Solvent-less environmentally benign amino ester, amide, and peptide synthesis enabled by resonant acoustic mixing

Abstract

The demand for sustainable methods for peptide synthesis is growing imperatively with their escalating use in therapeutic and biomedical applications. The cornerstone technology of solid-phase peptide synthesis has an unsustainable environmental impact due to its 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 liquid waste. Effective amide and ester bond formation was 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 the influences of liquid viscosity and base solubility on conversion efficiency. A preliminary comparison with conventional and ultrasonic stirring methods suggested that better conversions were obtained using the RAM at and above 60 g₀. 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.