Regiochemical Control in a Thiol-Epoxy 'Click' Reaction: Synthesis of Cysteine and Glutathione Chain-End Functionalized Polyethylene Glycols.

The cysteine-based thiol-epoxy 'click' reaction is demonstrated as an efficient and practical approach for the synthesis of zwitterionic structures. The transformation employs unprotected cysteine, proceeds in aqueous media, and affords quantitative conversions. Notably, acid- and base-catalyzed conditions provide exclusive access to different cysteine-based thioether regioisomers in aqueous conditions. The pH-responsive behavior of the resulting zwitterions is further elucidated by NMR spectroscopy. Finally, the synthetic strategy is extended to the preparation of cysteine- and glutathione-functionalized polyethylene glycol polymers, showcasing its utility for the preparation of amino acid-/peptide-containing macromolecular materials.