Heterotelechelic\nOrganometallic PEG Reagents Enable\nModular Access to Complex Bioconjugates

Organometallic oxidative addition complexes (OACs) have\nrecently\nemerged as a powerful class of reagents for the rapid and chemoselective\nmodification of biomolecules. Notably, the steric and electronic properties\nof the ligand and aryl group can be modified to tune the kinetic profile\nof the reaction and permit regioselective <i>S</i>-arylation.\nUsing the recently developed dicyclohexylphosphine-based bidentate <i>P</i>,<i>N</i>-ligated Au(III) OACs, we computationally\nand experimentally examined the effects of sterically bulky and electron\ndeficient aryl substrates to achieve selective <i>S</i>-arylation.\nWith this mechanistic insight, aryl substrates based on 4-iodoanisole\nand 3,5-dimethyl-4-iodoanisole were incorporated as end groups to\ngenerate a heterotelechelic bis-Au(III) poly(ethylene glycol) (PEG).\nThis reagent performed rapid and regioselective <i>S</i>-arylation with a model biomolecule, designed ankyrin repeat protein\n(DARPin), to form a protein–polymer OAC <i>in situ</i>. This OAC mediated a second <i>S</i>-arylation with biologically\nrelevant thiolated small molecules (metal chelator, saccharide, and\nfluorophore) and macromolecules (polymer and therapeutic peptide).\nIt is envisioned that this approach could be utilized for the rapid\nconstruction of biomacromolecular heteroconjugates with <i>S</i>-aryl linkages.