Automated stepwise PEG synthesis using a base-labile protecting group. (30th July 2022)

• Record Type: Journal Article
• Authors: Eriyagama, Dhananjani N.A.M.; Yin, Yipeng; Fang, Shiyue
• Is Part Of: Tetrahedron. Volume 119(2022)
• Publication Date: 2022-07-30
• Subjects: Automation -- Base-labile -- PEG -- Protecting group -- Sequence-defined polymer -- Solid phase synthesis; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tet.2022.132861
• Languages: English
• ISSNs: 0040-4020

Abstract

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 TsOPEG5 O(CH2 )2 Ph, 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 PEGn O(CH2 )2 Ph product was cleaved from the resin with TFA. Using the automated method, high quality monodisperse PEG10 O(CH2 )2 Ph and PEG15 O(CH2 )2 Ph derivatives were synthesized. The PEG20 O(CH2 )2 Ph 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. Graphical abstract: Image 1 Highlights: Stepwise PEG synthesis was automated using a peptide synthesizer. The use of a base-labile protecting group shortened the synthesis cycle to two steps. The base-labile phenethyl protecting group is stable under basic coupling conditions. The base-labile protecting group makes deprotection and coupling more efficient. The method may be adapted for automated assembly of sequence-defined polymers.