Stepwise PEG synthesis featuring deprotection and coupling in one pot

Abstract

The stepwise synthesis of monodisperse polyethylene glycols (PEGs) and their derivatives usually involves using an acid-labile protecting group such as DMTr and coupling the two PEG moieties together under basic Williamson ether formation conditions. Using this approach, each elongation of PEG is achieved in three steps – deprotection, deprotonation and coupling – in two pots. Here, we report a more convenient approach for PEG synthesis featuring the use of a base-labile protecting group such as the phenethyl group. Using this approach, each elongation of PEG can be achieved in two steps – deprotection and coupling – in only one pot. The deprotonation step, and the isolation and purification of the intermediate product after deprotection using existing approaches are no longer needed when the one-pot approach is used. Because the stepwise PEG synthesis usually requires multiple PEG elongation cycles, the new PEG synthesis method is expected to significantly lower PEG synthesis cost.

Striving for Uniformity: A Review on Advances and Challenges To Achieve Uniform Polyethylene Glycol

“…108,115 sity. [14][15][16][17]35,41,42,45,[51][52][53]57,58,116 Moreover, comparing with other techniques, this is the one that can provide more useful information about polymer end-group analysis. PEG can be easily ionized via adduct formation with alkali metal ions due to the oxygen-rich nature of this polymer.…”

“…To do so, a base-labile protecting group such as phenethyl was used. By employing this protecting group, the deprotonation step was not required . In 2022, the same base-labile approach was applied in solid-phase synthesis, having significant advantages over the acid-labile protecting group usually used (DMtr).…”

“…Lastly, NMR is widely used for polymer characterization, providing elucidation of the polymer structure and not dispersity. − ,,,,,− ,,, Besides the structure, NMR is used to calculate the purity and can be used to follow the synthetic pathways.…”

“…It is clear that the longer the PEG chain, the overall yield decreases significantly. 53 The major cause of this phenomenon is that longer PEG oligomers are not easily available. 55 Even though the reported publications state that uniform PEG was synthesized, most lack PDI values to support this information and its confirmation is mainly done by mass spectrometry.…”

“…Table lists all of the synthetic pathways developed to obtain uniform PEGs. It is clear that the longer the PEG chain, the overall yield decreases significantly . The major cause of this phenomenon is that longer PEG oligomers are not easily available …”