On-resin Photochemical Decarboxylative Arylation of Peptides

Abstract

Here we describe the application of photochemical decarboxylative arylation as a late-stage modification reaction for peptides. The reaction uses redox active esters of aspartic acid and glutamic acid on solid phase to provide analogues of aromatic amino acids. By using aryl bromides as arylation reagents a wide variety of amino acids can be accessed without having to synthesize them individually in solution. The reaction is compatible with proteinogenic amino acids and was used to perform a structure-activity relationship study on a PRMT5 binding peptide.

On-Resin Photochemical Decarboxylative Arylation of Peptides

“…However, a limitation of the activation of Asp as a RAE is that it will rapidly undergo aspartimide formation with the neighboring amino acid in the peptide sequence. Here, we first optimized the RAE-forming reaction conditions to mitigate aspartimide- or pyroglutamate (from Glu)-forming side reactions . Thereafter, the key solid-phase photochemistry reaction conditions were screened, and improved conditions were identified which enabled the functionalization of peptides in good yields.…”

“…Here, we first optimized the RAE-forming reaction conditions to mitigate aspartimide- or pyroglutamate (from Glu)-forming side reactions. 25 Thereafter, the key solid-phase photochemistry reaction conditions were screened, and improved conditions were identified which enabled the functionalization of peptides in good yields. The substrate scope was also investigated by reacting a broad selection of aryl bromides (Ar–Br) with a resin-bound model peptide.…”