Iron(II)-Thiolate S-Oxygenation by O₂: Synthetic Models of Cysteine Dioxygenase

Abstract

The synthesis of structural and functional models of the active site of the non-heme iron enzyme cysteine dioxygenase (CDO) is reported. A bis(imino)pyridine ligand scaffold was employed to synthesize a mononuclear ferrous complex, Fe II (LN 3 S)(OTf) (1), which contains 3 neutral nitrogen and one anionic thiolato donor. Complex 1 is a good structural model of the Cys-bound active site of CDO. Reaction of 1 with O 2 results in oxygenation of the thiolato sulfur, affording the sulfonato complex Fe II (LN 3 SO 3 )(OTf) (2) under mild conditions. Isotope labeling studies show that O 2 is the sole source of O atoms in the product, and that the reaction proceeds via a dioxygenase-type mechanism for two out of three O atoms added, analogous to the dioxygenase reaction of CDO. The zinc(II) analog, Zn(LN 3 S)(OTf) (4), was prepared and found to be completely unreactive toward O 2 , suggesting a critical role for Fe II in the oxygenation chemistry observed for 1. To our knowledge, S-oxygenation mediated by an Fe II -SR complex and O 2 is unprecedented.The utilization of O 2 for the oxidation of organic substrates is a critical process carried out by metalloenzymes, and a highly desirable one for synthetic chemists to replicate. Cysteine dioxygenase (CDO) is a mononuclear non-heme iron enzyme that catalyzes the Soxygenation of cysteine to cysteine sulfinic acid with O 2 as oxidant (Figure 1).1 Loss of CDO function has been correlated with Alzheimer's, Parkinson's, and other neurological disorders. CDO contains a mononuclear Fe II center bound by 3 His ligands, in contrast to the 2-His-1-carboxylate "facial triad" that is the canonical motif for non-heme Fe oxygenases. This unexpected structural variation suggests that the ligation of three neutral N donors may be important for CDO function.1h X-ray crystal structures of the native iron(II) CDO,1b a Cys-bound complex,1c and an intriguing Cys-persulfenate species1f have been determined (Figure 1). Little is known regarding the mechanism of CDO, although the persulfenate structure suggests an Fe-O 2 intermediate may be important.Herein we describe the first structural and functional synthetic models of CDO. To obtain biologically relevant models, we targeted polydentate ligand platforms that would 1) provide 3 neutral N donors, 2) stabilize Fe II , 3) allow for the facile incorporation of a thiolate donorCorrespondence to: David P. Goldberg, dpg@jhu.edu. Supporting Information Available: Experimental details, spectra, and crystallographic data for complexes 1, 3, and 4. This material is available free of charge via the Internet at htpp://pubs.acs.org. Attempts to crystallographically characterize 2 after O 2 addition were unsuccessful. However, demetalation and acid hydrolysis (1 M HCl), followed by quantitative reversephase HPLC (H 2 O/CH 3 CN 95/5, 0.1% TFA) shows that the expected oxygenated organic fragment 2-H 2 N-C 6 H 4 SO 3 H is formed in good yield (60%). These data confirm that Soxygenation occurs upon reaction of O 2 with 1. EPR spectra at 15 K of mixtures...

Activation of Dioxygen by Iron and Manganese Complexes: A Heme and Nonheme Perspective

“…134 An S -oxygenation reaction (Scheme 13) occurring from Fe II (SAr) + O 2 was described by our group in 2010. 140 A bis-imino pyridine (BIP) ligand (described as LN 3 S) providing three neutral N donors and a tethered thiolate donor was used in the former study. Reaction of [Fe II (LN 3 S)(OTf)] with O 2 in CH 2 Cl 2 (or in MeCN, THF) resulted in an immediate color change, and MS analysis of the reaction mixture was consistent with sulfonate formation (i.e., triple oxygenation at S).…”

Non‐Heme Imine‐Based Iron Complexes as Catalysts for Oxidative Processes

“…Complex [(LN 3 S)Fe(OTf)],w as indeed found to be highly reactive with atmospheric oxygen, forming the sulfonic acid in 60% yield (see Scheme 20a). [163] LDI-MSm onitoring of the reaction enabled detection of the intermediate sulfenate-iron complex, which is the product of the enzyme-catalyzed reaction, but it was not possible to stop the reaction at this stage.I sotopic analyses indicated that the oxygena toms inserted on the sulfurc enter come from atmospheric O 2 ,d emonstrating the dioxygenasetype activity of the complex. Iron was essential for the observed reactivity,a st he redox inactive Zn 2+ + complexd oes not react with O 2 .T he mechanism of O 2 activation was also computationally investigated.…”

A Trispyrazolylborato Iron Cysteinato Complex as a Functional Model for the Cysteine Dioxygenase

“…[5] In 2010, Goldberg et al showed for the first time that in an adequate ligand environment, Fe II À SR compounds can indeed react with O 2 selectively by S-oxygenation, whereas the SR function had been part of the ligand system (bis(imino)pyridine (BIP) framework) and was in the end triply oxygenated.…”