Peptide thioamides: exploiting a single-atom substitution

Peptide thioamides, in which a single backbone oxygen atom is replaced by sulfur, display markedly altered structural, spectroscopic and reactive properties relative to native amides. This personal perspective highlights our group’s exploration of the unique reactivity of peptide thioamides and the development of AgI-promoted transformations that exploit this subtle but powerful single-atom substitution. Initial studies demonstrated that thioamides undergo silver-mediated coupling with carboxylates to generate reactive isoimide intermediates that can then undergo 1,3-acyl transfer to generate imides, or be intercepted by appropriately reactive and positioned nucleophiles. This mechanistic platform has enabled the development of a diverse range of peptide transformations, including a N→C direction approach to peptide synthesis, an Asn-based ligation strategy, amino acid insertion and ring expansion of cyclic peptide thioamides, intermolecular peptide fragment couplings and a rapid, traceless, epimerisation-free method for head-to-tail peptide macrocyclisation. Extension of this chemistry to side-chain nucleophiles enabled late-stage macrolactonisation approaches to depsipeptides, together with backbone thioamide-directed Asp activation for peptide stapling and site-selective N-glycosylation. More recent work has explored peptide thioamides as versatile precursors to additional backbone isosteres and directing groups, including amidoxime ethers for late-stage C–H functionalisation. Collectively, these studies demonstrate how a seemingly minor O→S substitution can profoundly alter peptide reactivity, enabling chemoselective transformations and synthetic strategies that are difficult to achieve using native amide chemistry.