Synthetic Chemistry: Formation of the Amide Bond

Amide bonds are found ubiquitously in natural or synthetic molecules of biologic interest. Since the early days of synthetic organic chemistry, methods for the formation of amides have been described. More recently, with the development of solid-phase chemistry and automated peptide synthesis, new strategies and reagents have been devised to overcome typical problems such as low conversion and racemization. This article provides an overview of the methodology that is available today. Depending on the nature of the synthetic target and the associated synthetic challenges, different approaches can be envisaged. Methods range from the rather straightforward use of acyl halides, anhydrides, and carbodiimides, to the more elaborate, low-racemization inducing methods that use phosphonium/uronium-based reagents. New amide bond-mediated ligation methodologies now offer new convergent strategies for the synthesis of highly functionalized molecules of biologic interest.