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。

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.