Investigations into novel enantioconvergent reactions and the bioinspired synthesis of pyrroloquinoline alkaloids

Abstract

This thesis describes work towards two discrete projects; Chapter 1: Novel enantioconvergent reactions, and Chapter 2: Bioinspired synthesis of pyrroloquinoline alkaloids.Chapter 1: In asymmetric synthesis, kinetic resolutions are limited to 50% yield and often require costly separation of the enantioenriched product from the remaining starting material. Enantioconvergent reactions overcome this by converting both enantiomers to an enantioenriched product in a maximum 100% yield. To achieve an enantioconvergent reaction, the system level symmetry of the racemate must be broken. There are several conceptual approaches to how this can be done, however they all suffer from limited substrate scope as generally the stereogenic elements must be labile, and the substrate cannot contain multiple stereogenic elements. Stereoretentive enantioconvergent reactions overcome these limitations by incorporating both enantiomers in either an unsymmetrical dimerisation, or through a multicomponent reaction with an unsymmetrical linker.

This thesis details efforts to establish this concept in i) an unsymmetrical dimerisation through the formation of a distinct atropoisomer, via lithium-halogen exchange, and ii) an unsymmetrical dimerisation through a point-to-axial chirality exchange, via palladium-catalysed carbonylation.Chapter 2: The pyrroloquinoline alkaloids, such as martinellic acid and incargranine B, possess an unusual heterocyclic core, first described upon the isolation of the martinella alkaloids in 1995. These “deceptively simple” natural products have attracted considerable interest from the synthetic community due to their potentially useful biological activities, intriguing structures, and proposed biosynthetic origins. The Lawrence group have previously reported biomimetic syntheses of incargranine B and several other related alkaloids. These chemical syntheses mimicked proposed biosynthetic pathways involving oxidative deamination processes, which are mediated by transaminase enzymes. The use of transaminase biocatalysts in chemoenzymatic syntheses is now well-established, but is heavily focused on reductive amination processes. This thesis details efforts to explore the potential of transaminase biocatalysts for oxidative deamination processes in the chemoenzymatic synthesis of the pyrroloquinoline alkaloids, and to develop a biomimetic synthesis of martinellic acid.