Zhou Muxing, Gridneva Tatiana, Zhang Zhenfeng, He Ende, Liu Yangang, Zhang Wanbin
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.
School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.
Angew Chem Int Ed Engl. 2021 Jan 18;60(3):1641-1645. doi: 10.1002/anie.202012445. Epub 2020 Nov 17.
Utilizing a chiral bicyclic imidazole organocatalyst and adopting a continuous injection process, an alternative route has been developed for the efficient synthesis of chiral phthalidyl ester prodrugs via dynamic kinetic resolution of 3-hydroxyphthalides through enantioselective acylation (up to 99 % ee). The computational studies suggest a general base catalytic mechanism differing from the widely accepted nucleophilic catalytic mechanism. The structure analysis of the key transition states shows that the CH-π interactions and not the previously considered cation/π-π interactions between the catalyst and substrate is the dominant factor giving rise to the observed stereocontrol.
利用手性双环咪唑有机催化剂并采用连续注射工艺，通过对3-羟基苯酞进行对映选择性酰化（对映体过量高达99%）的动态动力学拆分，开发了一种高效合成手性苯酞酯前药的替代路线。计算研究表明，其通用碱催化机制不同于广泛接受的亲核催化机制。关键过渡态的结构分析表明，催化剂与底物之间的CH-π相互作用而非先前认为的阳离子/π-π相互作用是导致观察到的立体控制的主要因素。
