Late-Stage Peptide Nitroarylation: Stereoelectronic Tuning and Molecular Recognition

Aromatic amino acids lie at the center of protein structure and function. The large size, hydrophobic character, and electrostatic pi interactions of the aromatic amino acids found in proteins–phenylalanine, tyrosine, and tryptophan–provide substantial energetic driving forces for protein folding and interactions. Beyond these three, non-canonical aromatic amino acids are increasingly popular in peptide drug and materials discovery; however, these efforts are critically dependent on expensive amino acid building blocks. As such, there is a need for new approaches to generate libraries of stereoelectronically diverse non-canonical aromatic amino acids from inexpensive building blocks. Here we describe such an approach using nitroarylation of short, nucleophilic side-chains with o-fluoronitroarenes to efficiently produce dozens of nitroarylated peptides from shared peptide intermediates. This approach is broadly compatible with solid-phase peptide synthesis, including in clinically relevant peptides. Peptides bearing nitroaryl side-chains can be specifically detected via their near UV/visible absorption and are efficiently recognized as protease substrates. Chemoselective nitro reduction doubles the accessible chemical space to include electron-rich anilines. Access to dozens of stereoelectronically diverse aromatic amino acids from shared peptide intermediates permits rapid peptide library synthesis for structure-function studies, including peptide drug and materials discovery.