Amide and peptide synthesis via nickel-catalyzed cross-electrophile coupling

The epimerization-free formation of peptide bonds is essential for the development of peptide therapeutics and pharmaceuticals. Here, we report a versatile amide and peptide synthesis strategy via Ni-catalyzed reductive coupling reactions of carboxylic acids and electrophilic amines. The reaction tolerates a wide variety of functional groups, including secondary amines, esters, halides, silylethers, nitriles, unsaturated bonds, and heterocycles. Notably, this strategy is applicable for peptide synthesis without erosion of enantioselectivity. In particular, phenylglycine, which is very easy to racemize in peptide couplings, is proved to be well tolerated in this reaction. Additionally, the large-scale peptide synthesis and late-stage functionalization of complex bioactive molecules highlight potential practical utility, which should render this method a valuable tool in organic synthesis and drug discovery.