Enantioselective enolate protonation: Matching chiral aniline and substrate acidity

A comparison of chiral anilines 1a-f in the asymmetric protonation of enolate 15 shows that the optimum Delta pK(a) value (chiral acid vs protonated enolate) for the highest enantioselectivity is ca. 3 (Table 2). An extension of this concept to amino acid enolates was possible, and le was found to give the best enantioselectivity (85% ee) with the alanine-derived N-lithioenolate 5a (Table 3). Changes in aniline pK(a) due to variation of substituents at the aniline nitrogen were evaluated briefly, but these changes did not show consistent trends in the enantioselectivity vs pK(a).