Chapter 3 - Active Esters in Peptide Synthesis

Abstract

This chapter describes the development of active esters in peptide synthesis. The fundamental studies revealed that the ammonolysis and aminolysis rates of esters are related to the electron withdrawing properties of the acid or the alcohol component of the ester. Withdrawal of electrons enhances the electrophilic character of the carbonyl carbon and thereby facilitates the formation of the tetrahedral intermediate with the nucleophile. In the experiments described in the chapter, vinyl esters and phenyl esters exhibited extreme reactivity toward ammonia. The recognition that the reactivity of thiophenyl esters is less because of their being derivatives of thiols and more because of the fact that they are phenyl esters prompted investigations that led to the introduction of nitrophenyl esters of protected amino acids in peptide synthesis. The enhancement of the electron-withdrawing effect of the aromatic nucleus by the strong negative effect of one or two nitro groups rendered these compounds practical tools that were applied in the synthesis of many important peptides. Their general usefulness was first demonstrated in a synthesis of oxytocin.