Controlled Synthesis of Telechelic Polypeptides via Polymerization of <i>N</i>-Carboxyanhydrides Mediated by Phosphate Kinetic Modulators

Telechelic polypeptides add structural diversity to their homo- and block-analogues and have potentially expanded applications in supramolecular chemistry, drug delivery, and tissue engineering. Their synthesis via the ring-opening polymerization of amino acid <i>N</i>-carboxyanhydride (NCA), however, is limited by slow polymerization rates or poor control over molecular weights (MWs). Here, we report a diamine-initiated, diphenyl phosphate (DPP)-regulated cooperative covalent polymerization to achieve a controlled synthesis of telechelic polypeptides with predictable MWs and narrow dispersity (<i>Đ</i> < 1.1). Mechanistic studies reveal that DPP mediates noncovalent interactions with propagating amino chain-ends, suppressing side reactions, and facilitating controlled chain propagation. Remarkably, this robust method is compatible with crude NCAs, avoiding tedious purification steps that enable the scalable synthesis of telechelic polypeptides with tailored architectures and unprecedented simplicity.