Generation of Oxyphosphonium Ions by Photoredox/Cobaloxime Catalysis for Scalable Amide and Peptide Synthesis in...

Peptides are ubiquitous structural units in many therapeutic agents, agrochemicals, and organic materials. However, synthesizing these structures from amino acids typically results in considerable waste, which has led the American Chemical Society (ACS) Green Chemistry Institute (GCI) Pharmaceutical Roundtable to list "general methods for catalytic amide or peptide formation" as a highly desirable areas for sustainable synthetic method development. Here, we present a photocatalytic oxidation-reduction condensation process that involves successive single-electron oxidation of phosphine for the catalytic formation of acyloxyphosphonium ions in the presence of a stoichiometric or catalytic amount of triphenylphosphine (PPh₃). The synthetic utility of the method is demonstrated by its compatibility with all proteinogenic amino acids and its ability to assemble a wide range of oligopeptides, including pharmaceutically relevant targets. Furthermore, the process is compatible with solid-phase peptide synthesis (SPPS), and multigram scale synthesis can be achieved through the implementation of a continuous-flow reactor, showcasing the scalability of this photochemical reaction for further application in both academic and industrial laboratories.