N-carboxyanhydride (NCA)-derived synthetic polypeptides have long been explored as surrogates for native proteins and as novel polymeric materials. Polyproline (PP) based polypeptides have broad applications as protein mimics, ordered materials, hydrogels, and surface coatings. Despite its unique structural properties, the natural amino acid L-proline (Pro) has been largely overlooked as a building block for synthetic polypeptides. Factors contributing to this include challenges in synthesis, purification, and stability of Pro NCA, as well a lack of polymerization initiators that avoid the racemization and chain-terminating side reactions inherent with alkoxide and amine initiators. Transition metal complexes developed by Deming and coworkers to overcome these challenges failed to initiate polymerization of Pro NCA due to Pro’s lack of an amide proton. Here, we report Ni-amido amidate complexes that circumvent requirement of the amide proton and that catalyze controlled and living polymerization of Pro and trans-4-AcO-Pro (AcOPro) NCAs.<br/>We prepared Pro and AcOPro NCAs from Boc protected AAs using triphosgene and triethylamine as reported by others, however, we greatly improved the purification procedure by use of anhydrous flash chromatography. Use of an azide species the initiator will allow post-synthetic click-modifications for later attachment to targets or fluorophores.<br/>For over two decades, preparation of high MW PP via transition metal-initiated polymerization of Pro NCAs was presumed to be impossible due to Pro’s unique structure. PP-based materials have diverse applications in probing protein structure, as ordered materials, and as bioinspired protein mimics. In our own work toward NCA-derived synthetic mucins, we desired the incorporation of Pro NCA. This work shows a route to synthetic PP and PHP and opens doors to rapid, scalable synthesis and characterization of many more N-substituted AA and peptoid-based biopolymers. Further, our data has shed light on the general propagation mechanism of transition metal catalyzed NCA polymerization, which is different than the proposed, and widely cited, mechanism.

Development in transition metal catalyzed <i>N</i>-carboxyanhydride polymerization: Preparation of polyproline materials

ACS Spring 2022

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Development in transition metal catalyzed N-carboxyanhydride polymerization: Preparation of polyproline materials