Gold(III) Aryl Complexes as Reagents for Constructing Hybrid Peptide-Based Assemblies via Cysteine S-Arylation

Organometallic complexes have recently gained attention as competent bioconjugation reagents capable of introducing a diverse array of substrates to biomolecule substrates. Here, we detail the synthesis and characterization of an aminophosphine-supported Au(III) platform that provides rapid and convenient access to a wide array of peptide-based assemblies via cysteine S-arylation. This strategy results in the formation of robust C-S covalent linkages and is an attractive method for the modification of complex biomolecules due to the high functional group tolerance, chemoselectivity, and rapid reaction kinetics associated with these arylation reactions. This work expands upon existing metal-mediated cysteine arylation by introducing a class of air-stable organometallic complexes that serve as robust bioconjugation reagents enabling the synthesis of conjugates of higher structural complexity including macrocyclic stapled and bicyclic peptides as well as a peptide-functionalized multivalent hybrid nanocluster. This organometallic-based approach provides a convenient, one-step method of peptide functionalization and macrocyclization, and has the potential to contribute to efforts directed toward developing efficient synthetic strategies of building new and diverse hybrid peptide-based assemblies.