The Direct Catalytic Asymmetric Three-Component Mannich Reaction

The Mannich reaction is enormously useful for the construction of nitrogenous molecules.¹ In this transformation, three components, a ketone, an aldehyde, and an amine, react to form a β-amino-ketone. The increasing popularity of the Mannich reaction has been fueled by the ubiquitous nature of nitrogen in drugs and natural products as well as by the potential of this multicomponent reaction to generate diversity. Both direct variants with unmodified ketone donors and indirect variants utilizing preformed enolate equivalents have been described.¹ In addition, the imine intermediate may be preformed or its amine and aldehyde precursors used directly (eq 1).