development of new chemical reactions, and strategies, applicable to the enantioselective synthesis of aspidosperma alkaloids, in particular (–)-aspidophytine. The first chapter provides an introduction to the natural product (–)-aspidophytine and its parent compound (+)-haplophytine, detailing previous synthetic approaches, and the specific challenges expected in realising this goal. The latter section describes the development of new approaches suited to the synthesis of (–)-aspidophytine. Chapter two introduces the application of transition metal/nitroxide based oxidation reactions for the kinetic resolution and desymmetrisation of alcohols. The chapter then details the synthesis and application of a range of chiral racemic bi-functional nitroxide catalysts for the oxidation of activated alcohols. The employment of these catalysts to the synthesis of a range of aldehydes is outlined and efforts towards the development of enantioselective variant are discussed. The third chapter of this thesis details the development of a palladium catalyzed enantioselective decarboxylative allylation reaction of heterocycles bearing the indolone motif. The reaction provided an expedient approach to the synthesis of enantioenriched indolecontaining heterocycles with good yields and high levels of enantioinduction achieved. The scope of this reaction was examined with the synthesis of a range of functionalised carbazolones and indolones achieved. Having successful assembled a range of enantioenriched carbazolones, chapter four discusses the derivatisation of these substrates towards the synthesis of aspidosperma natural products. Challenges encountered when attempting to construct the aspidosperma tetracyclic core are detailed, specifically, formation of the D-ring and diastereoselective reduction of the resultant cyclic imine are outlined. In addition, manipulation of the allyl functionality is outlined culminating in the formal synthesis of (–)-aspidophytine. Chapter five of this thesis describes a related class of compounds belonging to the kopsia family of alkaloids. This chapter gives a brief introduction to kopsia alkaloids, specifically the recently discovered (+)-kopsihainanine A and B, then details efforts towards the synthesis of these compounds from the enantioenriched carbazolones introduced in chapter 3. The chapter concludes by outlining the first enantioselective formal synthesis of (+)-kopsihainanine A. Finally, the sixth chapter contains experimental procedures utilised within this project and the spectroscopic data derived from the compounds introduced in the preceding chapters.