Sustainable Peptide Synthesis by Photoredox-Catalyzed Picoc-SPPS

Peptide therapeutics constitute a vital class of pharmaceuticals that are prized for their high target specificity and favorable safety profiles. However, conventional peptide synthesis relies on Boc- or Fmoc-protecting groups (e.g., Boc/Fmoc), whose removal requires either corrosive trifluoroacetic acid (TFA) or regulated piperidine. These reagents not only pose environmental and safety concerns but also promote side reactions such as aspartimide and diketopiperazine formation. The development of novel protecting groups that allow mild, selective deprotection is therefore an urgent need. Here, we report a visible-light photocatalytic approach employing the hydrophilic Nα-Picoc group. This strategy eliminates the use of TFA and piperidine while operating efficiently under mild, environmentally benign conditions. Picoc-solid-phase peptide synthesis (Picoc-SPPS) suppresses common side reactions, is compatible with green solvents (e.g., water and γ-valerolactone), and can be performed in aqueous systems. Moreover, the immobilization of the photocatalyst on resin enables efficient catalyst recycling, further improving sustainability. This study positions Picoc-SPPS as a versatile, scalable, and environmentally sustainable alternative to traditional SPPS, with substantial promise for both research and pharmaceutical manufacturing.