Automated stepwise PEG synthesis using a base-labile protecting group

Abstract

Automated stepwise synthesis of polyethylene glycols (PEGs) was achieved using a custom modified peptide synthesizer and a monomer having a base-labile protecting group. The Wang resin, which contains an acid-labile para-methoxybenzyl linker, was used as the solid support. The PEG5 derivative TsOPEG5O(CH2)2Ph, which contains a tosyl leaving group and a base-labile phenylethyl protecting group, was used as the monomer. Automated assembly of PEGs was carried out by deprotonation of the para-methoxybenzyl alcohol on the Wang resin followed by reaction with the monomer in the first cycle. Subsequent cycles consisted of deprotection of the phenylethyl group under basic conditions, and direct coupling with the monomer under less basic conditions. The deprotection gave the PEG as an alkoxide, which made direct coupling with the monomer possible. A separate step for deprotonation was not needed. Purification of intermediates and products was simply achieved by washing the resin. In all the steps, materials were added into and removed from the reaction vessel controlled by the software of the synthesizer. At the end of synthesis, the PEGnO(CH2)2Ph product was cleaved from the resin with TFA. Using the automated method, high quality monodisperse PEG10O(CH2)2Ph and PEG15O(CH2)2Ph derivatives were synthesized. The PEG20O(CH2)2Ph derivative was also synthesized but small amount of impurity was observed. The yields of the syntheses should be close to 100% because the product would otherwise not be monodisperse. In addition for PEG synthesis, the automated method could be readily adapted for the synthesis of a wide range of sequence-defined oligomers and polymers.