C-terminal amide bond stability of peptides containing C,alfa,alfa-disubstituted glycines

Abstract

We have since long been interested in the synthesis of C,alfa,alfa-disubstituted glycines using the Ugi Four Component Condensation Reaction. Recently we have improved this method of synthesis by using 4-methoxybenzyl amine as the amine component of the Ugi reaction (A), which allowed an important simplification in the subsequent cleavage of the product. During the removal of the 4-methoxybenzyl group with hot neat TFA, we detected that not only this group was removed but also the C-terminal amide bond was cleaved. This result was independent of the nature of the amino acid residue so far generated and of the N-substituent at the C-terminal amide group. After work-up in aqueous media, the N-acetyl amino acids were isolated in quantitative yield. A similar behaviour was reported by Goodman et al., but with dimethylglycine derivatives having a methyl group at the nitrogen atom of this residue. In our case cleavage appears to occur even after removal of the N-alkyl group. These results prompted us to a further thorough study of the stability of this peptide bond under different conditions, by changing the acid used and the temperature of the reaction mixture.