Suppression of Side Reactions Associated With Use of the N~π-benzyloxymethylhistidine by Performing the HF reaction in the Presence of Hydroxyamine Derivatives^

摘要

His derivatives are known to be extremely prone to epimerization in activating and coupling steps involving the π -nitrogen of the imidazole moiety. Therefore, regioselective protection of the π -nitrogen is believed to reliably suppress this undesired side reaction [1]. In Boc chemistry, the N~π-benzyloxymethy (Bom) group is widely accepted as a protecting group for the His residue since it can effectively suppress the risk of epimerization and can be readily removed by HF [2]. However, the use of Boc-His(Bom) in peptide synthesis occasionally entails serious obstacles: 1) failure of N~α-Boc deprotection from His(Bom) occurs during TFA treatment for the standard SPPS, resulting in amino acid deletion products generated at the N-terminus of His(Bom) [3], and 2) formaldehyde generated from the Bom group during the HF treatment leads to modification with other functional groups in the same peptide. In particular, formaldehyde can almost^