Abstract
Ring-opening polymerization of α-amino acid N-carboxyanhydrides (NCAs) is a powerful synthetic methodology for generating well-defined functional polypeptides. However, conventional procedures require a compromise between obtaining controlled microstructures and employing the optimized polymerization conditions. Specifically, a versatile method to access sequenced cyclic polypeptides remains challenging due to the difficulty in site-specific cyclization. Here we describe a general and straightforward method for the synthesis of both linear and cyclic polypeptides using organocatalytic living polymerization of NCAs. The use of an air-stable organocatalyst, imidazolium hydrogen carbonate, allows for the rapid and controlled polymerization of a variety of NCAs, leading to high conversion within a few minutes under mild conditions. Linear and cyclic block copolypeptides are also accessible simply by controlling the type of initiators and the order of addition of NCA monomers.
Highlights
Ring-opening polymerization of α-amino acid N-carboxyanhydrides (NCAs) is a powerful synthetic methodology for generating well-defined functional polypeptides
In the presence of a primary amine, the N-heterocyclic carbene (NHC) act as potent organocatalysts for the ring-opening polymerization (ROP) of four representative types of NCAs, generating respective linear polypeptides with controlled molecular weights (MWs) and low Đ values (Table 1, entries 1−7). 1H NMR spectroscopy analysis corroborated the lPPep structure with primary amino end groups (Supplementary Figures 1−7)
In the absence of amine initiators, cyclic polypeptides (cPPeps) with tunable ring sizes (degree of polymerization (DP) = 20−300) were obtained (Table 1, entries 14−23), where the [NHC(H)(HCO3)] served as the sole initiator. 1H NMR spectra and electrospray ionization mass spectra (ESI MS) of the purified product clearly confirmed the proposed polymeric backbone with an NHC moiety affixed to the ring (Supplementary Figures [15−20] and 32)
Summary
Ring-opening polymerization of α-amino acid N-carboxyanhydrides (NCAs) is a powerful synthetic methodology for generating well-defined functional polypeptides. We describe a general and straightforward method for the synthesis of both linear and cyclic polypeptides using organocatalytic living polymerization of NCAs. The use of an air-stable organocatalyst, imidazolium hydrogen carbonate, allows for the rapid and controlled polymerization of a variety of NCAs, leading to high conversion within a few minutes under mild conditions. Linear and cyclic block copolypeptides are accessible by tuning the type of initiator and by sequential addition of monomers This bifunctional organocatalysis strategy was developed based on the conjecture that:[25,34,37] free NHCs can form a hydrogen bonding network with the initiating amines and the subsequently formed ω-amino terminus of the propagating chains (Fig. 2). While in the absence of amines, free NHCs might behave as a sole nucleophile to initiate NCAs and generate the imidazolium carbamate zwitterionic intermediate, allowing for subsequent intramolecular decarboxylation and chain propagation to yield cPPeps
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