Studies Towards the Formal and Total Syntheses of Ginkgolide Natural Products

This project falls within the EPSRC Synthetic Organic Chemistry research area. Total synthesis is central to chemistry as a whole. By finding new ways to make complex molecules, chemists tackle problems which can have far reaching consequences in fields such as methodology, spectroscopy, structural analysis, and computational chemistry, among others. In particular, the total synthesis of naturally occurring molecules - natural products - allows for the discovery of new drug molecules and the development of medical treatments. For example, Newman and Cragg highlighted in a recent review that since the approval of the first anti-tumour agent in 1946 the majority of clinically approved small molecule anti-cancer agents has been derived from natural products. In this context, the current project will focus on the synthesis of the ginkgolide family of natural products. Extracts from the Ginkgo biloba tree, found in China, have shown promise in the treatment of central nervous system disorders - multiple sclerosis, Parkinson's, Alzheimer's - as well as less severe cognitive ailments; e.g., tinnitus and migraines. It is believed that the ginkgolides, originally isolated in 1932, are key to the therapeutic potential of these extracts. As such, they are a relevant class of molecules and bear investigating. The aim of this project is to complete a novel formal synthesis of ginkgolide B and to investigate the potential for asymmetric syntheses of the remaining ginkgolide natural products. There will be a focus on economy of steps, improving on previously reported syntheses. Structurally, the ginkgolides are highly complex and pose a significant synthetic challenge. The main sources of this complexity are the numerous contiguous stereocentres and the presence of a tertiary-butyl group - a rarity in natural products. Therefore, this project offers the possibility of developing new strategies and methodologies as well as leveraging previously developed reactions in new ways. Finally, the successful synthesis of the ginkgolides will allow the investigation of derivatives as potential pharmaceuticals.