Dihydro Compounds Research Articles

Electron transfer. 140. Reactions of riboflavin with metal center reductants.

Riboflavin (I) is reduced in separable steps by indium(I), vanadium(II), europium(II), and titanium(III) in 0.02-1.0 M H+, yielding first the radical ion, II (lambdamax = 495 nm), and then the dihydro compound, III. The initial reduction with InI yields 2 equiv of the radical, but kinetic profiles exhibit no irregularity due to intervention of In(II), indicating that participation by the dipositive state is much more rapid than the In(I) reaction. Predominant paths involve the protonated form of the flavin, RbH+, and that of the radical, RbH2.+. Formation of the radical with excess V(II) and Ti(III) (but not with In(I)) is strongly autocatalytic, reflecting rapid comproportionation involving the flavin and the dihydro compound. The V(II) and Ti(III) rates for both steps greatly exceed the substitution-controlled limits for these states and therefore pertain to outer-sphere processes. The very high ratio kEu/kv for the first step, however, points to an inner-sphere reduction by the lanthanide cation. A kinetic inversion is observed for In(I) (kRbH.+ > kRbH2.+), implying a bridged reduction path for the initial step with this center as well.

Konfigurations- und konformationsisomere paratrope, rotationsdynamische Tetraepoxy[32]annulene(6.2.6.2) und diatrope Tetraoxa[30]porphyrin(6.2.6.2)-Dikationen: Nachweis eines Tetraepoxy[31]annulen(6.2.6.2)-Radikalkations

Configurational and Conformational Isomeric Paratopic, Rotational Dynamics Tetraepoxy[30]annulenes(6.2.6.2) and Diatropic Tetraoxa[30]porphyrin(6.2.6.2) Dications: Detection of a Tetraepoxy[31]annulene(6.2.6.2)Radical Cation The synthesis of tetraepoxy[32]annulenes(6.2.6.2) (4) by a cyclizing twofold Wittig reaction of (E,E,E)-5,5′-(hexa-1,3,5-triene-1,6-diyl)bis[furan-2-carbaldehyde] (6) and the corresponding bis-phosphonium salt 7 is described (Scheme 1). Contrary to the configuration of the educts, the obtained annulenes 4a and 4b are (Z,E,E,E,Z,E,E,E)- and (E,Z,E,E,E,Z,E,E)-configurated, respectively. The 1H-NMR spectra establish the paratropic, antiaromatic character of 4. The annulenes 4 are highly dynamic systems, the (E)-ethenediyl bridges rotate around the adjacent σ-bonds, these rotations are frozen at −80°. The McMurry condensation of dialdehyde 6 yields the (E,E,Z,E,E,E,Z)-4,5-dihydrotetraepoxy[32]annulene(6.2.6.2) (13a), where the configuration of the dialdehyde 6 – beside the hydrogenated double bond – is retained. As result of an intramolecular McMurry reaction of 6, (Z,E,Z,Z)-dioxa[16]annulene(6.2) 14 is formed. By oxidation of the [32]annulenes(6.2.6.2) 4a and 4b, a mixture of the four stereoisomeric tetraoxa[30]porphyrin(6.2.6.2) dications 5a/5a′/5b/5c is obtained; the configuration of the isomers is determined by COSY, NOESY, and NOE experiments. The Δδ values (26.81, 25.83, and 21.11 ppm) underline the diatropic, aromatic character of the dications 5, the Soret bands are shifted bathochromically to 550 nm, and the Q-bands are in the NIR region (896 – 1039 nm). The dihydroannulene 13a is dehydrogenated by p-chloroanil (tetrachloro-1,4-benzoquinone) to give the annulenes 4a and 4b, its oxidation with DDQ (=4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile) results in the same mixture of dications 5. Entirely different results are obtained by reaction of the dihydroannulene 13a with DDQ. Here, the (E,E,E,Z,E,E,E,Z) tetraoxa[30]porphyrin(6.2.6.2) dication 5c – formed only in traces from 4a/4b – is the main product. Beside 5c, a by-product (3%) can be isolated, which turns out (ESR, conductivity) to be the (E,E,E,Z,E,E,E,Z)-tetraoxa[31]porphyrin(6.2.6.2) radical cation 16, obviously the intermediate in the oxidation sequence of the annulene to the dication. This result leads to the conclusion that the reaction of the dihydro compound 13a with p-chloroanil and DDQ follows different reaction mechanisms. For all isolated stereoisomeric tetraepoxy annulenes and tetraoxaporphyrin dications, the ΔHf values are calculated by the semiempiric AM1 method. The results are in agreement with the experimental observations. All data confirm the antiaromaticity of the tetraepoxy[32]annulenes(6.2.6.2) 4 and the aromaticity of the tetraoxa[30]porphyrin(6.2.6.2) dications.

ChemInform Abstract: Reinvestigation of Birch Reduction of Benzo[1,3]dioxoles and Further Transformations of the Resulting Dihydro Compounds.

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Calcium/Calmodulin-dependent Conversion of 5-Oxoeicosanoids to 6,7-Dihydro Metabolites by a Cytosolic Olefin Reductase in Human Neutrophils

We previously showed that 6-trans isomers of leukotriene B4 but not leukotriene B4 itself are converted to dihydro metabolites by human neutrophils. The first step in the formation of these metabolites is oxidation of the 5-hydroxyl group by 5-hydroxyeicosanoid dehydrogenase. The objective of the present investigation was to characterize the second step in the formation of the dihydro metabolites, reduction of an olefinic double bond. We found that the olefin reductase reduces the 6,7-double bond of 5-oxoeicosanoids, is localized in the cytosolic fraction of neutrophils, and requires NADPH as a cofactor. Neutrophil cytosol converts a variety of both 5-oxo- and 15-oxoeicosanoids to dihydro products. However, conversion of 5-oxoeicosanoids to their 6,7-dihydro metabolites is inhibited by EGTA and a calmodulin antagonist and stimulated by the addition of calcium and calmodulin, whereas the reduction of 15-oxoeicosanoids to their 13,14-dihydro metabolites is slightly inhibited by calcium. Furthermore, eicosanoid Delta6- and Delta13-reductases could be separated by chromatography on DEAE-Sepharose. 5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is converted by the Delta6-reductase to 6,7-dihydro-5-oxo-ETE, which is 1000 times less potent than 5-oxo-ETE in mobilizing calcium in neutrophils. We conclude that neutrophils contain both 5-oxoeicosanoid Delta6-reductase and prostaglandin Delta13-reductase. Metabolism of 5-oxo-ETE by the Delta6-reductase results in loss of its biological activity.

Reinvestigation of Birch Reduction of Benzo[1,3]dioxoles and Further Transformations of the Resulting Dihydro Compounds

Reinvestigation of Birch Reduction of Benzo[1,3]dioxoles and Further Transformations of the Resulting Dihydro Compounds

SYNTHESIS AND INVESTIGATION OF MAO INHIBITORS: HYDRAZONES OF POTENTIAL BRAIN-SPECIFIC DELIVERY

A series of 1-methyl-3-[N-(substituted benzalimino)carbamoyl] pyridinium iodide and their corresponding dihydropyridines were prepared by conventional methods. The prepared compounds were tested in vitro for their MAO inhibitory activity on liver mitochondria by kynuramine fluorimetric assay. The results showed that MAOI activity of quaternaries is more than the corresponding dihydro compounds.

The molecular structures of three germacrolides related to parthenolide

The germacrolide-class sesquiterpene lactone, 1,10-epoxyparthenolide, C15H20O4,1, crystallizes with two independent molecules in monoclinic space groupP21 witha=10.6845(5),b=9.0763(4),c=15.4326(7) A, β=105.887(4)°,V=1439.4(3) A3,Z=4.R=0.037 for 2425 observed data. Its 11βH, 13-dihydro-derivative 1,10-epoxydihydroparthenolide, C15H22O4,2, crystallizes in orthorhombic space groupP212121 witha=7.6414(10),b=12.559(2),c=14.6821(14) A,V=1409.0(3) A3 Z=4.R=0.031 for 1555 observed data. The corresponding unexposidized compound, 11βH,13-dihydrocostunolide, C15H22O2,3, crystallizes with three independent molecules in orthorhombic space groupP212121 witha=7.3576(5),b=23.505(3),c=24.185(2) A,V=4182(1) A3,Z=12.R=0.070 for 2767 observed data. In all, the 10-membered rings adopt approximate chair-chair conformations. In all, the double bonds or epoxidized double bonds are E, both methyl groups on the 10-ring are β, and the α-methylene-γ-lactone (or α-methyl-γ-lactone) istrans-fused at C6 and C7 with H6 β and H7 α. In the dihydro compounds, the H at C11 is β.

Benzimidazolene-2-thiones: A New Class of Molecules for the Engineering of Molecular Tapes in the Organic Solid State

Derivatives of benzimidazolene-2-thione differing in substitution at the 4 and 5 positions have been synthesized and studied by single-crystal X-ray diffraction and/or X-ray powder diffraction. These derivatives include five monosubstituted compounds (1-SX; X = Me, F, Cl, Br, I), four disubstituted compounds (1-SX2; X = Me, F, Cl, Br), the parent dihydro compound (1-SH2), and the naphthyl compound (2-SH2). Five of these molecules gave crystals suitable for single-crystal X-ray diffraction. In all of these crystals, the molecules pack as parallel, hydrogen-bonded tapes. Alternate molecules of a tape occupy two different planes that are separated by approximately 1 A. The resulting structure is named a stepped tape. These stepped tapes are divided into two classes based on packing: tapes of 1-SH2, 1-SMe2, and 1-SF pack in flat, parallel planes. Tapes of 2-SH2, 1-SF2, and 1-SCl2 pack at an angle; of these, two (2-SH2 and 1-SF2) incorporate molecules of solvent. None of the structures is isomorphic.

Preparation and Properties of 1,1′-Disubstituted Δ2,2′-Bi-5,6-dihydropyrrolo[2,1-a]isoquinolin-3(2H)-one Dimers with a Twisted C=C Bond

Abstract 1,1′-Dimethyl and 1,1′-dichloro derivatives of the titled dimeric compound were prepared. A twisting of the central C2=C2′ double bond in the above-mentioned dimers was suggested based on the bathochromism observed in the absorption spectra. The 1,1′-dimethyl dimer was autoxidized at the enamine-type C1=C10b double bond to give 1,10b-dioxygenated products, while the 1,1′-dichloro dimer underwent a chlorine–hydrogen exchange to yield a 1,1′-dihydro compound upon heating in n-BuOH and 1,1,2,2-tetrachloroethane. These reactions might result from a strain around the twisted C2=C2′ double bond of the 1,1′-disubstituted dimers.

Stereochemistry of the Dihydro Compound From Lithium/Ammonia Reduction of 3-Methoxy-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran-6-one

X-Ray crystallography has established that the lithium/ammonia reduction of 3-methoxy-7,8,9,10-tetrahydro-6H-dibenzo[ b,d ]pyran-6-one gives the cis-dihydro compound (6aRS,10aSR)-3-methoxy-6a,7,8,9,10,10a-hexahydro-6H-dibenzo[ b,d ]pyran-6-one (7).

Nucleophilic addition of lithio derivatives to 1-substituted benzo[c][2,7]naphthyridines (2,9-diazaphenanthrenes)

Nucleophilic addition of lithio derivatives to 1-substituted benzo[c][2,7]naphthyridines and rearomatization of the intermediate dihydro compounds with MnO2 gives good overall yields of product.

Electron transfer 120. Reductions of the cuboidal mixed-valence molybdenum/sulfur cluster, [Mo 4S 4(H 2O) 12] 5+

The cuboidal mixed-valence Mo/S cluster, [Mo 4S 4(H 2O) 12] 5+ ( I), in which each of the four equivalent Mo atoms assumes a mean oxidation state of 3.25, is reduced to the isostructural Mo(III) tetramer, [Mo 4S 4(H 2O) 12] 4+, by equimolar quantities of Ti(III), Cr(II), Eu(II), V(II), Ru(NH 3) 6 2+ and Co II(sepulchrate), as well as by radicals derived from flavin-like heterocycles and by dihydro derivatives of these heterocycles. Reaction rates are independent of H + (within the range 0.5–2.0 M H +) for the metal center reductants and for the radicals, but feature prominent [H +] −1 -proportional terms for the dihydro compounds. All reactions appear to be outer-sphere. The deprotonated form of the dihydroriboflavin reacts 600 times more rapidly than the corresponding radical, a selectivity similar to that previously observed with an array of Co(III) oxidants. Specific rates for reductions by the metal-ion centers, in conjunction with the treatment of Marcus, lead to a self-exchange rate 10 3.8±1.6 M −1 s −1 for the couple [Mo 4S 4] 5+/4+. The latter lies very close to that recorded for the truncated cuboidal trinuclear OH-bridged system, Mo IV,III,III/(Mo III) 3. It is possible that the observed correspondence in rates reflects a similarity in net valence change in the absence of major alterations in bond connectivities or in molecular geometry.

Heteroatom-directed lateral lithiation: synthesis of isoquinoline derivatives from N-(tert-butoxycarbonyl)-2-methylbenzylamines

Methodology for the preparation of isoquinoline derivatives from N-(tert-butoxycarbonyl)-2-methylbenzylamines (1) was developed. Conversion of 1 to the dilithio species followed by condensation with DMF afforded Boc-3-hydroxy-1,2,3,4-tetrahydroisoquinolines 3, which could be dehydrated to 1,2-dihydroisoquinolines 4. Hydrogenation of dihydro compounds 4 afforded the corresponding tetrahydroisoquinolines 5. Treatment of the dilithio species from 1 with N-methoxy-N-methylamides afforded ketones 14, which were converted to 3-substituted dihydro-isoquinoline 15, tetrahydroisoquinolines (16, 17), or isoquinolines (20).

Biotransformation of 1,2-dihydronaphthalene and 1,2-dihydroanthracene by rat liver microsomes and purified cytochromes P-450. Formation of arene hydrates of naphthalene and anthracene.

Both 1,2-dihydronaphthalene and 1,2-dihydroanthracene were hydroxylated at the benzylic (1-) or the allylic (2-) position by rat liver microsomes and purified cytochrome P-450 enzymes to yield "arene hydrates". Two other classes of metabolites were formed, the dehydrogenation products naphthalene and anthracene, and trans-1,2-dihydroxy-1,2,3,4-tetrahydronaphthalene and its anthracene analog as products of the classical expoxide pathway. Regioselectivity (hydroxylation at benzylic or allylic positions) and stereoselectivity (hydroxylation at pro-R or pro-S hydrogen atoms) during metabolism of dihydroarenes to yield arene hydrates were found to be dependent upon the nature of the inducing agents used during pretreatment of the rats and thus the level of particular P-450 enzymes. This selectivity was more pronounced for anthracene than for naphthalene. Naphthalene and anthracene were formed enzymatically by direct dehydrogenation of the dihydro compounds rather than by dehydration of the arene hydrate metabolites. A general mechanism involving the intermediacy of benzylic and resonance-stabilized allylic carbon radicals can account for the formation of both enzyme-catalyzed hydroxylation (arene hydrate) and dehydrogenation (arene) metabolites of dihydroarene substrates.

Semiconductor Photocatalysis: Reaction Mechanisms for the Photoreductive cis–trans Isomerization of Electron-Deficient Alkenes Catalyzed by CdS Powder

Abstract Highly pure commercially available CdS powder (99.999%) catalyzes the effective cis–trans photoisomerization of electron-deficient alkenes under visible light irradiation using triethylamine (TEA) as an electron donor, accompanying the formation of the dihydro compound as a two-electron reduction product. The photoisomerization does not occur at all in the absence of TEA. Donor effect, solvent effect, deuterium incorporation experiments for photocatalysis, and MOPAC molecular orbital calculation (MNDO/PM3) of the intermediary radical anions from the alkenes were investigated in order to elucidate the mechanism of this photoisomerization. These results reveal that the CdS-catalyzed cis–trans photoisomerization should proceed through two pathways involving the photoreduction of alkenes: one through the back electron transfer from the radical anion of the alkene (alkene−•) towards the radical cation of TEA (TEA+•), both formed by photoexcited conduction band electrons and holes of CdS, respectively. The other is the reoxidation of a radical intermediate (alkyl•), formed by protonation of alkene−•, by TEA+•.

Synthesis of Cyclopent[a]azulenes and 1(3)-Methylenecyclopent[a]azulene Derivatives Having an Electron Withdrawing Group at the 9-Position

Abstract 1H- and 3H-Cyclopent[a]azulenes having an electron withdrawing group, such as a methoxycarbonyl or a cyano group, at the 9-position were synthesized from their dihydro compounds by means of bromination with NBS and succeeding dehydrobromination by refluxing in chloroform. Base-catalyzed condensation of these cyclopent[a]azulenes with carbonyl compounds afforded 1-methylene-1H- and 3-methylene-3H-cyclopent[a]azulene derivatives having an electron withdrawing group at the 9-position. The physical properties of these methylenecyclopent[a]azulenes are also discussed.

The [2,3] Wittig rearrangement: Studies toward the synthesis of the bicyclic core structure of the enediyne antibiotics

The dihydro compound 14 related to the bicyclic core structure of dynemicin and calicheamicin/esperamicin was obtained by a [2,3] Wittig ring contraction of the cyclic ether 13. Similar attempts with 4 gave the 12-membered carbocycle 6 resulting from a [1,2] shift.

Visible-light-induced photocatalysis of poly(pyridine-2,5-diyl). Photoreduction of water, carbonyl compounds and alkenes with triethylamine

Poly(pyridine-2,5-diyl)(PPy) exhibits heterogeneous and visible-light-induced photocatalysis toward the reduction of water, carbonyl compounds and alkenes in the presence of triethylamine (TEA) as a sacrifical electron donor. The water reductive H2 evolution is ehnanced by colloidal noble metals concurrently photoformed from noble metal halides, and colloidal Ru gives the highest apparent quantum yield of H2, 0.21 at 450 nm. With regard to the reduction of carbonyl compounds and electron-deficient alkenes, noble-metal-free PPy leads to the efficient and selective reduction to the corresponding alcohols and dihydro compounds, respectively. Carbonyl compounds whose reduction potentials are as negative as –1.83 V vs. SCE in acetonitrile are photoreducible. Deuterium incorporation experiments with dimethyl maleate and/or dimethyl fumarate in [O-2H]methanol have revealed that the photocatalysis of PPy should proceed through sequential two-electron transfer reduction, affording dideuteriated dimethyl succinate. Sequential electron transfer and hydride transfer mechanisms are proposed.

Metabolism of 12(R)-hydroxy-5,8,10,14-eicosatetraenoic acid (12(R)-HETE) in corneal tissues: Formation of novel metabolites

12( R)-Hydroxy-5,8,10,14-eicosatetraenoic acid [12( R)-HETE], a cytochrome P450 arachidonate metabolite, is metabolized by corneal tissues via three distinct metabolic pathways: β-oxidation, ω-hydroxylation, and keto-reduction. The major metabolite released from the intact rabbit corneal epithelium or cultured cells was identified by mass spectrometric analysis as 8-hydroxy-4,6,10-hexadecatrienoic acid, the tetranor metabolite derived following two steps of β-oxidation from the carboxy terminus. The β-oxidation pathway was expressed in both microsomes and mitochondria isolated from bovine corneal epithelium and was dependent on the addition of oxidizing equivalents. The major metabolite of 12( R)-HETE in subcellular fractions of bovine corneal epithelial cells was a dihydro compound, 12-hydroxy-5,8,14-eicosatrienoic acid (12-HETrE). This derivative is presumably formed by an oxidation of the hydroxyl group followed by two keto-reduction steps, since its formation was accompanied by the appearance of a keto metabolite identified as 12-oxo-5,8,14-eicosatrienoic acid. The ω-hydroxylation, in contrast to other cell types, was a minor route for 12( R)-HETE metabolism in these tissues. Since 12( R)-HETE has been implicated as a modulator of Na +-K +-ATPase activity and its related functions in ocular tissues, these findings raise the possibility that the newly described metabolites may be involved in regulating corneal functions. In addition, the presence of a keto reductase in the cornea may be of great importance following injury since 12( R)-HETrE resulting from 12( R)-HETE by this activity is a potent ocular proinflammatory compound.

Theoretical studies on the dihydrofolate reductase mechanism: electronic polarization of bound substrates.

We have applied local density functional theory, an ab initio quantum mechanical method, to study the shift in the spatial electron density of the substrate dihydrofolate that accompanies binding to the enzyme dihydrofolate reductase. The results shed light on fundamental electronic effects due to the enzyme that may contribute to catalysis. In particular, the enzyme induces a long-range polarization of the substrate that perturbs its electron density distribution in a specific and selective way in the vicinity of the bond that is reduced by the enzyme. Examination of the electron density changes that occur in folate reveals that a similar effect is seen but this time specifically at the bond that is reduced in this substrate. This suggests that the polarization effect may be implicated in the reaction mechanism and may play a role in determining the sequence whereby the 7,8-bond in folate is reduced first, followed by reduction of the 5,6-bond in the resulting dihydro compound.