Green solvent mixture for ultrasound-assisted solid-phase peptide synthesis: a fast and versatile method and its applications in flow and natural product synthesis

Peptides and depsipeptides play a significant role in diverse fields. Solid-phase peptide synthesis (SPPS) is the most renowned protocol for peptide production and can be coordinated with several process intensification techniques such as microwave, ultrasound, and continuous-flow. Until recently, most SPPS was carried out in N , N -dimethylformamide (DMF). However, the use of DMF has been restricted in the European Union since December 2023. Here we introduce a versatile N -formylmorpholine (NFM)/anisole (An) 1 : 1 solvent mixture that meets all green solvent criteria for SPPS. This innovation enables the first green ultrasound-assisted SPPS (US-GSPPS) and uses OxymaB to avoid hazardous benzotriazole-based compounds or OxymaPure coupling additives. Broad feasibility is demonstrated by successful synthesis of challenging peptides and natural products through on-resin esterification and solution/on-resin macrocyclization under ultrasound in NFM/An. Additionally, this mixture also functions as the first green solvent for continuous-flow solid-phase protocols. A green binary solvent mixture for ultrasound-assisted SPPS, combined with safe coupling reagents, enables versatile applications.