Sequential Oxidation Reactions Research Articles

ChemInform Abstract: On‐Column Solvent‐Free Oxidative Cleavage Reactions of Vicinal Diols by Silica Gel and Paraperiodic Acid: Application to in situ Sequential Oxidation and Knoevenagel Reactions.

AbstractThe on‐column oxidative cleavage of vicinal diols proceeds without the need for toxic, volatible organic solvents or aqueous work‐up and does not require pre‐preparation of the supported oxidant.

Rake mechanism for the deoxygenation of ethanol over a supported Ni2P/SiO2 catalyst

The catalytic conversion of ethanol was studied on a metallic Ni2P/SiO2 catalyst, and comparison was made with an acidic HZSM-5 catalyst. Chemisorption probes indicated that the Ni2P had substantial CO adsorption sites (134μmolg−1), while the HZSM-5 catalyst had large quantities of NH3 adsorption sites (565μmolg−1). The catalytic activity in ethanol deoxygenation of the Ni2P/SiO2 was higher than that of the HZSM-5 catalyst on the basis of these chemisorptions sites.In steady-state catalysis, contact time experiments indicated that for Ni2P, acetaldehyde was a primary product and ethylene was a secondary product. However, this was not the result of a sequential oxidation reaction followed by a reduction process, but rather, it was due to the formation of a surface intermediate that could desorb as acetaldehyde or react further to produce ethylene. This rake-type mechanism was supported by a simulation of the reaction sequence that produced good agreement with the experimentally determined acetaldehyde and ethylene yields. The mechanism was also supported by in situ Fourier transform infrared measurements, which revealed the presence of signals compatible with adsorbed acetaldehyde, the likely surface intermediate species involved in the reaction. The present studies indicate that the reactions of alcohols on metallic catalysts like Ni2P involve dehydrogenation/hydrogenation steps, rather than simple acid/base-catalyzed dehydration steps as occur in HZSM-5.

Selective arene functionalization through sequential oxidative and non-oxidative Heck reactions

A sequence of acetamide directed oxidative Heck reaction and deacetylation-diazotation-Heck coupling allows the traceless removal of the acetamide group and its dual exploitation as a catalyst directing group and a leaving group.

Functional Importance of Tyrosine 294 and the Catalytic Selectivity for the Bis-Fe(IV) State of MauG Revealed by Replacement of This Axial Heme Ligand with Histidine,

The diheme enzyme MauG catalyzes the posttranslational modification of a precursor protein of methylamine dehydrogenase (preMADH) to complete the biosynthesis of its protein-derived tryptophan tryptophylquinone (TTQ) cofactor. It catalyzes three sequential two-electron oxidation reactions which proceed through a high-valent bis-Fe(IV) redox state. Tyr294, the unusual distal axial ligand of one c-type heme, was mutated to His, and the crystal structure of Y294H MauG in complex with preMADH reveals that this heme now has His-His axial ligation. Y294H MauG is able to interact with preMADH and participate in interprotein electron transfer, but it is unable to catalyze the TTQ biosynthesis reactions that require the bis-Fe(IV) state. This mutation affects not only the redox properties of the six-coordinate heme but also the redox and CO-binding properties of the five-coordinate heme, despite the 21 Å separation of the heme iron centers. This highlights the communication between the hemes which in wild-type MauG behave as a single diheme unit. Spectroscopic data suggest that Y294H MauG can stabilize a high-valent redox state equivalent to Fe(V), but it appears to be an Fe(IV)═O/π radical at the five-coordinate heme rather than the bis-Fe(IV) state. This compound I-like intermediate does not catalyze TTQ biosynthesis, demonstrating that the bis-Fe(IV) state, which is stabilized by Tyr294, is specifically required for this reaction. The TTQ biosynthetic reactions catalyzed by wild-type MauG do not occur via direct contact with the Fe(IV)═O heme but via long-range electron transfer through the six-coordinate heme. Thus, a critical feature of the bis-Fe(IV) species may be that it shortens the electron transfer distance from preMADH to a high-valent heme iron.

Advanced glycation end products in diabetic and non-diabetic human subjects suffering from cataract

Advanced glycation end products (AGEs) play a pivotal role in loss of lens transparency, i.e., cataract. AGEs formation occurs as a result of sequential glycation and oxidation reaction between reducing sugars and protein. AGEs production takes place throughout the normal aging process but its accumulation is found to be more rapid in diabetic patients. In this study, we quantified AGEs and N-(carboxyethyl) lysine (CEL) in human cataractous lenses from non-diabetic (n=50) and diabetic patients (n=50) using ELISA. We observed significantly higher (p<0.001) levels of lens AGEs and CEL in diabetic patients with cataract as compared with their respective controls. The presence of AGEs and CEL was also determined by western blotting and immuno-histochemical analysis. Furthermore, isolated β-crystallin from cataractous lenses of non-diabetic and diabetic patients was incubated with different sugars to evaluate the extent of glycation in a time dependent manner. Our data indicated more pronounced glycation in patients suffering from diabetes as compared to non-diabetics subjects demonstrating the need to focus on developing normoglycemic approaches. Such studies may provide an insight in developing therapeutic strategies and may have clinical implications.

New kinetic and thermodynamic approach of one-pot synthesis of chiral alcohol by oxidoreductase from Candida parapsilosis

The stereoinversion process involving two sequential stereoselective oxidation and reduction reactions by oxidoreductases was a typical and important one-pot method for chiral secondary alcohol synthesis which has great potential for industrial application. The process to produce (S)-1-phenyl-1,2-ethanediol with whole cell was chosen as a model reaction to investigate the kinetic and thermodynamic properties of key enzymes which catalyzed the single oxidation and reduction step of the whole reaction. The kinetic data from initial rate experiments in the absence of product prove that both oxidation and reduction reactions follow Theorell-Chance BiBi mechanism. Parameters of V m and Δ S suggest that the oxidation reaction was thermodynamically unfavorable and the restrictive step of the one-pot process was inhibited at high concentration of substrate PED. To remove the inhibition of substrate, extractive biocatalytic methods were successfully applied to improve the substrate PED concentration from 15 g/l to 50 g/l with high optical purity of 91.6% and yield of 82.5%.

Azide as a Probe of Proton Transfer Reactions in Photosynthetic Oxygen Evolution

In oxygenic photosynthesis, photosystem II (PSII) is the multisubunit membrane protein responsible for the oxidation of water to O2 and the reduction of plastoquinone to plastoquinol. One electron charge separation in the PSII reaction center is coupled to sequential oxidation reactions at the oxygen-evolving complex (OEC), which is composed of four manganese ions and one calcium ion. The sequentially oxidized forms of the OEC are referred to as the Sn states. S1 is the dark-adapted state of the OEC. Flash-induced oxygen production oscillates with period four and occurs during the S3 to S0 transition. Chloride plays an important, but poorly understood role in photosynthetic water oxidation. Chloride removal is known to block manganese oxidation during the S2 to S3 transition. In this work, we have used azide as a probe of proton transfer reactions in PSII. PSII was sulfate-treated to deplete chloride and then treated with azide. Steady state oxygen evolution measurements demonstrate that azide inhibits oxygen evolution in a chloride-dependent manner and that azide is a mixed or noncompetitive inhibitor. This result is consistent with two azide binding sites, one at which azide competes with chloride and one at which azide and chloride do not compete. At pH 7.5, the Ki for the competing site was estimated as 1mM, and the Ki′ for the uncompetitive site was estimated as 8mM. Vibrational spectroscopy was then used to monitor perturbations in the frequency and amplitude of the azide antisymmetric stretching band. These changes were induced by laser-induced charge separation in the PSII reaction center. The results suggest that azide is involved in proton transfer reactions, which occur before manganese oxidation, on the donor side of chloride-depleted PSII.

Perturbations at the chloride site during the photosynthetic oxygen-evolving cycle

Photosystem II (PSII) catalyzes the oxidation of water to O2 at the manganese-containing, oxygen-evolving complex (OEC). Photoexcitation of PSII results in the oxidation of the OEC; four sequential oxidation reactions are required for the generation and release of molecular oxygen. Therefore, with flash illumination, the OEC cycles among five Sn states. Chloride depletion inhibits O2 evolution. However, the binding site of chloride in the OEC is not known, and the role of chloride in oxygen evolution has not as yet been elucidated. We have employed reaction-induced FT-IR spectroscopy and selective flash excitation, which cycles PSII samples through the S state transitions. On the time scale employed, these FT-IR difference spectra reflect long-lived structural changes in the OEC. Bromide substitution supports oxygen evolution and was used to identify vibrational bands arising from structural changes at the chloride-binding site. Contributions to the vibrational spectrum from bromide-sensitive bands were observed on each flash. Sulfate treatment led to an elimination of oxygen evolution activity and of the FT-IR spectra assigned to the S3 to S0 (third flash) and S0 to S1 transitions (fourth flash). However, sulfate treatment changed, but did not eliminate, the FT-IR spectra obtained with the first and second flashes. Solvent isotope exchange in chloride-exchanged samples suggests flash-dependent structural changes, which alter protein dynamics during the S state cycle.

CYP4F Enzymes Are the Major Enzymes in Human Liver Microsomes That Catalyze the O-Demethylation of the Antiparasitic Prodrug DB289 [2,5-Bis(4-amidinophenyl)furan-bis-O-methylamidoxime

DB289 [2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime] is biotransformed to the potent antiparasitic diamidine DB75 [2,5-bis(4-amidinophenyl) furan] by sequential oxidative O-demethylation and reductive N-dehydroxylation reactions. Previous work demonstrated that the N-dehydroxylation reactions are catalyzed by cytochrome b5/NADH-cytochrome b5 reductase. Enzymes responsible for catalyzing the DB289 O-demethylation pathway have not been identified. We report an in vitro metabolism study to characterize enzymes in human liver microsomes (HLMs) that catalyze the initial O-demethylation of DB289 (M1 formation). Potent inhibition by 1-aminobenzotriazole confirmed that M1 formation is catalyzed by P450 enzymes. M1 formation by HLMs was NADPH-dependent, with a Km and Vmax of 0.5 microM and 3.8 nmol/min/mg protein, respectively. Initial screening showed that recombinant CYP1A1, CYP1A2, and CYP1B1 were efficient catalysts of M1 formation. However, none of these three enzymes was responsible for M1 formation by HLMs. Further screening showed that recombinant CYP2J2, CYP4F2, and CYP4F3B could also catalyze M1 formation. An antibody against CYP4F2, which inhibited both CYP4F2 and CYP4F3B, inhibited 91% of M1 formation by HLMs. Two inhibitors of P450-mediated arachidonic acid metabolism, HET0016 (N-hydroxy-N'-(4-n-butyl-2-methylphenyl)formamidine) and 17-octadecynoic acid, effectively inhibited M1 formation by HLMs. Inhibition studies with ebastine and antibodies against CYP2J2 suggested that CYP2J2 was not involved in M1 formation by HLMs. Additionally, ketoconazole preferentially inhibited CYP4F2, but not CYP4F3B, and partially inhibited M1 formation by HLMs. We conclude that CYP4F enzymes (e.g., CYP4F2, CYP4F3B) are the major enzymes responsible for M1 formation by HLMs. These findings indicate that, in human liver, members of the CYP4F subfamily biotransform not only endogenous compounds but also xenobiotics.

Cyclization and Ring-expansion Reactions Involving Reductive Formation and Oxidative Ring-opening of Cyclopropanol Derivatives

Abstract FeCl3-promoted regioselective ring-opening reactions of cyclopropyl trimethylsilyl ethers, obtained by SmI2 reduction followed by silylation with Me3SiCl of bromoalkyl ketones and acyl chloride, were performed. Eventually, the sequential reduction and oxidation reactions starting from bromoalkyl ketones to give ring-expanded enones were achieved in one-pot.

14C]Pentachlorophenol mineralization in the rice rhizosphere with established oxidized and reduced soil layers

Flooded soils with rooted aquatic macrophytes have adjacent aerobic and anaerobic zones at the soil–water interface and rhizosphere where many common soil constituents undergo sequential oxidation and reduction reactions. To investigate whether pentachlorophenol (PCP) mineralization would also be enhanced under these conditions, a laboratory study was conducted to determine the conversion of [ 14C]PCP to 14CO 2, 14CH 4 and [ 14C]humic substances in soil microcosms with established aerobic–anaerobic zones at the soil–water interface and rice ( Oryza sativa) rhizosphere. Contrary to what was expected, PCP was least rapidly degraded in rhizosphere-soil microcosms that contained the most extensive amounts of aerobic–anaerobic interfaces (63% PCP loss in 82 d) and was most rapidly degraded in soil microcosms that lacked redox interfaces in the soil profile (94% PCP loss in 82 d). Decreased PCP mineralization in the presence of aerobic–anaerobic interfaces was explained by (i) lack of sufficient O 2 for aerobic PCP mineralization, due to the oxidation of other soil constituents in aerobic zones, and (ii) lack of an adequate supply of electron equivalents for reductive dechlorination of PCP, due to the reduction of other alternate electron acceptors in anaerobic zones. It was concluded that PCP mineralization is inhibited in flooded soils that contain extensive amounts of aerobic-anaerobic interfaces, due to redox cycling of other soil constituents that occur in these zones.

Functional studies of frataxin

Mitochondria generate adenosine triphosphate (ATP) but also dangerous reactive oxygen species (ROS). One-electron reduction of dioxygen in the early stages of the electron transport chain yields a superoxide radical that is detoxified by mitochondrial superoxide dismutase to give hydrogen peroxide. The hydroxyl radical is derived from decomposition of hydrogen peroxide via the Fenton reaction, catalyzed by Fe2+ ions. Mitochondria require a constant supply of Fe2+ for heme and iron-sulfur cluster biosyntheses and therefore are particularly susceptible to ROS attack. Two main antioxidant defenses are known in mitochondria: enzymes that catalytically remove ROS, e.g. superoxide dismutase and glutathione peroxidase, and low molecular weight agents that scavenge ROS, including coenzyme Q, glutathione, and vitamins E and C. An effective defensive system, however, should also involve means to control the availability of pro-oxidants such as Fe2+ ions. There is increasing evidence that this function may be carried out by the mitochondrial protein frataxin. Frataxin deficiency is the primary cause of Friedreich's ataxia (FRDA), an autosomal recessive degenerative disease. Frataxin is a highly conserved mitochondrial protein that plays a critical role in iron homeostasis. Respiratory deficits, abnormal cellular iron distribution and increased oxidative damage are associated with frataxin defects in yeast and mouse models of FRDA. The mechanism by which frataxin regulates iron metabolism is unknown. The yeast frataxin homologue (mYfhlp) is activated by Fe(II) in the presence of oxygen and assembles stepwise into a 48-subunit multimer (α48) that sequesters <2000 atoms of iron in a ferrihydrite mineral core. Assembly of mYfhlp is driven by two sequential iron oxidation reactions: a fast ferroxidase reaction catalyzed by mYfh1p induces the first assembly step (αα3), followed by a slower autoxidation reaction that promotes the assembly of higher order oligomers yielding α48. Depending on the ionic environment, stepwise assembly is associated with the sequestration of 50–75 Fe(II)/subunit. This Fe(II) is initially loosely bound to mYfh1p and can be readily mobilized by chelators or made available to the mitochondrial enzyme ferrochelatase to synthesize heme. However, as iron oxidation and mineralization proceed, Fe(III) becomes progressively inaccessible and a stable iron-protein complex is produced. In conclusion, by coupling iron oxidation with stepwise assembly, frataxin can successively function as an iron chaperon or an iron store. Reduced iron availability and solubility and increased oxidative damage may therefore explain the pathogenesis of FRDA.

Functional studies of frataxin.

Mitochondria generate adenosine triphosphate (ATP) but also dangerous reactive oxygen species (ROS). One-electron reduction of dioxygen in the early stages of the electron transport chain yields a superoxide radical that is detoxified by mitochondrial superoxide dismutase to give hydrogen peroxide. The hydroxyl radical is derived from decomposition of hydrogen peroxide via the Fenton reaction, catalyzed by Fe2+ ions. Mitochondria require a constant supply of Fe2+ for heme and iron-sulfur cluster biosyntheses and therefore are particularly susceptible to ROS attack. Two main antioxidant defenses are known in mitochondria: enzymes that catalytically remove ROS, e.g. superoxide dismutase and glutathione peroxidase, and low molecular weight agents that scavenge ROS, including coenzyme Q, glutathione, and vitamins E and C. An effective defensive system, however, should also involve means to control the availability of pro-oxidants such as Fe2+ ions. There is increasing evidence that this function may be carried out by the mitochondrial protein frataxin. Frataxin deficiency is the primary cause of Friedreich's ataxia (FRDA), an autosomal recessive degenerative disease. Frataxin is a highly conserved mitochondrial protein that plays a critical role in iron homeostasis. Respiratory deficits, abnormal cellular iron distribution and increased oxidative damage are associated with frataxin defects in yeast and mouse models of FRDA. The mechanism by which frataxin regulates iron metabolism is unknown. The yeast frataxin homologue (mYfh1p) is activated by Fe(II) in the presence of oxygen and assembles stepwise into a 48-subunit multimer (alpha48) that sequesters >2000 atoms of iron in a ferrihydrite mineral core. Assembly of mYfhlp is driven by two sequential iron oxidation reactions: a fast ferroxidase reaction catalyzed by mYfh1p induces the first assembly step (alpha --> alpha3), followed by a slower autoxidation reaction that promotes the assembly of higher order oligomers yielding alpha48. Depending on the ionic environment, stepwise assembly is associated with the sequestration of < or = 50-75 Fe(II)/subunit. This Fe(II) is initially loosely bound to mYfh1p and can be readily mobilized by chelators or made available to the mitochondrial enzyme ferrochelatase to synthesize heme. However, as iron oxidation and mineralization proceed, Fe(III) becomes progressively inaccessible and a stable iron-protein complex is produced. In conclusion, by coupling iron oxidation with stepwise assembly, frataxin can successively function as an iron chaperon or an iron store. Reduced iron availability and solubility and increased oxidative damage may therefore explain the pathogenesis of FRDA.

Yeast Frataxin Sequentially Chaperones and Stores Iron by Coupling Protein Assembly with Iron Oxidation

We have investigated the mechanism of frataxin, a conserved mitochondrial protein involved in iron metabolism and neurodegenerative disease. Previous studies revealed that the yeast frataxin homologue (mYfh1p) is activated by Fe(II) in the presence of O2 and assembles stepwise into a 48-subunit multimer (alpha48) that sequesters >2000 atoms of iron in 2-4-nm cores structurally similar to ferritin iron cores. Here we show that mYfh1p assembly is driven by two sequential iron oxidation reactions: A ferroxidase reaction catalyzed by mYfh1p induces the first assembly step (alpha --> alpha3), followed by a slower autoxidation reaction that promotes the assembly of higher order oligomers yielding alpha48. Depending on the ionic environment, stepwise assembly is associated with accumulation of 50-75 Fe(II)/subunit. Initially, this Fe(II) is loosely bound to mYfh1p and can be readily mobilized by chelators or made available to the mitochondrial enzyme ferrochelatase to synthesize heme. Transfer of mYfh1p-bound Fe(II) to ferrochelatase occurs in the presence of citrate, a physiologic ferrous iron chelator, suggesting that the transfer involves an intermolecular interaction. If mYfh1p-bound Fe(II) is not transferred to a ligand, iron oxidation, and mineralization proceed to completion, Fe(III) becomes progressively less accessible, and a stable iron-protein complex is formed. Iron oxidation-driven stepwise assembly is a novel mechanism by which yeast frataxin can function as an iron chaperone or an iron store.

Practical asymmetric synthetic route to 4,4,4-trifluoro-3-hydroxybutyrate: head-to-tail and head-to-head crystallizations through double and single hydrogen bonds of hetero- and homochiral 4,4,4-trifluoro-3-hydroxybutyrophenones.

A practical asymmetric synthetic route to 4,4,4-trifluoro-3-hydroxybutyrophenone and the butyric acid phenyl ester is described using heterochiral crystallization through double hydrogen bonding assembly in head-to-tail fashion and sequential Baeyer-Villiger oxidation reaction by trifluoroperacetic acid.

METABOLISM OF TERRITREM A BY LIVER MICROSOMES OF WISTAR RATS: IDENTIFICATION OF THE METABOLITES AND THEIR METABOLIC SEQUENCE

The metabolism of territrem A (TRA) was investigated in liver microsomes of male Wistar rats. The results indicated that three metabolites were produced from TRA and these metabolic reactions were inhibited by metyrapone, an inhibitor of cytochrome P450. Based on analysis by high-performance liquid chromatography (HPLC), mass, and nuclear magnetic resonance (NMR) spectroscopic techniques, the structure of these metabolites were identified as 4 g -hydroxymethyl-4 g -demethylterritrem A (MA 1 ), 4 g oxo-4 g -demethylterritrem A (MAX), and 2-dihydro-4 g -demethylterritrem A (MA ). It 2 was proposed that reactions proceeded by three sequential oxidative reactions in the pyran moiety of TRA: first, hydroxylation at the 4 g -C methyl group of TRA to form MA 1 ; second, oxidation at the 4 g -C hydroxyl group of MA to form MAX; and third, decar1 bonylation at the 4 g -C oxo group of MAX to form MA 2 .

Oxidation of the CDE Rings of Pentacyclic Quinoline Compounds Derived from Tetrahydroalstonine

New polycyclic 8,9-dihydro-7H-indolizino[1,2-b]quinolin-11-ones have been synthesized from tetrahydroalstonine (2) through sequential oxidation reactions.

Behavior of phenolic antioxidants in a partitioned medium: Focus on linoleic acid peroxidation induced by iron/ascorbic acid system

AbstractThe peroxidation of linoleic acid was induced by the Fe2+/ascorbic acid system in a micellar medium, and the kinetics of the produced conjugated dienes to a weak level (0.7 μM) in order to initiate only the sequential oxidative reactions without superimposed antioxidant activity. Other conditions were established to obtain a simple kinetic profile. With a linoleic acid/Fe2+ ratio of 10 and an Fe2/ascorbic acid ratio of 23 in the medium emulsified by Tween and saturated in oxygen, no limiting effect of substrates was observed for several hours. Fe2+ disappeared in less than 5 min, while a linear propagation rate was reached after 1 h for up to 15 h. Two parameters were chosen to quantify the level of the oxidation: the slope of the linear phase, and the extrapolated absorbance of this step at zero time. These two parameters were used in order to compare the antioxidant power of different phenolic compounds in this partitioned medium.

Partial synthesis of camptothecin analogs. Part 1: Pyrroloquinolone and pyrroloquinoline derivatives

Pyrroloquinolone 7 and pyrroloquinoline derivatives 11a-c have been synthesized from the alkaloid tetrahydroalstonine 1 according to sequential oxidation reactions.

Role of the Maillard reaction in diabetes mellitus and diseases of aging.

Advanced glycation end-products (AGEs) are formed by spontaneous chemical reactions between carbohydrates and tissue proteins. The accumulation of AGEs in long-lived proteins contributes to the age-related increase in brown colour, fluorescence and insolubilisation of lens crystallins and to the gradual crosslinking and decrease in elasticity of connective tissue collagens with age. These nonenzymatic reactions, known collectively as Maillard or browning reactions, are also implicated in the development of pathophysiology in age-related diseases such as diabetes mellitus, atherosclerosis, Alzheimer's disease, and in dialysis-related amyloidosis. Oxygen and oxidation reactions accelerates Maillard reactions in vitro, and the structurally characterised AGEs that accumulate in long-lived tissue proteins are in fact glycoxidation products, formed by sequential glycation and oxidation reactions. In addition to their immediate effects on protein structure and function, AGEs also induce oxidative stress, leading to inflammation and propagation of tissue damage. Thus, glycation of protein, formation of AGEs and resultant oxidative stress, which accelerate Maillard reactions, can initiate an autocatalytic cycle of deleterious reactions in tissues. Pharmacological inhibition of the Maillard reaction should improve the prognosis for a broad range of age-related diseases. The role of oxidative stress as a catalyst and the consequences of Maillard reaction damage in tissues suggests that antioxidant therapy may also retard the progression of age-related pathology.