Chapter 4 - The Azide Method in Peptide Synthesis

Abstract

This chapter describes the azide method in peptide synthesis. Attractive features of azide method includes minimal danger of racemization in peptide segment condensation, good performance in assembling peptide chains of up to 60 amino acid residues, facile conversion of three important carboxyl protecting groups into activated azide through hydrazides, and opportunity to employ minimal side chain protection. Hydrazides of Nα- and side chain-protected peptides are commonly prepared by hydrazinolysis of their carboxyl-terminal alkyl esters, essentially following the procedure for the preparation of simple N-protected amino acid hydrazides. It is found that with increasing chain length, the rate of hydrazinolysis may slow to the extent that several days are required for complete reaction. Concomitant with longer reaction times and/or larger excess of hydrazine, the danger of undesired side reactions with certain sensitive side chain or protecting group functions will increase. Moreover, most peptides are likely to contain a greater variety of different functionalities with increasing size. The most commonly used solvents for hydrazinolysis of protected peptide methyl, ethyl, or benzyl esters are dimethylformamide, methanol, or mixtures of both.