Highly Efficient Synthesis of Monodisperse Poly(ethylene glycols) and Derivatives through Macrocyclization of Oligo(ethylene glycols)

Abstract

A macrocyclic sulfate (MCS)-based approach to monodisperse poly(ethylene glycols) (M-PEGs) and their monofunctionalized derivatives has been developed. Macrocyclization of oligo(ethylene glycols) (OEGs) provides MCS (up to a 62-membered macrocycle) as versatile precursors for a range of monofunctionalized M-PEGs. Through iterative nucleophilic ring-opening reactions of MCS without performing group protection and activation, a series of M-PEGs, including the unprecedented 64-mer (2850 Da), can be readily prepared. Synthetic simplicity coupled with versatility of this new strategy may pave the way for broader applications of M-PEGs.

Recent Progress in the Design of Monodisperse, Sequence-Defined Macromolecules

“…Recently, Jiang et al reported a novel approach towards monodisperse OEGs based on a macrocyclic monomer, which is ring‐opened upon addition of glycol . This approach is also based on bidirectional growth, meaning that the glycol adds two macrocyclic monomers in one reaction step.…”

A Versatile and Scalable Strategy to Discrete Oligomers

“…Additionally, robust synthetic methods need to be established for coupling individual monomer units, preventing access to many important monomer classes, such as acrylates, styrenics, and functional siloxanes. 25–32 …”

Solid Phase Stepwise Synthesis of Polyethylene Glycols

“…The cycle is then repeated to give 6 . At this stage, the PEG is asymmetric, which is highly desirable in most applications but more challenging to make using other methods . However, if it were cleaved from the solid support, it would become symmetrical.…”

“…A significant advantage of the solid phase method is that the difficult‐to‐access asymmetric PEG derivatives can be easily synthesized . To demonstrate this, we prepared compounds 13 b – e (Scheme ).…”

“…8–40 ethylene glycol units) synthesis, one of the major problems is the need of multiple column chromatography to purify monomers, intermediates and the final product. This problem has severely impeded the practical use of stepwise synthesis for inexpensive large scale monodisperse PEG production ,,…”