One-Step Synthesis of Statistical Copolymers Containing Peptide, Ester, Ether, and Amine Linkages via <i>N</i>-Substituted Glycine <i>N</i>-Carboxyanhydrides and Epoxides

The ring-opening copolymerization of α-amino acid N-carboxyanhydrides (NCA) with nitrogen-free monomers including cyclic esters and epoxides recently emerged as a fascinating method to synthesize α-amino acid-based copolymers with backbones containing not only peptide linkages but also ester and ether ones. It enriched the toolbox for the modulation of the properties of polypeptides and polypeptoids as biomaterials and thermoplastic elastomers. Whereas, balancing the activities of nitrogen- and oxygen-terminal living centers in a single catalytic system was extremely challenging. In this contribution, the first example of random copolymerization of N-substituted glycine NCAs with epoxides was succeeded catalyzed by transition-metal triflates including lutetium triflate (Lu(OTf)3). The copolymers with four types of linkages including amide, ether, ester, and tertiary amine groups were synthesized in a one-step and one-pot procedure. The molar ratios of cyclohexene oxide (CHO) to sarcosine NCA (Sar-NCA) in copolymers were designed from 0.17:1 to 0.51:1 and the Mn,SEC of P(Sar-co-CHO) varied between 2.4 and 27.0 kg/mol. The copolymerization followed a coordination anionic ring-opening mechanism and was versatile for various alkyl- and aryl-substituted glycine NCAs as well as diverse epoxides such as CHO, propyl oxide (PO), and 1,2-epoxy-4-vinylcyclohexane (VCHO). P(Sar-co-CHO) was noncytotoxic and biodegradable by porcine pancreatic lipase due to the ester linkages in its backbone. P(Sar-co-VCHO), a PSar with multiple vinyl pendant groups, was capable of forming a hydrogel through thio-ene click reaction. In summary, we provided a novel, simple, and efficient approach to synthesize random copolymers of N-substituted glycine NCAs with epoxides, thereby diversifying the copolymer structures and advancing the synthetic methodology for the copolymerization of NCA with nitrogen-free monomers.