Chiral Bicyclic Imidazole-Catalyzed Acylative Dynamic Kinetic Resolution For The Synthesis Of Chiral Phthalidyl Esters

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-pi interactions and not the previously considered cation/pi-pi interactions between the catalyst and substrate is the dominant factor giving rise to the observed stereocontrol.