Chiral Aldehyde Catalysis Enables Direct Asymmetric Substitution Reaction of N-Unprotected Amino Acids with Halohydrocarbons

The direct catalytic hydrocarbylation of readily available amino acids with halohydrocarbons is one of the most straightforward methods leading to disubstituted non-proteinogenic amino acid compounds. However, all the re-ported methodologies depend on N-protected amino acids as starting materials. Herein, we report on three highly efficient aldehyde-catalyzed direct hydrocarbylations of N-unprotected amino acid esters with aryl-, allyl-, and benzyl halides. By promoting a simple chiral BINOL-aldehyde catalyst or combining catalysts of a chiral aldehyde and Lewis acid ZnCl2, the asymmetric arylation, allylation, and benzylation of amino acid esters with the corresponding halohydrocarbons proceed smoothly, producing disubstituted amino acids in moderate-to-high yields and good-to-excellent enantioselectivities. The asymmetric arylation reaction can be applied in the formal synthesis of the clinical candidate compound (+)-AG-041R. Based on the results given by control experiments, three reaction models are proposed to illustrate the stereoselective-control outcomes.