Chirality-Matched Cyclopropenimine–Thiourea Organocatalysis for Regiocontrolled Ring-Opening Polymerization of Methyl Glycolide

Abstract Poly(lactic-co-glycolic acid) (PLGA) is widely used in biomedical applications owing to its high biodegradability and biocompatibility. Although the ring-opening polymerization (ROP) of methyl glycolide (MeG) offers a route to synthesizing alternating PLGA, the comparable reactivity of its two electrophilic ring-opening sites hampers precise microstructural control. Chirality-matching strategies based on enantiopure monomers and chiral catalysts have been pursued in both organometallic catalytic and organocatalytic systems; however, the presence of metal residues remains a significant limitation, whereas organocatalytic approaches still lack a fundamental mechanistic understanding of site selectivity and fail to achieve a unified control over reaction conditions, rates, and regioselectivity. Herein, we report a rapid and regioselective synthesis of alternating PLGA through the ROP of enantiopure MeG enabled by chiral cyclopropenimine–thiourea bifunctional organocatalysts. By leveraging a superbase-mediated hydrogen-bonding system, we achieved rapid polymerization at room temperature within minutes, affording copolymers with high regioselectivity (P up to 0.90) and narrow dispersities. Through in-depth experimental and computational analyses, we elucidated the intrinsic origins of site-selectivity from initiation to propagation and identified the specific roles of the catalyst active sites in controlling these pathways. The resulting alternating PLGAs, while amorphous, exhibit semicrystallinity upon stereocomplexation, with significantly enhanced melting temperatures in systems with high sequence regularity. By uncovering the mechanisms behind selective polymer synthesis, this work provides a robust platform for the development of sequence-defined biodegradable materials.