Phenylpropynones as Selective Disulfide Rebridging Bioconjugation Reagents

Simple 1-phenylpropynones undergo a selective double thia-Michael addition with thiols in buffered media, yielding an interesting dithioacetal linkage joining two thiols. The reactivity of various Michael-alkyne reagents is compared in this chemoselective, atom economical, and non-oxidative cross-linking of two thiols. The stability and chemical reactivity of the dithioacetal links are studied, and the utility of the disulfide targeting bioconjugation methodology is shown by the selective rebridging of native cyclic peptides after the reductive cleavage of their disulfide bridge.