The myth of coupling reagents.

Coupling reagents have been proposed for peptide synthesis ever since the introduction of the method because of the convenience of the procedure, which consists of peptide bond formation by addition of a specific condensing agent to the mixture of carboxyl and amine components. However, truly efficient and yet innocuous coupling reagents are hard to find. Most coupling reagents give rise to unwanted reactions, which can be traced to certain characteristic structural features in their molecules. Such features are illustrated with the intermediates generated by dicyclohexylcarbodiimide and N-ethyl-5-phenyl-isoxazolium-3'-sulfonate (Woodward's reagent K). Some side reactions can be avoided if peptide bond formation is carried out in two separate steps: activation of the carboxyl group of the carboxyl component in the form of an active ester, followed by the catalyzed aminolysis of the active ester.