Synthesis of cysteine-terminated linear polystyrene (PS)-b-poly(e-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 azidealkyne cycloaddition (CuAAC), DielsAlder, and nitroxide radical coupling (NRC) reactions. N-acetyl-L-cysteine methyl ester was first clicked with a-allyl-?-azide-terminated PS via thiol-ene reaction to create a-cysteine-?-azide-terminated PS. Subsequent CuAAC reaction with PCL, followed by the introduction of the PMMA/or PtBA and PEG blocks via DielsAlder and NRC, respectively, yielded final cysteine-terminated multiblock copolymers. By 1H NMR spectroscopy, the DPns 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 polymerpolymer coupling. Successful quadruple click reactions were also confirmed by gel permeation chromatography. (C) 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012