基于酶催化氧化[3+2]环加成反应的高氧化α-CPA天然产物的发散性合成

α-环匹阿尼酸（α-cyclopiazonic acid，α-CPA）是1968年从青霉菌Penicillium cyclopium培养液中分离得到的吲哚生物碱。它是一种强效的神经毒素，植物生长素拮抗剂，也是为数不多的纳摩尔级肌质网钙泵（SERCA）抑制剂。受限于复杂的笼状骨架和连续多个手性中心，目前还未有立体专一性合成高氧化态α-CPA的文献报道。本项目将采用酶催化的不对称氧化[3+2]环加成反应，解决α-CPA天然产物多环骨架立体选择性构建难题。主要研究内容包括：1. 环化前体β-CPA的快速大量制备。2. 氧化[3+2]环化酶CpaO体外催化功能的验证以及酶学性质考察。3. 高氧化态α-CPA天然产物speradines和aspergillines的化学酶法合成。本项目可望得到一条10步内规模化合成高氧化态α-CPA天然产物的路线，为以α-CPA作为先导结构的相关药物研发打下坚实的物质基础。

α-Cyclopiazonic acid (α-CPA), a 3,4-fused polycyclic indole alkaloid firstly isolated from the fungus Penicillium cyclopium in 1968, is a potent mycotoxin and nanomolar SERCA inhibitor. Attracted by the caged scaffold and intriguing biological activities, scientists have made a lot of efforts on the synthesis, however, by now no enantioselective total synthesis has been reported due to the complex and polyhydroxylated architecture. In this project, we would like to take advantage of the CpaO, a FAD monooxygenase that catalyzes the oxidative [3+2] cycloaddition in the α-CPA biosynthesis to enatioselectively construct the α-CPA scaffold. The research is inculding: 1. Rapid synthesis of β-CPA, the precursor of oxidative [3+2] cycloaddition; 2. Characterization, engeneering of CpaO and process optimization for large-scale in vitro preparation; 3. Divergent synthesis of polyhydroxylated α-CPAs. We are expecting to develop a robust and scalable chemoenzymatic approach within 10 steps and lay a good foundation for further drug discovery.