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.
Shen
Bo
B
Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235-1822, USA.
Makley
Dawn M
DM
Johnston
Jeffrey N
JN
D000473:Alkanes / Q000138:chemical synthesis* / Q000737:chemistry; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D002244:Carbon / Q000737:chemistry*; D004980:Ethane / Q000031:analogs & derivatives / Q000737:chemistry; D005998:Glycine / Q000737:chemistry; D008956:Models, Chemical; D009574:Nitro Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D009584:Nitrogen / Q000737:chemistry*; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry
D000473:Alkanes; D000577:Amides; D000588:Amines; D009574:Nitro Compounds; D010455:Peptides; D002244:Carbon; C533588:bromonitromethane; D004980:Ethane; D009584:Nitrogen; D005998:Glycine