Enantioselective Alcoholysis of meso-Glutaric Anhydrides Catalyzed by Cinchona-Based Sulfonamide Catalysts

The bifunctional Cinchona-based sulfonamide catalysts showed the highest levels of enantioselectivity reported to date in the alcoholytic desymmetrization of meso-glutaric anhydrides. Density functional theory (DFT) computational studies provide detailed insight into the observed sense of enantioselectivity. Moreover, detailed experimental studies and single crystal X-ray analysis confirmed that these bifunctional organocatalysts 3 do not form H-bonded self-aggregates in both solution and solid state. The synthetic utility of this methodology was also demonstrated in the synthesis of pharmaceutically important g-amino acids, such as (S)-pregabalin. Of the many asymmetric syntheses of enantiomerically pure (S)-pregabalin reported to date, our synthesis requires the least number of and the simplest steps.