ArPNO-Catalyzed Acylative Dynamic Kinetic Resolution of 3-Hydroxyphthalides: Access to Enantioenriched Phthalidyl Esters

Org Lett. 2023 Aug 4;25(30):5585-5590. doi: 10.1021/acs.orglett.3c01915. Epub 2023 Jul 20.

Abstract

A chiral 4-aryl-pyridine-N-oxide nucleophilic organocatalyst was used to synthesize chiral phthalidyl ester prodrugs by the acylative dynamic kinetic resolution process. By using the 3,5-dimethylphenyl-derived ArPNO catalyst, the phthalidyl esters were obtained in up to 97% yield with 97% ee at room temperature. Two phthalidyl esters of prodrugs, talosalate and talmetacin, were generated. By control experiments and density functional theory calculations, an acyl transfer mechanism was proposed.