Aliphatic C–C Bond Cleavage of α-Hydroxy Ketones by Non-Heme Iron(II) Complexes: Mechanistic Insight into the Reaction Catalyzed by 2,4′-Dihydroxyacetophenone Dioxygenase

Abstract

2,4'-Dihydroxyacetophenone dioxygenase (DAD) is a bacterial non-heme enzyme that carries out oxygenative aliphatic C-C bond cleavage of 2,4'-dihydroxyacetophenone (an α-hydroxy ketone) with the incorporation of both the oxygen atoms of dioxygen into the cleavage products. The crystal structure of the iron enzyme DAD has recently been determined, but very little is known about the mechanism of the C-C bond cleavage reaction. With the objective of gaining insights into the mechanism of the reaction catalyzed by DAD, six new biomimetic iron(II)-α-hydroxy ketone complexes, [(Tp(Ph2))Fe(II)(PHAP)] (1), [(Tp(Ph2))Fe(II)(HCH)] (2), [(Tp(Ph2))Fe(II)(HBME)] (3), [(Tp(Ph2))Fe(II)(CHPE)] (4), [(6-Me3-TPA)Fe(II)(PHAP)](+) (5), and [(6-Me3-TPA)Fe(II)(HCH)](+) (6) (Tp(Ph2) = hydrotris(3,5-diphenylpyrazol-1-yl)borate, 6-Me3-TPA = tris(6-methyl-2-pyridylmethyl)amine, PHAP-H = 2-phenyl-2-hydroxyacetophenone, HCH-H = 2-hydroxycyclohexanone, HBME-H = 2-hydroxy-1,2-bis(4-methoxyphenyl)ethanone, and CHPE-H = 1-(4-chlorophenyl)-2-hydroxy-2-phenylethanone), have been isolated and characterized. The single-crystal X-ray structure of 2 shows a five-coordinate iron(II) complex with one tridentate facial ligand and a monoanionic bidentate α-hydroxy ketone, resulting in a distorted-square-pyramidal coordination geometry at the iron center. The iron(II) complexes react with dioxygen to oxidatively cleave the aliphatic C-C bonds of the coordinated α-hydroxy ketones to afford 2 equiv of carboxylic acids. Mechanistic studies reveal that the C-C bond cleavage reaction proceeds through an intradiol pathway. Additionally, the coordinated α-hydroxy ketones in all of the complexes, except in complex 4, undergo two-electron oxidation to form the corresponding 1,2-diketones. However, the yields of 1,2-diketones are higher with the iron complexes of the tripodal N4 ligand (6-Me3-TPA) in comparison to the facial N3 ligand (Tp(Ph2)). These results strongly support the natural selection of a facial N3 environment at the active site of the iron enzyme DAD.

Bio‐inspired Oxidation of 1‐Aminocarboxylic Acids by a Nonheme Iron(II) Complex: Mimicking the Activity of 1‐Aminocyclopropane‐1‐carboxylic Acid Oxidase

“…Similar binding mode of ACC has been observed in structurally characterized (BPMEN)Fe II ‐ACC complex . The iron‐nitrogen bond lengths of 1 in the range of 2.139(2)–2.210(2) Å are in good agreement with the reported high‐spin iron(II) complexes of the Tp Ph2 ligand (Table ) , , . Of note, the crystal structure of the substrate bound ACCO enzyme reveals a mononuclear pentacoordinate iron(II) atom surrounded by two histidines (His177 and His234), one carboxylate (Asp179) residue of the protein backbone and a bidentate monoanionic ACC .…”

“…The colorless complexes did not show any characteristic CT bands in the optical spectra (Figure S1, Supporting Information). The 1 H NMR spectra of the complexes showed relatively sharp, well‐resolved and paramagnetically shifted proton resonances similar to other high‐spin iron(II) complexes of the Tp Ph2 ligand (Figures S2–S4, Supporting Information) …”

“…The 1 H NMR spectra of the complexes showed relatively sharp, wellresolved and paramagnetically shifted proton resonances similar to other high-spin iron(II) complexes of the Tp Ph2 ligand ( Figures S2-S4, Supporting Information). [22][23][24] The composition and binding mode of the ligands in the complexes 1 and 2 were confirmed by single-crystal X-ray diffraction studies ( Table 1). The iron(II)-ACC complex 1 crystallized from a solvent mixture of tetrahydrofuran and hexane (1:2 ratio) at room temperature.…”

“…[18] The ironnitrogen bond lengths of 1 in the range of 2.139(2)-2.210(2) Å are in good agreement with the reported high-spin iron(II) complexes of the Tp Ph2 ligand ( Table 2). [22,23,26] Of note, the crystal structure of the substrate bound ACCO enzyme reveals a mononuclear pentacoordinate iron(II) atom surrounded by two histidines (His177 and His234), one carboxylate (Asp179) residue of the protein backbone and a bidentate monoanionic ACC. [6] The structure of 1 thus bears resemblance to the enzyme-substrate adduct and represents a structural model of ACCO.…”

Aliphatic C−C Bond Cleavage in α‐Hydroxy Ketones by a Dioxygen‐Derived Nucleophilic Iron–Oxygen Oxidant

“…[2,24] We recentlyr eported the CÀCb ond cleavage of ahydroxy ketones containing a-H atoms by iron(II) complexes of nitrogen-donor polydentate ligands. [25,26] However,t he iron(II) complexes were unable to cleave the CÀCb ond of the a-hydroxy ketones without a-CÀHb onds. Since an ucleophilic iron(III)-hydroperoxides peciesh as been invoked as ar eactive intermediate in the CÀCb ond cleavage reaction by CYP17A1, am etal basedn ucleophilic iron-oxygen speciesi se xpected to cleavet he CÀCb ond of a-hydroxyk etones.I nt his direction, we have investigatedt he reactivity of an iron(II)-benzilate complex, [(Tp Ph2 )Fe II (benzilate)] (1), [27] supported by af acial N 3 ligand( Scheme 2), toward various a-hydroxy ketones as model substrates.…”