Solvent–Less Environmentally Benign Amino Ester, Amide, and Peptide Synthesis Enabled by Resonant Acoustic Mixing

The demand for sustainable methods for peptide synthesis grows imperatively with their escalating use in therapeutic and biomedical applications. The cornerstone technology of solid-phase peptide synthesis has unsustainable environmental impact due to high process mass intensity and reliance on hazardous solvents. The reported study presents pioneering use of a resonant acoustic mixer (RAM) for sustainable peptide bond formation at elevated concentration with minimal solvent waste. Effective amide and ester bond formation were achieved rapidly under mild conditions using the RAM in “green” solvents such as ethyl acetate and 1,2-dimethoxyethane (DME), with minimal levels of epimerization. Peptide coupling was systematically studied under various conditions, indicating influences of solvent viscosity and base solubility on conversion efficiency. Comparisons with conventional and ultrasonic stirring confirmed the superiority of resonant acoustic mixing at and above 60 g0 for promoting higher conversions. Assessment in different peptide model systems prone to racemization and fragment couplings confirmed comparable conversion and minimal epimerization to that observed using solution-phase and mechanochemical methods. The RAM approach proved to be robust and scalable providing an environmentally friendly platform for the synthesis of amino esters, amides, and peptides, thereby presenting novel opportunities for the sustainable production of peptide-based therapeutics.