β分泌酶1（BACE1）是生成β-淀粉样蛋白的限速酶，是干扰阿尔茨海默病进程的重要靶点。天然产物Asperterpenes A是一类含有6个手性中心的独特碳骨架的萜类化合物，Asperterpene A和Asperterpene B 对BACE1酶有强的抑制活性，其全合成工作尚未有报道。本项目拟采用不对称α甲基酮的α芳基化及烷基化去芳构化反应（alkylative dearomatization）为关键步骤的合成路线，开展Asperterpene A和Asperterpene B的全合成研究；并在全合成的基础上，合成多个系列骨架修饰的Asperterpene A类似物，初步获得构效关系。本项目不仅有望完成Asperterpene A和Asperterpene B的首次全合成，为Asperterpenes类化合物的全合成提供策略，还有望获得一个结构简单、活性高的BACE 1酶抑制剂候选药物。

β-Secretase1（BACE 1）is a rate-limiting enzyme capable of hydrolyzing β-amyloid precursor protein to amyloid peptides (Aβ), and has been considered to be an attractive therapeutic target for the treatment of Alzheimer’s disease. Asperterpene A is a meroterpenoid with unprecedented carbon skeletons, comprising 6 chiral centers. Asperterpenes A and B displayed significant inhibitory activity against BACE 1 in vitro. However, there is no report on total synthesis of asperterpenes. Synthesis of Asperterpenes A and B has been designed with α-arylation of α-substituted ketone and alkylative dearomatization reaction as key steps. Preliminary structure-activity relationship (SAR) against β-secretase 1 will be established via bioassay. This project may not only accomplish the first total synthesis of natural compounds Asperterpenes A and B, obtain SAR against β-secretase 1, but also identify drug candidate targeting β-secretase 1, and elucidate more information about the target structure for designing and synthesis of drugs to selectively inhibit β-secretase 1.