Game Change from Reagent- to Substrate-Controlled Peptide Synthesis

An account of the development of Lewis-acid-catalyzed methods for racemization-free peptide synthesis is presented. These methods are based on the substrate control concept that has been exploited extensively in stereoselective reactions, but the concept has never previously been applied to peptide synthesis. The most important difference that has emerged between our methods and the conventional methods based on reagent control concept such as coupling-reagent-mediated and boronic-acid-catalyzed peptide bond-forming reactions is how to activate the reaction sites and racemization control. The reagent-controlled methods proceed by generating highly reactive esters in situ, leading to occasional racemization through the formation of oxazolone intermediates. On the other hand, our substrate-controlled methods do not go through the known racemization processes because the Lewis acids we use herein are designed to activate moderately as an anchor a specific carbonyl group that is located at a reasonable distance from the directing group. Based on the substrate control concept, we have developed six novel methodologies for peptide bond-forming reactions over the last five years.