截短侧耳素Pleuromutilin及其类似物的全合成及生物活性研究

Antibiotic resistance has become a global threat to human health, thus it is in urgent demand to develop new antibiotics that is not easy to induce drug resistance. Pleuromutilin and its analogues have attracted widespread attention due to their unique tricyclic structure and novel antibacterial mechanism. However, efficient synthetic route toward them still remains a great challenge. This project is aimed to access (+)-pleuromutilin and (+)-12-epi-pleuromutilin divergently and efficiently by developing a general synthetic route. The critical synthetic strategies include constructing the common tricyclic skeleton by using Ueno-Stork radical cyclization, intramolecular carbonyl-olefin metathesis, ring-closing metathesis and epoxide opening reactions, and introducing the C12 chiral center by face-selective Michael addition. Based on the chemical synthesis, a series of structure-activity relationship studies will be carried out to pave the way to new antibiotics discovery.

抗生素耐药性已经成为危害人类健康的全球性问题，研发不易诱发耐药性的新型抗生素刻不容缓。截短侧耳素pleuromutilin及其类似物以其独特三环结构和新颖的抗菌作用机制引起了广泛关注，然而如何实现其高效的合成仍然是亟待解决的问题。本项目拟发展一条通用的合成路线，多样性地实现(+)-pleuromutilin和 (+)-12-epi-pleuromutilin的高效全合成。合成的关键策略包括通过Ueno-Stork自由基环化反应，分子内羰基烯烃复分解反应，关环烯烃复分解反应，环氧开环反应等关键步骤构建其三环核心骨架以及通过面选择性Michael加成反应引入目标分子C12位手性中心。随后以此为基础开展构效关系研究，为新型抗生素药物的研发奠定重要基础。

截短侧耳素是具有抗革兰氏阳性菌的二萜类天然产物。由于人类当前面临日益严峻的抗生素耐药性危机，研究新型的抗生素迫在眉睫。过去三年中，在本项目的支持下，我们实验室开展了对截短侧耳素的全合成研究，构建了其核心的三环骨架，后续仅需对骨架进行修饰即可得到目标分子。同时，我们实现了相关的二萜类天然产物pharbinilic acid的首次全合成。并结合全合成中的问题，我们发展了多种有用的有机合成方法，为全合成的进行提供了重要支撑。本项目的研究成果将为相关天然产物的进一步生物活性研究奠定重要基础，为新药的开发提供新的思路。