Heterotelechelic Organometallic PEG Reagents Enable Modular Access to Complex Bioconjugates.

Organometallic oxidative addition complexes (OACs) have recently emerged as a powerful class of reagents for the rapid and chemoselective modification of biomolecules. Notably, the steric and electronic properties of the ligand and aryl group can be modified to tune the kinetic profile of the reaction and permit regioselective S-arylation. Using the recently developed dicyclohexylphosphine-based bidentate P,N-ligated Au(III) OACs, we computationally and experimentally examined the effects of sterically bulky and electron deficient aryl substrates to achieve selective S-arylation. With this mechanistic insight, aryl substrates based on 4-iodoanisole and 3,5-dimethyl-4-iodoanisole were incorporated as end groups to generate a heterotelechelic bis-Au(III) poly(ethylene glycol) (PEG). This reagent performed rapid and regioselective S-arylation with a model biomolecule, designed ankyrin repeat protein (DARPin), to form a protein-polymer OAC in situ. This OAC mediated a second S-arylation with biologically relevant thiolated small molecules (metal chelator, saccharide, and fluorophore) and macromolecules (polymer and therapeutic peptide). It is envisioned that this approach could be utilized for the rapid construction of biomacromolecular heteroconjugates with S-aryl linkages.