Chiral Bicyclic Imidazole-Catalyzed Acylative Dynamic Kinetic Resolution for the Synthesis of Chiral Phthalidyl Esters

Muxing Zhou; Tatiana Gridneva; Zhenfeng Zhang; Ende He; Yangang Liu; Wanbin Zhang

doi:10.1002/anie.202012445

Chiral Bicyclic Imidazole-Catalyzed Acylative Dynamic Kinetic Resolution for the Synthesis of Chiral Phthalidyl Esters

Angew Chem Int Ed Engl. 2021 Jan 18;60(3):1641-1645. doi: 10.1002/anie.202012445. Epub 2020 Nov 17.

Authors

Muxing Zhou¹, Tatiana Gridneva², Zhenfeng Zhang¹, Ende He¹, Yangang Liu¹, Wanbin Zhang^{1

2}

Affiliations

¹ Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.
² School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.

PMID: 33009704
DOI: 10.1002/anie.202012445

Abstract

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.

Keywords: bicyclic imidazole; dynamic kinetic resolution; enantioselective acylation; organocatalyst; phthalidyl ester prodrugs.

Publication types

Research Support, Non-U.S. Gov't