Catalytic enantioselective Mannich-type reactions of ketoimines

The first example of catalytic enantioselective Mannich-type reactions of simple ketoimines is described. The optimized conditions for aromatic ketoimines include the use of CuOAc-DTBMSEGPHOS as the catalyst (10 mol %) and (EtO)(2)Si(OAc)(2) as the trapping reagent (1 equiv) of the intermediate copper amide (generated via the addition of a copper enolate to the imine). The trapping reagent significantly facilitated the catalyst turnover. Excellent enantioselectivity was produced from a range of aromatic ketoimines, including heteroaromatic and ethyl-substituted ketoimines. The optimized conditions for aliphatic ketoimines include the use of CuOAc-4-Bu-t-cyclohexyl-DuPHOS as the catalyst and (EtO)(3)SiF as the trapping reagent. When aliphatic substrates were used, the enantioselectivity was in the 77-81% ee range. The products were converted to , beta beta-disubstituted amino acids, which are a very important class of chiral building blocks for natural product synthesis, pharmaceuticals, and conformationally regulated artificial proteins.