Novel acylation catalysts in peptide synthesis: derivatives of N-hydroxytriazoles and N-hydroxytetrazoles

Abstract

Six new derivatives of 1-hydroxy-1,2,3-triazole (1-hydroxytriazole in the following) and N-hydroxytetrazole have been evaluated in a direct competition assay to investigate their efficiency as catalysts in the formation of peptide bonds. Furthermore, three well known catalysts, 1-hydroxy-7-azabenzotriazole (HOAt), 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (Dhbt-OH) and 1-hydroxybenzotriazole (HOBt) have been compared. All nine compounds have been used for activation in combination with N,N′-diisopropylcarbodiimide (DIPCDI) in solid-phase synthesis using the fluoren-9-ylmethoxycarbonyl (Fmoc) strategy. The capability of the catalysts to suppress racemization has also been analysed. The results demonstrate that three of the new compounds are competitive with HOAt and HOBt in the suppression of racemization. 5-Chloro-1-hydroxytriazole is found to be a highly efficient acylation catalyst; however, it does not show sufficient suppression of racemization. Its catalytic effect in the synthesis of Aib–Aib-containing peptides is superior to that of HOAt. Also, 2-hydroxytetrazole has a catalytic efficiency superior to that of HOAt and suppressed racemization as efficiently as HOBt. The hydroxytetrazoles are explosive in a hammer test whereas the triazoles are stable compounds.