A practical approach for oligopeptide synthesis via synergistic photoredox, cobaloxime and organophosphorus triple catalysis

Abstract

Peptides are ubiquitous structural units in many therapeutic agents, agrochemicals and organic materials. However, the construction of these structures from amino acids typically produces unacceptable amounts of waste, which has led the ACS GCI Roundtable to list “general methods for catalytic amide or peptide formation” as one of the most desirable areas for sustainable synthetic method development. Here we show that peptides can be assembled via synergistic photoredox, cobaloxime, and organophosphorus triple catalysis. The catalytic oxidation–reduction condensation process involves successive single-electron oxidation of phosphine for the catalytic formation of acyloxyphosphonium ions in the presence of a substoichiometric amount of PPh₃ when TMDS was employed as a terminal reductant. The synthetic utility of the method is highlighted by its compatibility with all proteinogenic amino acids and by the assembly of a wide range of oligopeptides including pharmaceutically relevant targets. Furthermore, the process is operational with solid-phase peptide synthesis (SPPS) and multigram scale synthesis can be achieved through the implementation of a continuous-flow reactor, which demonstrated the scalability of this photochemical reaction for further application in both academic and industrial laboratories.