Chiral Primary Amine Catalysis for Asymmetric Mannich Reactions of Aldehydes with Ketimines: Stereoselectivity and Reactivity

Herein we show the application potential of primary amine catalysts in the context of Mannich reactions of aldehydes with ketimines exemplified by isatins-derived ketimines and cyclic trifluoromethyl ketimines. Primary amine catalysts exhibit either unusual stereoselectivity or reactivity, which is not observable with secondary amine catalysts. Moreover, reversal of diastereofacial selectivity between primary and secondary amine catalysts is disclosed. These new reactions provide useful methods for the syntheses of chiral 3-substituted 3-amino-2-oxindoles and dihydroquinazolinones bearing a trifluoromethylated quaternary stereocenter. The synthetic utility of the reactions is demonstrated through the formal synthesis of AG-041R and DPC 083 and the total synthesis of (-)-psychotriasine.