Green and Sustainable Solvents for Solid-Phase Peptoid Synthesis

Peptoids are a class of sequence-controlledpolymers that providea versatile platform for the design of bioinspired materials. Solid-phasesynthetic methods offer absolute control over the polypeptoid sequenceand have been optimized to improve reaction efficiency and versatility.However, these solid-phase strategies rely on the use of reprotoxicand restricted solvents, N,N-dimethylformamide(DMF) and N-methyl-2-pyrrolidone (NMP), resultingin significant hazardous solvent consumption and waste generation.Here, we report the solid-phase synthesis of peptoids with completeelimination of DMF and NMP and their replacement with greener solventsand binary mixtures to minimize the environmental impact and improvethe sustainability of peptoid synthesis. We investigate the resinswelling performance of the green solvents (gamma-valerolactone, dimethylsulfoxide, ethyl acetate, and binary mixtures) and show that the purityprofile and yield of the final peptoids are not adversely affectedwhen compared to those synthesized in traditional solid-phase solvents.Furthermore, we adapt these greener methods for use in automated synthesizersfor the synthesis of peptoids with different sequences and long chainlengths. The replacement of hazardous solvents in solid-phase peptoidsynthesis represents an advancement in the sustainability of peptoidresearch, which could improve the translation of peptoids from academiclabs to industry. Thiswork presents the successful replacement of hazardousand restricted solvents, N,N-dimethylformamide(DMF) and N-methyl-2-pyrrolidone (NMP), with greenand sustainable solvents for the synthesis of polypeptoids.