Mechanistic Insight into the Lability of the Benzyloxycarbonyl (Z) Group inN-Protected Peptides under Mild Basic Conditions

Abstract

The unexpected lability of Z protecting group under mild basic conditions at room temperature is explained by a mechanism based on anchimeric assistance. It is found that the vicinal amide group stabilizes the tetrahedral intermediate formed after the nucleophilic addition of hydroxide to the carbonyl of the Z group. This effect operates in N-protected tripeptides and tetrapeptides but Z-protected dipeptides are stable under the same conditions due to the blockage of the vicinal amide NH by intramolecular H-bonding with terminal carboxylate moiety.