Highly Efficient Desymmetrization of Glutaric Anhydrides

Abstract

Significance: The authors report a highly efficient desymmetrization of glutaric anhydrides by the cinchona-based sulfonamide catalyst 1. The obtained 3-substituted glutaric hemiesters can be easily converted into valuable chiral synthons, such as HMG-CoA reductase inhibitors (statins), baclofen, pregabalin, and paroxetine. Extensive screening of bifunctional cinchona-based catalysts revealed that sulfonamide-derived catalyst 1 showed superior reactivity and enantioselectivity than thiourea-and squaramide-based catalysts.Comment: Organocatalytic enantioselective alcoholysis of meso-anhydrides is well established since the pioneering works by Oda and co-workers (J. Chem. Soc. Chem. Commun. 1985, 1717 and see Review below). However, desymmetrization of 4-substituted glutaric anhydrides suffers from lower enantioselectivity than bi-and tricyclic anhydrides. Herein, a highly enantioselective desymmetrization of glutaric anhydrides is achieved by using catalyst 1 and a silyl-protected 4-hydroxyl glutaric anhydride as a substrate (er = 99:1 with BnOH). The obtained sense of enantioselectivity and other mechanistic insights were elucidated by DFR calculations and X-ray structure analysis.