Diversifying Amino Acids and Peptides via Deaminative Reductive Cross-Couplings Leveraging High-Throughput Experimentation

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.