Nitroalkanes as thioacyl equivalents to access thioamides and thiopeptides

Abstract

Abstract Thioamides are an important, but a largely underexplored class of amide bioisostere in peptides. Replacement of oxoamide units with thioamides in peptide therapeutics is a valuable tactic to improve biological activity and resistance to enzymatic hydrolysis. This tactic, however, has been hampered by insufficient methods to introduce thioamide bonds into peptide or protein backbones in a site-specific and stereo-retentive fashion. In this work, we developed an efficient and mild thioacylation method to react nitroalkanes with amines directly in the presence of elemental sulfur and sodium sulfide to form a diverse range of thioamides in high yields. Notably, this convenient method can be employed for the controlled thioamide coupling of multifunctionalized peptides without epimerization of stereocenters, including the late stage thioacylation of advanced compounds of biological and medicinal interest. Experimental interrogation of postulated mechanisms currently supports the intermediacy of thioacyl species.