设计和构建具有重要生物活性的二萜类天然产物在合成化学中极具挑战。本项目以具有抗菌活性的天然产物——截短侧耳素作为目标分子，对其进行全合成研究并结合其与靶点的共单晶结构展开构效关系的研究。当前科学家对此化合物的活性研究主要基于对C14侧链的半合成修饰，未涉及到三环核心骨架的修饰，考虑到此种策略固有的局限性，我们希望通过全合成手段完成对截短侧耳素的合成。其中的关键步骤包括：(1) 手性二级胺催化的不对称羟基化反应；(2) 过渡金属催化的1,4-Michael加成构建具有挑战性的季碳中心；(3) 光促进的DeMayo反应，通过[2+2]/逆Aldol扩环反应构建6/8桥环体系； (4) SmI2促进的还原偶联反应。在完成截短侧耳素的全合成基础上，我们拟对截短侧耳素结构进行修饰和改造来提高生物活性和克服耐药性。

The design and construction of complex diterpenoids natural products with significant biological activities are challenging in synthetic chemistry. In this proposal, a total synthetic plan is proposed toward pleuromutilin, which shows excellent antibacterial activity. At the same time, the structure-activity relationship between pleuromutilin and target will be studied based on the co-crystal structure. So far, semi-synthetic modification on C14 side chain is the main strategy for the bioactivity study, which does not diversify the tricyclic core skeleton of the pleuromutilin. Considering the inherent limitations of the semi-synthetic strategy, a total synthetic strategy is designed toward pleuromutilin. The key steps include :(1) asymmetric hydroxylation catalyzed by chiral secondary amines; (2) 1, 4-Michael addition catalyzed by transition metal to construct challenging quaternary carbon center; (3) the light-induced DeMayo reaction to forge the bridged 6/8 ring system via [2+2]/ retro Aldol ring expansion process; (4) reductive coupling reaction promoted by SmI2 to complete the heavy atom skeleton of the pleuromutilin. After completion of this natural product, further modification on pleuromutilin will be developed to improve the bioactivity and overcome the resistance.