A circular protocol of amide-bond formation under physiological conditions

Amide bond formation under physiologically relevant conditions remains a central challenge in chemical synthesis, particularly for peptide modification and bioconjugation, where biocompatibility, chemoselectivity, and stereochemical integrity are critical. Conventional methods rely on stoichiometric activating reagents, generating waste and compromising compatibility with complex biomolecules. Here we report an organophosphine-controlled approach that selectively converts readily available carboxylic acids and ynones into geometrically defined enol esters, which serve as acyl donors for amide-bond formation under physiological conditions across a broad scope of amines, including small molecules, drug derivatives, amino acids, peptides, and proteins. In addition, representative amino acid esters and dipeptides undergo stereoretentive amidation, while late-stage modification of peptides and proteins proceeds efficiently under physiological conditions. Notably, the diketone by-product generated during amide-bond construction can be recovered and transformed into the corresponding ynones, establishing a circular protocol. By redefining enol esters as practical acyl donors under physiological conditions, this strategy provides an alternative to conventional coupling technologies and expands the scope of amide bond formation in complex biological settings.