A synthetic quest for tris(imidazolyl) carboxylates and their metal complexes: active site models for quercetin 2,3-dioxygenases and other non-heme redox metalloenzymes

Abstract

Synthetic routes to tris(imidazolyl)carboxylate ligands and representative metal complexes are reported, which provide more accurate active site models for several classes of redox metalloenzymes. In the first route a hydroxypivalate ester is converted in four regioselective steps to an imidazole diester 4; this is then converted to tris(imidazolyl)carboxylic acid ligand 9, featuring regiospecific double addition of an N-protected lithio-imidazole to an imidazole diester 8. Ligand 9 forms a Co(III) complex, (9)(9-H)Co (10), characterized by X-ray diffraction, coordinated via two imidazole units and the carboxylate. A second route was developed, which provides more soluble ligands that are less prone to form oligomeric complexes. It utilizes addition of the Grignard reagent from 4-iodo-2-isopropylimidazole 12 to an imidazole diester 13, producing atropisomeric tris(imidazolyl)carbinol esters 15M. Treatment of 15M with [Cu(CH3CN)4]PF6 gives a trinuclear complex 16 having alkoxide bridges between neighboring Cu atoms. A third route avoids the bridging alkoxo groups by reduction of tris(imidazolyl)carbinol 15M to the tris(imidazolyl)methane ester 17, which is hydrolyzed to the tris(imidazolyl)methane carboxylic acid 11a. This ligand reacts with [Cu(CH3CN)4]PF6 to produce dinuclear complex [(11a-H)2Cu2](PF6)2 (18), whose X-ray crystal structure shows each copper in a distorted square pyramidal geometry with coordination to the three imidazoles and two bridging carboxylate oxygens. Complex 18 is geometrically similar to the active site copper in quercetin 2,3-dioxygenase.