Multifactorial Perspective for Greening Solid‐Phase Peptide Synthesis: Rigid Polyacrylate Macroporous Resin in Combination with Green Solvents

Until now, efforts to 'green' solid-phase peptide synthesis (SPPS) have largely focused on identifying a single solvent capable of replacing dimethylformamide, while relying exclusively on polystyrene-based resins. This approach has proven both challenging and limiting. Here, we propose that the most effective strategy for incorporating greener solvents into SPPS is to identify resin solvent combinations that can simultaneously support the two key reactions in peptide synthesis: coupling and Fmoc deprotection. When a relatively rigid resin is used, resin swelling is no longer a critical parameter in SPPS. This, in turn, enables the use of solvents that do not need to swell the resin, greatly expanding the range of greener solvent options that can be considered. This concept is exemplified by a novel polyacrylate-based rigid macroporous resin, which has enabled the SPPS synthesis of small- to medium-sized peptides using EtOAc, TEP, 2-MeTHF, acetone, and MeCN as single solvents.