HBTU mediated 1-hydroxybenzotriazole (HOBt) conjugate addition: synthesis and stereochemical analysis of β-benzotriazole N-oxide substituted γ-amino acids and hybrid peptides.

Abstract

HBTU is a standard coupling agent commonly used for the activation of free carboxylic acids during the solution and solid phase peptide synthesis. 1-Hydroxybenzotriazole (HOBt) plays a significant role in reducing the racemization during peptide synthesis; hence it is regularly used as a coupling additive. Here, we are reporting the mild and facile conjugate addition of HOBt to E-vinylogous γ-amino acids mediated by the HBTU. The reaction is moderately diastereoselective and novel β-benzotriazole N-oxide (β-BtO) substituted γ-amino acids were isolated in moderate to good yields. The single crystal analysis of methyl esters of major (anti) and minor (syn) conjugate addition products infers the formation of exclusively N-alkylated benzotriazole N-oxides instead of O-alkylation of HOBt. In addition, we showed the utilization of β-BtO substituted γ-amino acids in peptide synthesis and studied their conformations in single crystals.