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−DTBM−SEGPHOS 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- t Bu−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 β,β-disubstituted amino acids, which are a very important class of chiral building blocks for natural product synthesis, pharmaceuticals, and conformationally regulated artificial proteins.