Oxidative Couplings of <i>N</i>-Aryl Peptides in Organic Solvent: Preventing Amino Acid Side Chain Loss

We report conditions for the oxidative coupling of <i>N</i>-aryl peptides with α-nucleophiles in organic solvents, increasing side chain diversity at the site of ligation. While some <i>N</i>-(<i>p</i>-Me₂N-Ph)-amino acids were found to be unstable in buffer (e.g., Ser, Trp, and Tyr), stable ketoxime linkages were obtained when <i>N</i>-(<i>p</i>-MeO-Ph)-peptides were heated in organic solvents. Such divergent reactivity provides interesting mechanistic insight into oxidative couplings of <i>N</i>-aryl peptides and significantly expands the scope of accessible amino acids at the site of oxime ligation.