Copper-Catalyzed Enantioselective Henry Reactions of α-Keto Esters:  An Easy Entry to Optically Active β-Nitro-α-hydroxy Esters and β-Amino-α-hydroxy Esters

Abstract

The catalytic enantioselective Henry reaction of alpha-keto esters with nitromethane has been developed. The reaction conditions have been optimized by the screening of different chiral Lewis acids, solvents, and bases, and it was found that the copper(II)-tert-butyl bisoxazoline complex in combination with triethylamine catalyzed a highly enantioselective reaction giving optically active beta-nitro-alpha-hydroxy esters in high yields and with excellent enantiomeric excesses. The scope of the reaction is demonstrated by the reaction of a variety of different alpha-keto esters. The catalytic enantioselective Henry reaction of beta,gamma-unsaturated-alpha-keto esters proceeds as a 1,2-addition reaction exclusively, in contrast to the uncatalyzed reaction where both the 1,2- and 1,4-addition products are formed. It is demonstrated that the beta-nitro-alpha-hydroxy esters can be converted into, e.g., Boc-protected beta-amino-alpha-hydroxy esters in high yields and without loss of optical purity. The mechanism for the reaction is discussed, and it is postulated that both the alpha-keto ester and nitromethane/nitronate is coordinated to the metal center during the reaction course.