Chemical and Enzymatic Mechanosynthesis of Organocatalytic Peptide Materials Based on Proline and Phenylalanine

Abstract In recent years, mechanosynthesis of peptides through either chemical or enzymatic routes has been accomplished. In part, this advancement has been driven due to the organocatalytic properties of peptide‐based biomaterials. In this work, we report the merging of chemical and enzymatic protocols under mechanochemical conditions to synthesize peptide materials based on L‐proline and L‐phenylalanine. Compared to traditional step‐by‐step peptide synthesis in solution, our mechanochemical approach combining peptide coupling reagents with the proteolytic enzyme papain offers a more sustainable route by reducing the number of synthetic steps, shortening reaction times, increasing chemical yields, and minimizing waste production. Notably, the mechanosynthesized peptides exhibited organocatalytic activity in the asymmetric aldol reaction between cyclohexanone and 4‐nitrobenzaldehyde.