Desymmetrizing 4-Substituted Cyclohexanones via Asymmetric Aldol Reaction

Significance

Herein, the authors report an asymmetric desymmetrization (ADS) of prochiral 4-substituted cyclohexanones via a proline amide catalyzed direct aldol reaction. In the reaction of 4-methyl cyclohexanone, the resulting aldol products with three stereogenic centers are obtained in moderate to good yields with excellent diastereo- (dr from 92:8 to >99:1) and high enantioselectivities (up to er >99.5:0.5). As aldehyde component, mainly electron-deficient aromatic aldehydes have been employed. The generality of the method could also be shown by varying the 4-substituent of the cyclohexanone. Synthetic application of the desymmetrization process has been illustrated by using the aldol products in subsequent transformations, e.g. Baeyer-Villiger reaction, with no loss of enantioselectivity.