Rethinking Transition Metal Catalyzed N-Carboxyanhydride Polymerization: Polymerization of Pro and AcOPro N-Carboxyanhydrides

Abstract

Polyproline (PP) based polypeptides have broad applications as protein mimics, ordered materials, hydrogels, and surface coatings. However, a lack of rapid and efficient preparatory methods has challenged synthesis of well-defined high molecular weight materials. Here, we report facile and high-yielding methods for preparation and polymerization of Pro and trans-4-acetoxy-Pro N-carboxyanhdrides (NCAs). For decades, transition metal initiators of NCA polymerization were assumed to be nonstarters with Pro due to the lack of an amide NH proton. We carefully considered the known steps in the initiation mechanism and applied a Ni initiator that intercepts an intermediate and does not require an NH group. This initiator efficiently catalyzes controlled, living polymerization of Pro NCAs, revealing that routes alternate to the previously proposed mechanism must be at play. We also found Co species can catalyze Pro NCA polymerization, and we improved the synthetic methods to prepare the NCA monomers. Our methods are high-yielding and rapid and give tunable, end-functional PP-based homo, statistical, and block polypeptides. We characterized the conformation of PP and trans-4-hydroxy-PP by CD and confirmed the time scale for quantitative conversion from PPI to PPII helices. Overall, our data shed light on the general propagation mechanism of transition metal catalyzed NCA polymerization and have opened the door for efficient preparation of a desirable class of biomaterials.

Water-assisted and protein-initiated fast and controlled ring-opening polymerization of proline N-carboxyanhydride

“…However, polymerization with amine-based initiators usually requires more than a week to reach 60%–80% monomer conversion in organic solvents. During the reviewing process of this work, Kramer achieved relatively faster PLP synthesis (1–2 h typically) via the use of highly efficient organometallic catalysts [ 24 ]. However, the M n and Đ of the obtained PLPs were not stringently characterized using SEC due to solubility issues.…”

Scalable Preparation of Synthetic Mucins via Nucleophilic Ring-Opening Polymerization of Glycosylated N-Carboxyanhydrides

“…Several of these conditions are summarized in Table . The Ni 0 initiators bipyNi­(COD) and depeNi­(COD) were selected because they are used widely for NCA ring-opening polymerizations ,,, and are commercially available or prepared in a single step, respectively . We found bipyNi­(COD) did not form any polymer (Table , entry 9), while depeNi­(COD) gave an M n of 4.76 kDa, yield of 7.8%, and Đ of 1.42 (Table , entry 11).…”

“…The ring-opening polymerization of NCA monomers (Scheme ) was selected as the polymerization strategy because it has been used for over a century to provide synthetic polymers with polypeptide backbones; under certain conditions, it behaves like a living polymerization that can achieve high molecular weight polymers with narrow polydispersity indices ( Đ ), ,, and it has been deployed successfully to polymerize glycosylated NCA monomers. − For example, Okada et al created high M w and stereoregular polymers of O -(tetra- O -acetyl-β- d -glucopyranosyl)- l -serine-NCA . Bertozzi and co-workers reported the first synthesis of poly­(α-GalNac-Ser), poly­(β-GalNac-Ser), and copolymers with other NCAs using an organometallic initiator, and, upon conjugation with an azide-terminated anchor, the resulting synthetic membrane mucin mimic was produced on the milligram scale for cell-binding studies. , Gupta polymerized O -glycosylated lysine-NCAs to afford end-functionalized amphiphilic and fluorescently labeled glycopolymers .…”

“…Several of these conditions are summarized in Table 1. The Ni 0 initiators bipyNi(COD) and depeNi(COD) were selected because they are used widely for NCA ring-opening polymeriza- tions 61,65,68,92 and are commercially available or prepared in a single step, respectively. 61 We found bipyNi(COD) did not form any polymer ( 93,94 and dimethylethanolamine (DMEA), 95 are common initiators for NCA ring-opening polymerizations and those were explored as well.…”

N-Carboxyanhydrides Directly from Amino Acids and Carbon Dioxide and their Tandem Reactions to Therapeutic Alkaloids

“…Proline (3e) and other cyclic compounds 3f and 3g were successfully converted to 4e, 4f, and 4g, respectively, in moderate to high yields (41-85%). Because polyproline materials have many useful applications, 40 NCAs derived from 1e are in high demand. Once again, we were able to obtain NCA products with high purity after workup, which makes our approach more efficient than those requiring complicated procedures to remove unreacted starting materials and uncyclized acyl chloride impurities.…”