C−H Bond Activation by a Ferric Methoxide Complex:  A Model for the Rate-Determining Step in the Mechanism of Lipoxygenase

Abstract

Lipoxygenases (LOs) are mononuclear, non-heme iron enzymes found in both plants and animals that catalyze the oxidative conversion of 1,4-diene-containing fatty acids to alkyl hydroperoxides. 1,2 The rate-determining step (RDS) of the mechanism is generally accepted to be a hydrogen atom abstraction (HA) of the weak, substrate C-H bond (∼77 kcal/ mol) 3 to generate a substrate-radical which is subsequently trapped by dioxygen. 4,5 The species postulated to be responsible for the HA is a ferric-hydroxide complex, which is subsequently reduced by the H-atom to a ferrous-water complex (eq 1). 6 The reactivity of LOs under anaerobic conditions are consistent with this mechanism as substrate reduces the active ferric site and generates alkyl-radicals. 7,8 However, this mechanism contrasts with traditional biological mechanisms which are generally thought to proceed through a high-valent ironoxo or ferric-peroxy species. 9,10 Presented here is an example of C-H bond HA by a ferric-methoxide complex providing chemical precedent for the proposed RDS of LOs. Additionally, the properties of the substrates and products predict that this reaction is thermodynamically favorable. The chemical similarities of this model complex to the iron-sites in LOs strongly support a HA by a ferric-hydroxide species.The iron coordination environment in LOs generates an iron center with a very positive Fe(III)/Fe(II) reduction potential (∼0.6 V vs SHE). 11 X-ray structural analysis and spectroscopy suggest that 6-coordinate ferrous and ferric forms of soybean-1 LO have a single exogenous water and hydroxide ligand, respectively. 12-16 Of the remaining five endogenous ligands, only one is anionic, which is consistent with the positive redox potential. A short iron-ligand bond distance observed in the ferric form is attributed to a hydroxide ligand. 15 Reduction of this species results in little change in the coordination environment beyond lengthening a single iron-ligand bond distance.A new ligand has been designed and synthesized (Scheme 1) to mimic specific attributes of the iron coordination site in LOs, namely a 5-coordinate environment which can accommodate a sixth exogenous solvent ligand. The ligand, 2,6-bis-((2-pyridyl)methoxymethane)pyridine (PY5), is composed of five pyridine subunits and accommodates a single metal in a nearly idealized square pyramidal coordination. A 6-coordinate ferrous complex is isolated directly from a 1:1 mixture of Fe-(OTf) 2 and PY5 as a methanol solvate: [Fe(PY5)(MeOH)]-(OTf) 2 (1). 17 As in the resting state forms of the various plant and animal LOs, 18,19 the complex is air-stable and high-spin. 20 The structure of 1‚MeOH 21,22 reveals a 6-coordinate ferrous cation bound to all five of the pyridyl subunits and an exogenous methanol ligand. The Fe-O bond length of 2.04 Å is notably short for methanol bound to a divalent metal. The oxidation potential of +0.930 V (in methanol vs SHE), 21 is similar to other ferrous complexes composed of neutral nitrogen atom ligands. 23,24 Oxidation of 1 with 0.5 e...

Proton-Coupled Electron Transfer in Organic Synthesis: Fundamentals, Applications, and Opportunities

“…Exploiting the concept of bond-weakening upon coordination to redox-active metals [223][224][225][226][227][228][229][230][231][232], our lab demonstrated that a redox-active titanium catalyst Cp* 2 Ti III Cl and a weak hydrogen atom acceptor TEMPO enable intramolecular additions of amides to Michael acceptors ( Figure 32) [223]. The substrate scope allows for N-H activation of amides, carbamates, thiolcarbamates, and ureas bearing phenyl or electron-rich arenes in uniformly high yield.…”

The Role of Radicals in Metal‐Assisted Oxygenation Reactions

“…There are also a variety of biochemical processes that appear to involve one or more hydrogen-atom transfer steps, these include metal-free systems, such as the anticancer drug bleomycin and other DNA cleaving reagents, [50] but also systems where metals play decisive roles: Hydrogen-atom transfer has been implicated in the catalytic cycles of a variety of metalloenzymes, including the oxidation of fatty acids by lipoxygenases [51] (see above), the biosynthesis of dopamine, [52] and the processing of various metabolites and xenobiotics by cytochrome P450 enzymes.…”

Carbocations in the synthesis of prostaglandins by the cyclooxygenase of pgh synthase? a radical departure!

“…They have also been implicated, albeit less securely, in several oxygenase systems: the NIH shift~Vanelli & Hooper, 1995!, the decarboxylation by mevalonate pyrophosphate decarboxylase~Dhe-Paganon et al, 1994!, the formation of ethylene from nitrosoethylamines~Ding & Coon, 1988!, and the oxidation of heme to biliverdin~Ortiz de Montellano, 1998!. In studies on enzymes related to cytochrome P-450, which, like PG synthase, are heme-based but differ in requiring a sulfide ligand and NADH, no clear decision has been reached~Jonas & Stack, 1997;Collman et al, 1998;Mayer, 1998;Shaik et al, 1998;Toy et al, 1998;Vaz et al, 1998!. On the other hand, oxidation by methane monooxygenase appears to offer a case of the co-existence of radical and carbocationic modes. The catalytic site differs rather widely from that in PGH synthase as depends upon an oxodiiron cluster, with no requirement for heme, to oxidize simple hydrocarbons to monoalcohols~Green & Dalton, 1989;Lipscomb, 1994;Dalton & Wilkins, 1997;Mayer, 1998;Ortiz de Montellano, 1998!.…”