Umpolung reactivity in amide and peptide synthesis

The amide bond is one of nature’s most common functional and structural elements, as the backbones of all natural peptides and proteins are composed of amide bonds. Amides are also present in many therapeutic small molecules. The construction of amide bonds using available methods relies principally on dehydrative approaches, although oxidative and radical-based methods are representative alternatives. In nearly every example, carbon and nitrogen bear electrophilic and nucleophilic character, respectively, during the carbon–nitrogen bond-forming step. Here we show that activation of amines and nitroalkanes with an electrophilic iodine source can lead directly to amide products. Preliminary observations support a mechanism in which the polarities of the two reactants are reversed (German, umpolung) during carbon–nitrogen bond formation relative to traditional approaches. The use of nitroalkanes as acyl anion equivalents provides a conceptually innovative approach to amide and peptide synthesis, and one that might ultimately provide for efficient peptide synthesis that is fully reliant on enantioselective methods. Amide bonds are ubiquitous as the backbone of natural peptides and proteins, and are also present in many therapeutic small molecules. Conventional laboratory synthesis of the bond relies principally on dehydrative approaches, with the carbon and nitrogen retaining electrophilic and nucleophilic characters, respectively, during carbon–nitrogen bond formation. Shen et al. describe a new route for amide synthesis involving a reversal of reactant polarity (a process known as umpolung) through the iodonium activation of amines and nitroalkanes. It has a number of advantages over current techniques, including convenience and the availability of a wide variety of starting compounds, and has the potential to develop as an efficient means of enantioselective synthesis of peptides and amide-containing small molecules. The backbones of all natural peptides and proteins are composed of amide bonds. In the laboratory, the construction of such bonds generally relies on dehydrative approaches, although there are alternatives. It is now shown that the activation of amines and nitroalkanes with an electrophilic iodine source can lead directly to amide products.