Ambiguine型吲哚生物碱的不对称全合成研究

Ambiguine吲哚生物碱是一类具有独特结构和多样生物活性的hapalindole吲哚生物碱，受到合成化学家的密切关注。四环ambiguine H和特殊的不含异氰取代的五环成员ambiguine P是仅有的实现全合成的2个家族成员。本项目聚焦于未被攻克的具有家族特色的含异氰取代的五环ambiguine家族成员的高效集约式不对称全合成。拟利用多环吲哚的催化不对称烯丙基去芳构化反应构建吲哚C3位的季碳手性中心，引入首个手性中心。发展仿生的Cope重排/aza-Prins环化策略高效构建多取代六元D环，并精准控制环上4个连续手性中心的立体构型，实现ABDE四环核心骨架的构建。最后采用集约式合成策略预计完成3个家族成员的高效不对称全合成。获得足够的天然产物样品和类似物，为后续生物活性测试和作用机制研究提供物质基础。

Ambiguine indole alkaloids, a subset of hapalindole with intriguing structures and diverse biological activities, have been the focus of synthetic chemists for many years. Tetracyclic ambiguine H and the special pentacyclic ambiguine P without isocyanide substitution were the only two members that have been synthesized, while the representative pentacyclic ambiguines featuring isonirile substitution have not been conquered thus far. This project is focused on the asymmetric total synthesis of three pentacyclic ambiguine members containing isonirile substitution. The catalytic asymmetric allyl dearomatization reaction of polycyclic indoles would be used to construct the quaternary stereogenic center at the C3-position of indole and introduce the first chiral center. A biomimetic Cope rearrangement/aza-Prins cyclization strategy would efficiently construct the cyclohexyl D ring with excellent stereocontrol of the four consecutive stereogenic centers, achieving the ABDE tetracyclic core skeleton. A late-stage collective synthesis strategy is expected to complete the asymmetric total synthesis of the three target molecules and provide enough ambiguines and analogs for the elaborate evaluation of biological potential and related mechanism research.