中药五味子活性成分降三萜类天然产物Propindilactones的仿生合成

With the rapid development of new organic synthetic strategies and methodologies, organic synthetic chemistry has made remarkable progress on the chemical synthesis of complex natural products. However, this process still can’t provide a series of natural products and their derivatives in large diversities and quantities for the new drug research and development. In this regard, it’s still a significant challenge for synthetic organic chemists to develop an efficient synthesis of natural products to meet the demand of providing enough samples for the new drug development. Propindilactones, isolated from Chinese herbal medicine Schisandra, are a family of nortriterpenoid natural products with unique chemical structures and important anti-HIV and anti-HBV activities. In order to elucidate the mode of action of Schisandra and develop new drugs, it’s of great significance to intensively study the structure-activity relationship of this type of natural products. This project is designed to develop efficient and practical synthetic strategies and methods for the collective synthesis of nortriterpenoid natural products Propindilactones and their derivatives, in order to provide enough samples (both in diversity and quantity) for the biological investigation of this family of natural products. The key scientific problems that would be dealt with in this project include the selective C-H bond functionalization of complex molecules, C-C bond reorganization and cyclopropane ring opening, etc. In addition, this project is aimed to provide a fruitful investigation on the challenging task, i.e. efficient and collective syntheses of complex natural products.

日新月异的有机合成新策略和方法使复杂天然产物的化学合成得到显著发展，但是目前它仍然无法满足新药研发对天然产物及其类似物种类及量的需求，如何实现天然产物高效合成以满足新药研发对样品的需求仍然是有机合成化学家所面临的重大挑战任务之一。天然产物Propindilactones是存在于中药五味子中一类结构独特而复杂的降三萜化合物，具有抗艾滋和乙肝病毒等重要生物活性，深入研究此类天然产物的构效关系对于阐明中药五味子的治病原理和发展新药具有重要意义。针对中药五味子生物学研究对降三萜类天然产物Propindilactones及其类似物种类及量的需求，本申请项目旨在对复杂分子选择性C-H键官能化、C-C键重组和环丙烷开环等基本科学问题深入研究基础上，发展高效实用的降三萜类天然产物Propindilactones及其类似物的集成合成策略和方法，为解决复杂天然产物高效集成合成挑战性任务做出有成效的探索。

天然产物Propindilactones是存在于中药五味子中一类结构独特而复杂的降三萜化合物，具有抗艾滋和乙肝病毒等重要生物活性，深入研究此类天然产物的构效关系对于阐明中药五味子的治病原理和发展新药具有重要意义。针对中药五味子生物学研究对降三萜类天然产物Propindilactones及其类似物种类及量的需求，本项目旨在对复杂分子选择性C-H键官能化和C-C键重组等基本科学问题深入研究基础上，发展高效实用的降三萜类天然产物Propindilactones及其类似物的合成策略和方法，为解决复杂天然产物高效合成这一挑战性任务做出有成效的探索。. 本项目从剑麻皂甙元的降解物甾体内酯出发，以20步反应实现了五味子降三萜天然产物propindilactone G的仿生合成。甾体内酯首先通过Breslow和Suárez两次远程自由基C-H官能团化反应实现了C9和C19位的选择性氧化，得到关键的C19-OH中间体。随后我们利用Wagner-Meerwein重排反应得到了B环扩环为七元环的中间体。由于新生成的C10-叔醇的手性与天然产物中的相反，我们经过Mukaiyama反应在C9位引入了一个过氧硅基官能团，进而由过氧参与的分子内环化反应实现了C10-叔醇手性中心的翻转。在得到七元不饱和内酯中间体后，我们通过仿生的转移酯化/氧杂-Michael加成串联反应一步构建了天然产物5/5/7/6/5核心骨架结构，进而引入丁烯酸内酯侧链完成了天然产物propindilactone G的合成。该项目的成功实施为天然产物合成中两个核心的科学问题，即官能团的选择性引入和骨架的可控重排提供了新方法，为天然产物的精准合成提供了新思路。作为该家族天然产物的首次仿生合成，该合成工作也为这类天然产物的生源合成假设提供了实验支持。