A side reaction in solid phase synthesis Insertion of glycine residues into peptide chains via Nim→ Nα transfer

Abstract
In solid-phase peptide synthesis using Nα-Boc-Nim-tosyl-histidine (Boc-His(Tos)), byproducts having extra Gly residues in the peptide chain were observed at a high rate. When a Boc-amino acid such as Asn was incorporated after assembly of Boc-His(Tos), the Nim-tosyl group was partially or fully cleaved by an activating agent, 1-hydroxybenzotriazole. In the successive coupling reactions, Boc-Gly was incorporated into the free Nim ring as well as the α-amino function, and the Nim-Gly was then transferred to the α-amino group of Gly of the peptide chain after removal of these Boc groups to give extra Gly residues at the position of Gly. This was observed in only the coupling reaction with Boc-Gly and could be circumvented using a more stable Nim protecting group for His, such as a dinitrophenyl group.