Accelerated and Controlled Polymerization of Tryptophan N -Carboxyanhydride

Tryptophan (Trp or W) was distinguished among eukaryotic amino acids due to its unique physicochemical properties, enabling diverse applications in biomedical research. However, synthesizing well-defined, high-molecular-weight poly(l-tryptophan) (PLW) via controlled ring-opening polymerization (ROP) of l-tryptophan N-carboxyanhydride (Trp-NCA) remains challenging, primarily due to slow kinetics and interference of the secondary structure. In this work, we present a synergistic organic acid–base catalytic strategy to overcome these obstacles. The organic base disrupts the inhibitory indole–amine interactions, thereby accelerating the polymerization, while the organic acid mitigates uncontrolled two-stage polymerization kinetics by eliminating the initial lag phase. This approach enables well-controlled ROP of NCAs that exhibits features of a living polymerization, thus achieving precise synthesis of PLW homopolymers and Trp-rich copolypeptides with predictable molecular weights (MWs), narrow dispersity (Đ < 1.20), and different segment structures. Appealing MW-dependent secondary structures and Trp content-dependent fluorescence properties were characterized based on these polypeptides. This strategy provides an efficient route to Trp-containing polypeptides, expanding their utility in protein mimicking and functional biomaterials.