Silver Oxide Mediated Monotosylation of Poly(ethylene glycol) (PEG): Heterobifunctional PEG via Polymer Desymmetrization

Heterobifunctional poly­(ethylene glycol)­s (PEGs) are key structures for bioconjugation in the context of the “PEGylation” strategy to enhance blood circulation times of, for example, peptide drugs or “stealth” liposomes. The formation of heterobifunctional PEGs from symmetric PEG diols is challenging because of limited yields of the targeted monofunctional product and difficulties associated with separation steps. On the basis of a detailed comparison of reaction conditions, we have investigated a “polymer desymmetrization” strategy to maximize the yields of monofunctional PEG tosylate. The tosylation reaction in the presence of the heterogeneous catalyst silver oxide and potassium iodide in a specific stoichiometric ratio proved to be highly efficient, resulting in 71–76% yield of monofunctional PEG depending on molecular weight, exceeding the expected value of 50% in a statistical reaction without addition of a catalyst. For characterization as well as for the preparative separation of monotosylated PEG, we developed a HPLC method, using an evaporative light scattering detector, enabling both analytical and semipreparative separation of monotosylated PEGs on gram scale up to 20 000 g mol–1. To demonstrate the efficiency of the procedure, an α-azido-ω-methacryloyl-PEG was prepared as a building block suitable for azide–alkyne click-type reactions that can be incorporated into polymer networks via radical polymerization. We click-functionalized α-azido-ω-methacryloyl-PEG with a mannose-functionalized alkyne to enable functionalization of nanogels for enhanced cellular uptake via the mannose receptor. The synthesis strategy is suitable for a broad range of applications in the field of PEGylation and for hydrogel and nanogel functionalization.