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

Abstract

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.

Selectivity of 1-O-Propargyl-d-Mannose Preparations

“…The last step ( Scheme 4 ) based on the deprotection of the hydroxyl groups of mannose [ 39 , 43 ] resulted in the production of pure propargyl-α- d -mannopyranoside (α-2), which is in agreement with the literature, which describes only the α-pyranoside form in 89–98% [ 32 , 33 , 35 , 39 , 41 , 44 , 45 ]. The NMR characteristics of all products are listed in the Supplementary Materials, Table S1 .…”

Convenient Access to α‐Amino‐ω‐Hydroxyl Heterobifunctional PEG and PPO via a Sacrificial Hexahydro‐Triazine Star Strategy

“…In a subsequent step, the demanding separation of the heterobifunctional PEG from the statistical reaction mixture is mandatory. In this context we recently demonstrated a desymmetrization strategy for PEG, based on catalytic tosylation and HPLC separation . The second method relies on the direct initiation with a protected functional initiator and termination with a different functional group, which affords heterobifunctional PEG in high yields.…”

Polymer Product Design: Considering Detailed Polymer Attributes and Production Guidelines

“…The synthesis of polymer with high molecular weights has been reported in many recent studies. Difficulties have been found in the purification of polymers, which leads to a reduction in the conversion and yields of polymers . The synthesis of some high-molecular-weight polymers requires very high reaction temperature, long reaction time, or very high pressure; otherwise, high-molecular-weight polymers cannot be obtained.…”

“…Difficulties have been found in the purification of polymers, which leads to a reduction in the conversion and yields of polymers. 37 The synthesis of some high-molecular-weight polymers requires very high reaction temperature, long reaction time, 38 or very high pressure; 39 otherwise, high-molecular-weight polymers cannot be obtained. Furthermore, even exactly stoichiometric ratios and high-purity monomers are needed to synthesize polyesters, 40 and other difficulties can also be found in the synthesis of polysaccharides, 41 conjugated polymers, 42 and cyclic polymers.…”