Catalysis in Peptide Synthesis with Active Esters. I. Bifunctional Catalysis in the Aminolysis of Benzyloxycarbonyl-L-phenylalaninep-Nitrophenyl Ester in Dioxane

The aminolysis reaction of benzyloxycarbonyl-L-phenylalanine p-nitrophenyl ester (I) with glycine t-butyl ester (II) was kinetically investigated in anhydrous dioxane. The spontaneous reaction was confirmed to follow the equation:d[p-nitrophenol]⁄dt=kobs[I]=(k0+kamine[II])[I][II]The catalytic actions of various additives were studied at a 2×10−3M concentration of I and II, where the amine-catalyzed term could be neglected. Of the many additives, only carboxylic acids and α-pyridone were effective as catalysts. The catalytic effect apparently decreased in the sequence: trimethylacetic acid>acetic acid>α-pyridone>monochloroacetic acid. For these catalyses, a bifunctional, concerted mechanism was proposed which involves an 8-membered transition state.