Combinatorial synthesis of PEG oligomer libraries

A simple chain-extending approach was established for the scale-up of the monoprotected monodisperse PEG diol materials. Reactions of THP-(OCH2CH2)n-OMs (n=4, 8, 12) with a large excess of commercially available H-(OCH2CH2)n-OH (n=1-4) under basic conditions led to THP-(OCH2CH2)n-OH (n=5-15). Similarly, Me-(OCH2CH2)n-OH (n=4-11, 13) were prepared from Me-(OCH2CH2)n-OMs (n=3, 7, 11). For the chain elongation steps, 40-80% yields were achieved through extraction purification. PEG oligomer libraries I and II were generated in 50-95% overall yields by alkylation or acylation of THP-(OCH2CH2)n-OH (n=1-15) followed by deprotection. Alkylation of Me-(OCH2CH2)n-OH (n=1-11, 13) with X-(CH2)m-CO2R (X=Br or OMs) and subsequent hydrolysis led to PEG oligomer library III in 30-60% overall yields. Combinatorial purification techniques were adapted to the larger-scale library synthesis. A total of 498 compounds, each with a weight of 2-5 g and a minimum purity of 90%, were synthesized.