Application of Dual Nickel-Photoredox Catalysis to the Synthesis of Unnatural Amino Acids

Abstract

Non-proteinogenic amino acids represent powerful tools and building blocks in the study and development of new biologically active molecular scaffolds. A metallaphotoredox cross-electrophile coupling is herein applied to the synthesis of unnatural phenylalanine derivatives using aryl and heteroaryl bromides and the widely available natural amino acid (L)-serine as a precursor for the cross-coupling partners. The combination of the tris(trimethylsilyl)silyl radical mediation with photoredox and transition metal catalysis provides mild yet robust conditions for this transformation, efficiently allowing the C\(_{sp}\)\(^{2}\)−C\(_{sp}\)\(^{3}\) bond formation without racemization of the native a-amino stereocenter. Additionally, the potential application of this transformation on a large scale through flow technologies and to the direct functionalization of peptides could open innovative possibilities for the synthesis of biologically active molecular motifs and pharmaceutical targets.