TEMPO-Promoted Thioacid-Amine Coupling for Peptide Synthesis

Abstract

We report a mild and epimerization-free strategy for peptide bond formation based on a TEMPO-promoted oxidative coupling of thiocarboxylic acids with amines. In this protocol, thiocarboxylic acids are selectively oxidized in situ to the corresponding diacyl disulfides, which subsequently undergo efficient aminolysis to furnish di- and tripeptides in good yields. The reaction proceeds under operationally simple conditions, tolerates partial aqueous media, and avoids the use of conventional coupling reagents. A broad range of amino acid substrates is compatible, including those bearing sensitive functional groups such as thioethers, secondary amines, and indole moieties. Notably, no detectable epimerization at the α-stereocenter is observed, highlighting the advantage of this redox-driven approach over traditional peptide coupling methods. Mechanistic investigations combining UV-visible spectroscopy, electronic substituent effect analysis, ESI-MS analysis, and density functional theory (DFT) calculations support a TEMPO-promoted oxidation pathway leading to reactive diacyl disulfide intermediates. Overall, this work expands the synthetic utility of TEMPO-based redox chemistry and provides a practical, chemoselective, and stereochemically robust platform for peptide bond assembly under mild conditions.