A deaminative reductive coupling of amino acid pyridinium salts with aryl bromides has been developed to enable efficient synthesis of noncanonical amino acids and diversification of peptides. This method transforms natural, commercially available lysine, ornithine, diaminobutanoic acid, and diaminopropanoic acid to aryl alanines and homologated derivatives with varying chain lengths. Attractive features include ability to transverse scales, tolerance of pharma-relevant (hetero)aryls and biorthogonal functional groups, and the applicability beyond monomeric amino acids to short and macrocyclic peptide substrates. The success of this work relied on high-throughput experimentation to identify complementary reaction conditions that proved critical for achieving the coupling of a broad scope of aryl bromides with a range of amino acid and peptide substrates including macrocyclic peptides.

A deaminative reductive coupling of amino acid pyridinium salts with aryl bromides has been developed to enable efficient synthesis of noncanonical amino acids and diversification of peptides. This method transforms natural, commercially available lysine, ornithine, diaminobutanoic acid (DAB), and diaminopropanoic acid (DAP) to aryl alanines and homologated derivatives with varying chain lengths. Attractive features include scalability, tolerance of pharma-relevant (hetero)aryls and functional groups, applicability to both monomeric amino acid and short peptide substrates, and compatibility with biorthogonal handles useful for chemical biology. Furthermore, these cross-couplings can be conducted in microscale and nanoscale and are amenable to solid-phase peptide synthesis platforms. The success of this work relied on an academic/industry collaboration and high-throughput experimentation to identify complementary conditions that proved critical for achieving broad scope of aryl bromides and pyridinium substrates.