Dioxygen activation at mononuclear nonheme iron active sites: enzymes, models, and intermediates.

A new iron(III) halide-promoted aza-Prins cyclization between γ,δ-unsaturated tosylamines and aldehydes provides six-membered azacycles in good to excellent yields. The process is based on the consecutive generation of γ-unsaturated-iminium ion and further nucleophilic attack by the unsaturated carbon−carbon bond. Homoallyl tosylamine leads to trans-2-alkyl-4-halo-1-tosylpiperidine as the major isomer. In addition, the alkyne aza-Prins cyclization between homopropargyl tosylamine and aldehydes gives 2-alkyl-4-halo-1-tosyl-1,2,5,6-tetrahydropyridines as the only cyclic products. The piperidine ring is widely distributed throughout Nature, e.g., in alkaloids,1 and is an important scaffold for drug discovery, being the core of many pharmaceutically significant compounds.2,3 The syntheses of these type of compounds have been extensively studied in the development of new drugs containing six-membered-ring heterocycles.4 Reactions between N-acyliminium ions and nucleophiles, also described as amidoalkylation or Mannich-type condensations, have been frequently used to introduce substituents at the R-carbon of an amine.5 There are several examples that involve an intramolecular attack of a nucleophilic olefin into an iminium cation for the construction of a heterocyclic ring system.6 Traditionally, the use of hemiaminals or their derivatives as precursors of N-acyliminium intermediates has been a common two-step strategy in these reactions.6a Among this type of cyclization is the aza-Prins cyclization,7 which uses alkenes as intramolecular nucleophile. However, cy† X-ray analysis. E-mail address: malopez@ull.es. (1) (a) Fodor, G. B.; Colasanti, B. Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S. W., Ed.; Wiley: New York, 1985; Vol. 23, pp 1-90. (b) Baliah, V.; Jeyarama, R.; Chandrasekaran, L. Chem. ReV. 1983, 83, 379-423. (2) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679-3681. (3) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103, 893-930. (4) Buffat, M. G. P. Tetrahedron 2004, 60, 1701-1729 and references therein. (5) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3187- 3856 and references therein. (6) (a) Hiemstra, H.; Speckamp, W. N. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, O., Heathcock, C. H., Eds.; Pergamon: New York, 1991; Vol. 2, pp 1047-1081. (b) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367-4416. (7) (a) Dobbs, A. P.; Guesne, S. J. J.; Hursthouse, M. B.; Coles, S. J. Synlett 2003, 11, 1740-1742. (b) Dobbs, A. P.; Guesne, S. J. J.; Martinove, S.; Coles, S. J.; Hursthouse, M. B. J. Org. Chem. 2003, 68, 7880-7883. (c) Hanessian, S.; Tremblay, M.; Petersen, F. W. J. Am. Chem. Soc. 2004, 126, 6064-6071 and references therein. (d) Dobbs, A. P.; Guesne, S. J. Synlett 2005, 13, 2101-2103. ORGANIC

Iron-Catalyzed Reactions in Organic Synthesis

Direct C-H transformation via iron catalysis.

ion step follows the decarboxylation, which is consistent with the deuterium isotopic effects observed for thymine 7-hydroxylase which indicate that an irreversible step (or steps) occurs prior to the C-H bond breaking.395 It has also been shown for prolyl 4-hydroxylase that a substrate-derived radical is generated in the reaction, which is consistent with a rebound mechanism.437 It is important to point out that no oxygen intermediate (i.e., bridged superoxo or oxo-ferryl) has been observed for any R-KGdependent enzyme. This warrants future theoretical and experimental study. A detailed molecular mechanism has been proposed for IPNS based on spectroscopic and crystallographic studies.422 Resting IPNS/FeII is also 6C and thus relatively stable toward dioxygen. Substrate ACV binds directly to FeII IPNS through its thiolate group, providing an open coordination position at the FeII. O2 can then react to form an FeIII-superoxo intermediate. This intermediate is suggested422 to perform the first hydrogen-atom abstraction step and close the â-lactam ring, resulting in the formation of the first water molecule and generating an FeIVdO-II intermediate, which completes the second ringclosure process by hydrogen-atom abstraction forming a thiazolidine ring. Previously proposed mechanisms of ACCO involved direct binding of cosubstrate ascorbate to the iron before O2 as part of the oxygen activation process.438,439 The EPR and ESEEM studies of the NO complex of ACCO suggested a quite different molecular mechanism for ACCO.435 An FeIII-superoxo intermediate is proposed. Whether it is preceded by a 6C f 5C process with substrate binding is presently under study.440 This intermediate is thought to initiate a radical process by single hydrogen-atom abstraction or electron-coupled proton transfer (PT)ion or electron-coupled proton transfer (PT) from the bound amino group. The resulting substrate radical may undergo spontaneous conversion into products. The role of cosubstrate ascorbate is proposed to reduce the toxic peroxo byproduct to water. Alternatively, the two-electron reduction of FeIIIsuperoxo by the cosubstrate ascorbate could result in an FeIVdO-II intermediate which initiates the radical reaction.435 4. Rieske-Type Dioxygenases Biochemical Characterization. The Rieske ironsulfur center is a two iron-two sulfur cluster ([2Fe2S]) which has a 2His (on one iron), 2Cys (on the other iron) coordination environment, instead of the 4Cys present in plant ferredoxins. It plays a key role in the electron transport pathway in membranebound cytochrome complexes as well as in some dioxygenases.441 The latter are mainly comprised of two protein components: a reductase containing flavin and a ferredoxin [2Fe-2S], and a terminal oxygenase containing a Rieske [2Fe-2S] cluster and a non-heme iron active site.442 Except for the recently reported alkene monooxygenase that has a binuclear iron site in its terminal oxygenase,10 most of the Rieske-type oxygenases have a mononuclear iron site, which is believed to be the site of dioxygen activation and substrate oxygenation.442,443 The majority of the Rieske-type mononuclear non-heme oxygenases form a family of enzymes which are aromatic-ring-hydroxylating dioxygenases. These catalyze the regioand stereospecific cis-dihydroxylation of an aromatic ring using dioxygen and NAD(P)H (Table 1). Examples include benzene dioxygenase (BDO, EC 1.14.12.3),444 phthalate dioxygenase (PDO, EC 1.14.12.7),445 toluene dioxygenase (EC 1.14.12.11),446 and naphthalene 1,2-dioxygenase (NDO, EC 1.14.12.12),447 which initiate the aerobic degradation of aromatic compounds in the soil bacteria and are targets for bioengineering in bioremediation. This step is the first step in the pathway that ultimately leads to ring cleavage by the intraand extradiol dioxygenases (sections II.B.2 and II.C.1).443 Besides these bacterial dioxygenases, other Rieske-type mononuclear non-heme oxygenases include anthranilate 1,2-dioxygenase (EC 1.14.12.1),448 which deaminates and decarboxylates the substrate to produce catechol; chlorophenylacetate 3,4-dioxygenase (EC 1.14.2.13),449 which converts substrate to catechol with chloride elimination; and 4-methoxybenzoate O-demethylase (putidamonooxin),450 which catalyzes the conversion of 4-methoxybenzoic acid to 4-hydroxybenzoic acid and formaldehyde. The reductase component is usually a monomer (MW ) 12-15 kDa) and utilizes flavin to mediate ET from the two-electron donor NAD(P)H to the oneelectron acceptor [2Fe-2S] cluster and is specific to each terminal oxygenase; other electron donors do not support efficient oxygenation.442 The crystal structure of phthalate dioxygenase reductase is available.451 The terminal oxygenases are large protein aggregates (MW ) 150-200 kDa) containing either multiples of R subunits (BDO R2, PDO R4) or an equimolar combination of R and â subunits (toluene dioxygenase R2â2, NDO R3â3). The R subunits contain a Rieske [2Fe-2S] cluster and a catalytic non-heme FeII center. â subunits do not seem to be involved in the catalytic function (vide infra). Kinetics. Steady-state kinetic studies coupled with various rapid reaction studies of the partial reactions of PDO allowed Ballou et al. to propose a kinetic scheme (Scheme 15).443 On the basis of steady state 278 Chemical Reviews, 2000, Vol. 100, No. 1 Solomon et al.

Geometric and Electronic Structure/Function Correlations in Non-Heme Iron Enzymes

Iron Catalysis in Organic Synthesis

Biomimetic nonheme iron catalysts for alkane hydroxylation

Mononuclear iron(III) species with end-on and side-on peroxide have been proposed or identified in the catalytic cycles of the antitumor drug bleomycin and a variety of enzymes, such as cytochrome P450 and Rieske dioxygenases. Only recently have biomimetic analogues of such reactive species been generated and characterized at low temperatures. We report the synthesis and characterization of a series of iron(II) complexes with pentadentate N5 ligands that react with H2O2 to generate transient low-spin FeIII−OOH intermediates. These intermediates have low-spin iron(III) centers exhibiting hydroperoxo-to-iron(III) charge-transfer bands in the 500−600-nm region. Their resonance Raman frequencies, νO-O, near 800 cm-1 are significantly lower than those observed for high-spin counterparts. The hydroperoxo-to-iron(III) charge-transfer transition blue-shifts and the νO-O of the Fe−OOH unit decreases as the N5 ligand becomes more electron donating. Thus, increasing electron density at the low-spin Fe(III) center we...

/pdf/end-on-and-side-on-peroxo-derivatives-of-non-heme-iron-5bnil0aqlu.pdf

End-on and side-on peroxo derivatives of non-heme iron complexes with pentadentate ligands: models for putative intermediates in biological iron/dioxygen chemistry.

Modeling Rieske Dioxygenases: The First Example of Iron-Catalyzed Asymmetric cis-Dihydroxylation of Olefins

In an effort to gain more insight into the factors controlling the formation of low-spin non-heme FeIII−peroxo intermediates in oxidation catalysis, such as activated bleomycin, we have synthesized a series of iron complexes based on the pentadentate ligand N4Py (N4Py = N,N-bis(2-pyridylmethyl)-N-(bis-2-pyridylmethyl)amine). The following complexes have been prepared:  [(N4Py)FeII(CH3CN)](ClO4)2 (1), [(N4Py)FeIICl](ClO4) (2), [(N4Py)FeIIIOMe](ClO4)2 (3), and [(N4Py)2Fe2O](ClO4)4 (4). Complexes 1 and 2 have low- and high-spin FeII centers, respectively, whereas 3 is an FeIII complex that undergoes a temperature-dependent spin transition. The iron centers in the oxo-bridged dimer 4 are antiferromagnetically coupled (J = −104 cm-1). Comparison of the crystal structures of 1, 3, and 4 shows that the ligand is well suited to accommodate both FeII and FeIII in either spin state. For the high-spin FeIII complexes 3 and 4 the iron atoms are positioned somewhat outside of the cavity formed by the ligand, while in ...

https://pure.rug.nl/ws/files/3629027/1999InorgChemRoelfesSupp.pdf

Iron Chemistry of a Pentadentate Ligand That Generates a Metastable Fe(III)-OOH Intermediate.

The reactions of FeIII(TPA) (TPA = tris(2-pyridylmethyl)amine) complexes with 2-methyl-1-phenyl-2-propyl-hydroperoxide (MPPH) delivered by syringe pump under anaerobic conditions afford nearly quantitative conversion of MPPH to products derived from the benzyl radical. These results unequivocally show that MPPH breaks down by O−O bond homolysis, leading to the formation of the benzyl radical and a high valent Fe(IV)O species. Without added substrates, the benzyl radical reacts with the high valent species to form benzyl alcohol or benzyl halides. The Fe(IV)O species can also effect the two-electron oxidation of added substrates such as thioanisole, cyclohexanol, and cyclooctene under appropriate conditions. The oxidation of thioanisole and cyclohexanol is likely facilitated by pre-equilibrium binding of the substrate to the metal center, allowing these substrates to intercept the high valent iron−oxo species as it forms. These results suggest the importance of close proximity to direct the high valent met...

Kui Chen

Papers

Biomimetic nonheme iron catalysts for alkane hydroxylation

End-on and side-on peroxo derivatives of non-heme iron complexes with pentadentate ligands: models for putative intermediates in biological iron/dioxygen chemistry.

Modeling Rieske Dioxygenases: The First Example of Iron-Catalyzed Asymmetric cis-Dihydroxylation of Olefins

Iron Chemistry of a Pentadentate Ligand That Generates a Metastable Fe(III)-OOH Intermediate.

"Intermolecular" trapping of a nonheme Fe(IV)=O intermediate.