Controlled Ring‐Opening Polymerization of Methyl Glycolide with Bifunctional Organocatalyst

A bifunctional thiourea‐amine‐based organocatalyst (Takemoto's catalyst), employing a metal‐free approach, is presented for the regioselective ring‐opening polymerization (ROP) of optically active (D and L) methyl glycolide (MG). In this study, a chiral version of Takemoto's catalyst efficiently promotes the ROP of MG at room temperature, yielding poly(lactic‐co‐glycolic acids) (PLGAs) with predicted molecular weights and narrow polydispersity indices (PDI≤1.2). These PLGAs exhibit highly alternating structures without transesterification, as confirmed by 1H NMR, SEC, and MALDI‐TOF analyses. Additionally, various macromolecular architectures, including linear and star‐shaped PLGAs, were successfully synthesized using the corresponding multi‐functional alcohol initiators while maintaining the same alternating structures and regioselectivity with PLGA obtained from benzyl alcohol as initiator. Computational studies were conducted to elucidate the mechanism of alternating PLGA formation, revealing two key transition states (TSs): TS‐1, which implicates the nucleophilic attack of the hydroxyl group of the initiator or propagating chain on the carbonyl carbon of MG, and TS‐2, which involves the subsequent ring‐opening of the cyclic ester. The results indicate that ring‐opening occurs at both the glycolyl and lactyl sites, with a preference for the glycolyl site, as supported by experimental results. The resulting atactic PLGAs are amorphous, rendering them suitable for drug delivery applications. For the first time, a bifunctional thiourea‐amine‐based organocatalyst has been employed in the ring‐opening polymerization of optically active D‐ and L‐methyl glycolide (MG) at room temperature. This innovative, metal‐free catalytic approach leads to highly alternating poly(lactic‐co‐glycolic acids) (PLGAs), both in linear and star‐shaped forms. The synthesized PLGAs exhibit high regioselectivity, consistent alternating structure, recyclability, and atactic microstructure, making them suitable for drug delivery applications.