Asymmetric Michael Addition of α-Substituted β-Keto Amides

Significance

Rodriguez, Constantieux and coworkers report the enantioselective organocatalytic Michael addition of α-substituted β-keto amides to enones leading to all-carbon quaternary stereocenters. The reaction is catalyzed by a bifunctional amino-thiourea (A). In the proposed transition state the enolate resulting from α-deprotonation of the β-keto amide is stabilized by hydrogen bonding to the thiourea scaffold, while the ammonium form of the catalyst’s amine binds to the amide oxygen. These interactions block the si-face of the enolate leading to Michael addition via the re-face. When acrolein was used as electrophile spontaneous spiro-hemiacetalization was observed. After oxidation the corresponding spiro-imide was obtained with high enantioselectivity.