The robust synthesis of unprotected α-amino acid N-carboxyanhydrides (NCAs) was recently reported by our group, but the polymerization behaviors of these new monomers have not been studied in detail. Here, we report the one-pot synthesis of thiol-functionalized polypeptides from unprotected D-penicillamine N-carboxyanhydride (Pen-NCA). This method prepares linear polypeptides functionalized with tertiary thiol efficiently in one step, omitting the traditional time-consuming protection-deprotection process. The main challenge of Pen-NCA polymerization comes from monomer isomerization, which not only reduces the conversion of monomer to polymer but also leads to extra chain initiation. By copolymerizing Pen-NCA with a second NCA monomer, we successfully boost the selectivity of polymerization over isomerization and thus high molecular weight polypeptides with expected end group could be obtained. We also demonstrate the application of Pen copolypeptides as a platform for post-polymerization modification or macromolecular multi-functional initiators. This work is the first in-depth study on the polymerization behavior of side-group unprotected NCAs (UP-NCAs), and we believe further exploration of these monomers will eventually provide a new toolbox for polypeptide synthetic chemistry.

One-pot synthesis of thiol-functionalized polypeptides from unprotected N-carboxyanhydrides

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