基于双金属协同催化策略非蛋白质α-氨基酸衍生物的不对称合成研究

本项目旨在研究以价廉易得的天然氨基酸酯衍生醛亚胺为原料，利用双金属协同活化策略发展高效催化体系和新型催化不对称烯丙基化、炔丙基化及氮杂烯丙基化反应。通过两种手性催化剂的合理组合，对参与反应的亲核性金属化亚甲胺叶立德物种与亲电性金属化物种实施相对独立的立体化学控制，实现高阶手性非蛋白质α-氨基酸及其衍生物的立体选择性与结构多样性高效合成，特别是为含两个手性中心非蛋白质α-氨基酸四个光学异构体中任意一个异构体的立体选择性精准构建提供简洁高效的合成方法。利用发展的方法学实现一些具有生理活性和重要药用价值的天然产物及其光学异构体的精准合成，为手性化合物光学异构体的生理活性构效关系评估提供方法学基础，进而为新药筛选提供候选结构；结合催化不对称反应机理的深入研究，探索各种因素对不对称催化反应活性和立体选择性的调控机制，揭示并总结双金属协同催化反应过程中的手性诱导、手性传递与手性放大的本质及规律性。

Enantioenriched nonproteinogenic α-amino acids (α-AAs) skeletons are frequently found in the core structures of active pharmaceutical ingredient and many bioactive natural products, and α,α-disubstituted or α-quaternary α-amino acids have been widely used not only in the design of novel non-natural peptides and proteins with enhanced biological properties due to its stability towards racemization and restricted conformational flexibility, but also employed as enzyme inhibitors themselves. In view of synthetic chemistry, developing efficient methodologies for the stereoselective construction of α,α-disubstituted α-amino acid derivatives, especially precise and stereodivergent synthesis of the full complement of stereoisomers of α-AAs bearing two adjacent stereogenic centers, is of great significance to the evaluation of the structure-activity relationship (SAR) of chiral molecules, new drug discovery and the innovation of the key drug synthesis. This project will focus on utilizing the strategy of synergistic bimetallic activation to develop novel and efficient catalytic systems for the precise construction of enantioenriched nonproteinogenic α-amino acids with multiple stereocenters, high functionality and stereodivergence. The success of this protocol is based on the use of two distinct chiral metal complex catalysts and each is capable of exercising full control over the configuration of the stereogenic center in the corresponding nucleophile and electrophile, independently. The cheap and ready-available natural α-amino acid derived imino esters will be utilized to in situ form the nucleophilic metallated azomethine ylide, and then realize a series of novel asymmetric α-allylic alkylations, α-2-aza-allylic alkylations and propargylic substitution reactions with a variety of in situ-generated electrophilic metal species. Furthermore, the asymmetric synthesis of some biologically important and pharmaceutically useful natural products or its key intermediates will be attempted with thus developed methodologies. Meanwhile, reaction mechanism study will be deeply performed to investigate the steric and electronic effect of the bimetallic chiral complexes on the reactivity and diastereo-/enantioselectivity, and further reveal and summarize the inherent principle of chirality induction, transfer and amplification in synergistic bimetallic asymmetric catalysis.