Quadruple click reactions for the synthesis of cysteine-terminated linear multiblock copolymers

Synthesis of cysteine-terminated linear polystyrene (PS)-b-poly(ε- caprolactone) (PCL)-b-poly(methyl methacrylate) (PMMA)/or poly(tert-butyl acrylate)(PtBA)-b-poly(ethylene glycol) (PEG) copolymers was carried out using sequential quadruple click reactions including thiol-ene, copper-catalyzed azide-alkyne cycloaddition (CuAAC), Diels-Alder, and nitroxide radical coupling (NRC) reactions. N-acetyl-L-cysteine methyl ester was first clicked with α-allyl-ω-azide-terminated PS via thiol-ene reaction to create α-cysteine-ω-azide-terminated PS. Subsequent CuAAC reaction with PCL, followed by the introduction of the PMMA/or PtBA and PEG blocks via Diels-Alder and NRC, respectively, yielded final cysteine-terminated multiblock copolymers. By ¹H NMR spectroscopy, the DP _ns of the blocks in the final multiblock copolymers were found to be close to those of the related polymer precursors, indicating that highly efficient click reactions occurred for polymer-polymer coupling. Successful quadruple click reactions were also confirmed by gel permeation chromatography.