Stereoretentive enantioconvergent multicomponent reactions and total synthesis of (±)-ulodione A

Abstract

This thesis describes the work of two discrete projects. Chapters 2 to 3 detail the development of new enantioconvergent methodology - stereoretentive enantioconvergent multicomponent reactions. Chapters 4 to 5 detail the biomimetic total synthesis of the natural product ulodione A.

CHAPTERS 2 TO 3: When using racemic substrates in asymmetric synthesis, a yield of 100% can only be achieved through the use of enantioconvergent reactions (cf. kinetic resolutions (KR), maximum 50% yield). There are three established approaches for achieving enantioconvergency; stereomutation (e.g., dynamic kinetic resolutions), stereoablation and stereodifferentiation. These three concepts all have their own particular advantages. However, they all suffer from common limitations in their substrate scope. The stereogenic elements of the starting material must be labile towards mutation, ablation, or inversion. Additionally, substrates containing multiple stereogenic elements are generally not amenable to any of these established approaches.

This thesis describes our investigations into a new stereoretentive approach to enantioconvergent reactions. Stereoretention in enantioconvergent reactions is possible if the two enantiomers of a racemate are selectively coupled together to form a non-meso product. Uniquely, racemic substrates with robust and/or multiple stereogenic elements will be compatible with these enantioconvergent reactions. Our efforts to develop an enantioconvergent domino nucleophilic acyl substitution/SN2 reaction sequence are described. Chapter 2 focuses on the development of new kinetic resolution methodology of secondary alcohols and the application of this methodology to perform stereoretentive reactions. Chapter 3 focuses on the development of new kinetic resolution methodology of secondary amines and the application of this methodology to perform stereoretentive reactions.

CHAPTER 4 – 5: The racemic natural product (±)-ulodione A was isolated by Lou and co-workers from the endolichenic fungus Ulospora bilgramii, alongside ulodione B. (±)-Ulodione A is a selective butyrylcholinesterase (BuChE) inhibitor. BuChE inhibitors pose good targets for the development of Alzherimer’s therapeutics. The biological activity, along with the intriguing biosynthetic pathway proposed by Lou and co-workers made ulodione A an interesting target for a bioinspired total synthesis. This thesis describes our successful synthesis of (±)-ulodione A and our investigations into the biosynthetic pathway. During the synthesis, a bioinspired dehydrative/Diels–Alder domino reaction was developed using T3P as a phosphorylating reagent. Two, new, anticipated natural products (±)- ulodione C and D were also synthesised and characterised. The synthesis was achieved in two steps from commercially available starting material, with a 48% yield overall improving the only previous total synthesis of 9 steps with a 5 – 6% yield.