Rapid and Scalable Synthesis of Monodisperse Poly(ethylene glycol) Derivatives via KHMDS-Promoted Iterative Exponential Growth and Its Applications

Monodisperse poly(ethylene glycol) (PEG) derivatives are of great significance for studying the relationship between the structure and properties of PEGylated drugs, but their efficient and scalable synthesis faces many challenges. Here, we report an iterative exponential growth method for the preparation of monodisperse PEG derivatives. Potassium bis(trimethylsilyl)amide (KHMDS) is unprecedentedly used to facilitate the completion of key Williamson ether synthesis steps within 20 min, greatly improving synthesis efficiency. The monodisperse PEGs with repeat units of 48 and 128 were prepared with a total yield of about 32.3% and 12.8%, respectively, on a gram -scale within 1 week. Moreover, the monodisperse mPEG 48 -SC and its applications in the synthesis of mPEG 48 -DSPE and mPEG 48 -Octreotide have been implemented. The self-assembly comparison experiment between mPEG 48 -DSPE and mPEG-DSPE-2k revealed the potential advantages of monodisperse PEG derivatives in drug delivery. Additionally, the successful synthesis of mPEG 48 -Octreotide laid the foundation for subsequent pharmacokinetic studies of PEGylated drugs.