Metalloenzymes catalyze various reactions and in particular dioxygenases insert dioxygen into organic substrates. Since these enzymes usually utilize histidines as ligands for the metal cofactor, we focused our attention on the 3-His-1-carboxylate binding motif as it has been shown recently to be a common feature of the cupin superfamily. Most structural and functional models studied substitute the imidazole rings by pyrazoles, pyridines and alkyl amines to simplify the synthetic challenge. However, the different donor/acceptor properties and basicity of imidazole render these models inaccurate. We therefore developed the synthesis of imidazole-containing ligand mimics of the 3-His-1-carboxylate motif. The synthesis of the known tris[(4)-imidazolyl]carbinol, 4-TIC 31, a mimic of the 3-His binding motif, was improved and optimized making this ligand now easily accessible on gram scale. This access allowed us to characterize its 2:1 complex with iron (III) 52 by X-ray crystallography, the first crystal structure of a metal complex incorporating 4-TIC.

Moreover, we also report the synthesis of a functionalized mixed tripodal unit bearing a short side-chain 73. Its coordination chemistry has been explored and a 2:1 cobalt complex was prepared and characterized by X-ray crystallography 104. The coordination properties of the ligand can be described as an N2O-donor. We also expanded the synthetic route to incorporate an extended side-chain onto a mixed tripodal unit 106. However, the coordination chemistry was difficult due to the low solubility of the ligands in polar aprotic organic solvents and its propensity to form intractable solids when mixed with metal ions. We thus optimized the ligand design and synthesized 105 with a N3O binding mode with Cu (II) and characterized complex 129 by X-ray crystallography. Complex 129 is the first structural model complex of the 2,3-quercetin dioxygenase incorporating all three imidzoles and a carboxylate functional group and is compared to the active site of the enzyme.