Studies Towards the Formal and Total Syntheses of Ginkgolide Natural Products

该项目属于EPSRC合成有机化学研究领域的福尔斯。全合成是整个化学的核心。通过寻找制造复杂分子的新方法，化学家们解决了可能在方法学、光谱学、结构分析和计算化学等领域产生深远影响的问题。特别是，天然存在的分子-天然产物-的全合成允许发现新的药物分子和开发医学治疗。例如，纽曼和克拉格在最近的综述中强调，自1946年批准第一种抗肿瘤剂以来，大多数临床批准的小分子抗癌剂都来源于天然产物。在这方面，目前的项目将侧重于天然产物银杏内酯家族的合成。在中国发现的银杏树提取物已显示出治疗中枢神经系统疾病-多发性硬化症，帕金森氏症，阿尔茨海默氏症-以及不太严重的认知疾病的前景;例如，耳鸣和偏头痛据信，最初于1932年分离的银杏内酯是这些提取物治疗潜力的关键。因此，它们是一类相关的分子，值得研究。本项目的目的是完成银杏内酯B的新型形式合成，并研究其余银杏内酯天然产物的不对称合成潜力。将重点放在步骤的经济性上，改进以前报告的合成。在结构上，银杏内酯是高度复杂的，并提出了重大的合成挑战。这种复杂性的主要来源是许多连续的立构中心和叔丁基的存在-天然产物中很少见。因此，该项目提供了开发新战略和方法以及以新方式利用以前开发的反应的可能性。最后，银杏内酯的成功合成将允许作为潜在药物的衍生物的研究。

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.