Rethinking transition metal catalyzed N-carboxyanhydride polymerization: polymerization of Pro and trans-4-acetoxy-Pro N-carboxyanhydrides

Sep 3, 2026

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Polyproline (PP) based polypeptides enable protein-mimic ordered materials, hydrogels, and surface coatings, yet conventional synthesis has lacked rapid, efficient routes to well-defined high molecular weight polymers. This work introduces facile, high-yield preparation and polymerization methods for Pro and trans-4-acetoxy-Pro N-carboxyanhydrides (NCAs). Transition metal initiation is re-examined: a Ni initiator intercepts a key intermediate without requiring an amide NH proton, yielding controlled living polymerization. Co species are shown to catalyze Pro NCA polymerization, improved NCA monomer synthesis, and tunable end-functional PP homo-, statistical, and block polypeptides. Conformation and conversion from PPI to PPII helices are confirmed by CD.

LanguageEnglish

CategoryGeneral

FormatPDF

Pages8

Reading Time3 min

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Introduction

NCA-derived synthetic polypeptides and Pro as a building block

Challenges and prior transition-metal initiation

Background on Pro and PP conformations

PPI and PPII helices

Biological relevance of Pro-rich proteins

Preparation and polymerization context of Pro NCAs

Historical synthesis and limitations of earlier routes

# Rethinking transition metal catalyzed N-carboxyanhydride polymer -ization: polymerization of Pro andAcOPro N-carboxyanhydrides. Rachel E. Detwiler, Austin S. Schlirf, Jessica R. Kramer* . *jessica.kramer@utah.edu Department of Biomedical Engineering, University of Utah, Salt Lake City, Utah, 84112, USA. KEYWORDS. Polyproline, proline, N-carboxyanhydride, transition metal catalysis, PPI, PPII. 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-definedhigh molecular weight materials. Here, wereport facile and high-yielding methods for preparation and polymerization of Proand trans-4-acetoxy-Pro N-carboxyanhdrides (NCAs) . For decades, transition metal initiators of NCA polymerization wereassumed to be nonstarters with Pro due tothe lack of an amide NH proton. We carefully considered the known steps in theinitiation mechanism and applied a Ni initiator that interceptsan intermediate and does not require an NH group. This initi -ator efficiently catalyzes controlled, living polymerization of Pro NCAs, revealing that routes alternate to the previously pro -posed mechanism must be at play. We also found Co species can catalyze Pro NCA polymerization, and we improved thesynthetic methods to prepare the NCA monomers. Our methods are high-yielding, 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 andconfirmed the timescale for quantitative conversion from PPI to PPII helices. Overall, our data sheds light on the generalpropagation mechanism of transition metal catalyzed NCA polymerization and has opened the door for efficient preparationof a desirable class of biomaterials. Introduction. N-carboxyanhydride (NCA)-derived syn -thetic polypeptides have been explored for over 100 years assurrogates for native proteins and as novel polymeric materi -als. Diverse applications include nanoparticles1, hydrogels2,engineered surfaces2 and cells3, synthetic leather4, and FDAapproved drug Glatiramer5. To impart new properties to poly -peptides beyond the chemical groups of naturally occurring α -amino acid (AAs), 100+ synthetic NCA monomers have beenreported. 6,7 Considering these efforts, it is surprising that de -spite its unique structural properties, the natural amino acid L -proline (Pro) has been largely overlooked as a building blockfor synthetic polypeptides. Factors contributing to this dearthinclude challenges in synthesis, purification, and stability ofPro NCA8–10, as well a lack of polymerization initiators thatavoid the racemization and chain-terminating side reactionsinherent with alkoxide and amine initiators11–13. Nearly 25years ago, Deming and coworkers developed a series of transi -tion metal complexes that overcame these challengesand effi -ciently initiate and catalyze controlled, living NCA polymeriza -tion.14–16 However, the Ni0 and Co0 complexes failed to initiatepolymerization of Pro NCA duetothe lack of an amide proton.Here, we report Ni and Co amido-amidate complexes that cir -cumvent requirement of the amide proton and that catalyzecontrolled and living polymerization of Pro and trans-4-AcO -Pro NCAs. Our method results in tunable, high molecularweight, end-functional polyPro (PP) based homo, statistical,and block polypeptides. Further, our data sheds light on thegeneral mechanism of transition metal catalyzed NCApolymerization. Pro isa unique AAin that its sidechain isa 5-membered ringlocked by a covalent bond to the nitrogen atom. This ring limits bond rotation between the α-carbon and nitrogen atoms, re -sulting in backbone dihedral angles that render the equilib -rium between cis and trans peptide conformations more favor -able than for anyother AA residue17. In peptides, the Pro nitro -gen lacks a proton and th

FAQs

Why is Pro N-carboxyanhydride polymerization difficult with traditional initiators?

Pro lacks an amide NH proton, and prior Ni0/Co0 transition-metal initiators were assumed unable to initiate polymerization for this reason.

What strategy enables controlled living polymerization in this work?

The authors use a Ni initiator that intercepts a known initiation intermediate and does not require an amide NH group, enabling controlled, living polymerization of Pro NCAs.

How do the authors verify the structure and PPI/PPII conversion?

They characterize PP and trans-4-hydroxy-PP conformations using CD and confirm quantitative conversion timescales from PPI to PPII helices.

Sep 3, 2026

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