Photocatalytic C–X Bond Cleavage Facilitates Peptide Synthesis

Abstract

The ability to selectively cleave C-heteroatom bonds is critically important in chemical science, from peptide and protein synthesis to biomolecule manipulation. For example, C-heteroatom bond cleavage is widely used in fluorenylmethyloxycarbonyl/tert-butyl (Fmoc/tBu)-based solid-phase peptide synthesis (SPPS). Despite its usefulness, it has inextricable limitations, such as issues with hydrophobicity and side reactions, owing to the need for the use of a strong trifluoroacetic acid (TFA, a pervasive forever chemical) as the cleavage reagent. To overcome these drawbacks, alternative strategies to replace Fmoc/tBu-based protection and deprotection for SPPS are urgently needed. Here, we introduce a novel SPPS platform based on Fmoc/pyridinemethyl (Pic) chemistry, which enables the orthogonal protection of amino acid side chains and their efficient removal via photocatalytic C-heteroatom bond cleavage under mild conditions. Our approach utilizes the feedstock Pic group to cage amino acid side chains, which eliminates the need for TFA, thereby offering an environmentally friendly alternative to traditional peptide synthesis. Furthermore, this approach seamlessly integrates with automated peptide synthesizers, enabling acid-free, on-resin photorelease of structurally complex peptides, which remains challenging for conventional SPPS methodologies.