Facile and Controlled Synthesis of Poly(ethylene glycol)-Polypeptide in an Acidic, Biphasic System

Poly(ethylene glycol) (PEG)-polypeptides are typically synthesized via the PEG-NH₂-initiated ring-opening polymerization of N-carboxyanhydrides (NCAs), which may otherwise result in broad, uncontrolled, multimodal molecular weight distributions, omitting tedious monomer purification, an anhydrous setup, and the use of specially designed initiators and/or catalysts. The cooperative covalent polymerization in a biphasic system that we recently developed shows substantially improved simplicity but still relies on the use of PEG-helical polypeptide macroinitiators for the synthesis of the intended PEG-polypeptides. Herein, we report the preparation of PEG-polypeptides directly from a PEG-NH₂ initiator in such a biphasic system by simply tuning its aqueous or organic phase to acidic pH and using the subsequently formed protonated (dormant)/nonprotonated (active) equilibrated chain-end group to modulate polypeptide chain propagation, yielding a variety of PEG-polypeptide materials with controlled molecular weights and diverse side-chain functionalities. Additionally, the biphasic segregation effect enables the in situ purification of NCAs, rendering controlled polymerization from crude monomers. As setting up a biphasic system and tuning its pH are very easy, PEG-NH₂ is readily available, and the crude NCAs can be easily prepared by following standard protocols; this robust polymerization method should be simple enough for anyone who has basic synthetic skills to manage the controlled preparation of PEG-polypeptides.