Halogen-bonding-mediated synthesis of amides and peptides

Abstract

Amide and peptide bonds are found in numerous natural products and biologically active compounds, including pharmaceuticals; and the formation of these bonds constitutes one of the most important reactions in organic chemistry. Herein, we report the first method for halogen-bonding-mediated formation of amide and peptide bonds, which was accomplished by using a coupling system comprising N-iodosuccinimide, 1,4-diazabicyclo[2.2.2]octane (DABCO), and an N-heterocyclic carbene precursor. The method could be used not only for synthesizing amides from carboxylic acids and amines but also for synthesizing peptides from both standard and sterically hindered amino acids in good to excellent yields without racemization. Remarkably, the coupling system allowed us to smoothly synthesize a protected form of the pentapeptide neurotransmitter Leu-enkephalin. Moreover, we also were able to use potassium persulfate, an inexpensive readily available inorganic oxidant, along with DABCO and the carbene precursor for efficient synthesis of various dipeptides. Density functional theory calculations and experimental studies showed that the bond-formation reactions involve a 2-iodobenzimidazolium intermediate that has an activated carboxyl group that forms a reactive acyloxybenzimidazolium intermediate; this intermediate is then attacked by the amino group of an amine or amino acid to afford an amide or a peptide.