Radical Approaches to Alangium and Mitragyna Alkaloids

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.

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.

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.

Chapter 5, which builds on previous work within Chapter 4, discusses the cyclisation of vinyl bromides bearing an a,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).