Organocatalytic Desymmetric Carbon-Carbon Bond Cleavage of Unstrained Cyclohexanones.

Enantioselective skeletal editing of unstrained cyclohexanones via C-C bond cleavage remains a major synthetic challenge. Herein, we report a chiral enamine-catalyzed desymmetrizing Dieckmann condensation of prochiral cyclohexanones to deliver enantioenriched γ-lactams and γ-amino ketones. Using a cinchona-derived amine catalyst and K2CO3, aprotic dichloroethane furnishes γ-lactams, whereas the addition of methanol as a nucleophile affords γ-amino ketones. Mechanistic studies reveal that reversible enamine formation is nonenantiodetermining and that C-C bond cleavage is both rate-limiting and enantiodetermining. This method provides access to valuable chiral building blocks, including dipeptides and a key intermediate for the synthesis of pyrrolam A.