<br/>Polypeptides are typically synthesized by ring-opening polymerizations of α-amino acid derived N-carboxyanhydrides (NCAs). As NCAs are highly sensitive towards moisture, their synthesis, purification, storage, and polymerization have to be conducted under anhydrous conditions. By contrast, α-amino acid derived N-thiocarboxanhydride (NTAs) are thermally and hydrolytically much more stable than the NCA analogs. Yet their polymerization has proven to be challenging. In this presentation, we will report our recent efforts in the development of controlled polymerization of α-amino acid derived NTAs to produce well-defined polypeptides. We have found that NTAs can be polymerized in a controlled fashion either by (1) an interfacial polymerization in non-solvents (e.g., hexanes or heptane) or (2) solution-phase polymerization in good solvents using a primary amine initiator (and together with a mild acid catalyst in the latter case) (Figure 1). The key for a controlled polymerization of α-amino acid derived NTAs bearing N-H proton is to modulate the relative reactivity of the elimination of COS, the rate-limiting event in the chain propagation versus the elimination of H<sub>2</sub>S that results in chain termination. Due to the enhanced thermal and hydrolytic stability of NTAs, their polymerization can be conducted in air using regular ACS grade solvents without the need for rigorous exclusion of moisture, enhancing the appeal of the methods for polypeptide synthesis.

Moisture-tolerant and operationally simple synthesis of polypeptides by ring-opening polymerization of α-amino acid derived N-thiocarboxyanhydrides

2019 Fall National Meeting

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