Regio- and enantioselective hydrolysis of phenyloxiranes catalyzed by soluble epoxide hydrolase

The regio- and enantioselective hydrolysis of several phenyloxiranes catalyzed by soluble epoxide hydrolase (sEH) was investigated using recombinant human, mouse or cress sEH. Results indicate that human and mouse sEH enantioselectively hydrolyze (S,S)-alkyl-phenyloxiranes faster than the (R,R)-alkyl-phenyloxiranes investigated in this study, while cress sEH displayed opposite enantioselectivity. Preparation of pure (2R,3R)-3-phenylglycidol from the racemic mixture was achieved with a 31% yield using human sEH as catalyst. The sEH enzymes were found to be regioselective at the benzylic carbon of the phenyloxiranes, supporting the proposed mechanism in which one or more tyrosine residues in the active site of the enzyme act as a general acid catalyst in the alkylation half reaction.     

Theoretical study of the full reaction mechanism of human soluble epoxide hydrolase

The complete reaction mechanism of soluble epoxide hydrolase (sEH) has been investigated by using the B3LYP density functional theory method. Epoxide hydrolases catalyze the conversion of epoxides to their corresponding vicinal diols. In our theoretical study, the sEH active site is represented by quantum-chemical models that are based on the X-ray crystal structure of human soluble epoxide hydrolase. The trans-substituted epoxide (1S,2S)-beta-methylstyrene oxide has been used as a substrate in the theoretical investigation of the sEH reaction mechanism. Both the alkylation and the hydrolytic half-reactions have been studied in detail. We present the energetics of the reaction mechanism as well as the optimized intermediates and transition-state structures. Full potential energy curves for the reactions involving nucleophilic attack at either the benzylic or the homo-benzylic carbon atom of (1S,2S)-beta-methylstyrene oxide have been computed. The regioselectivity of epoxide opening has been addressed for the two substrates (1S,2S)-beta-methylstyrene oxide and (S)-styrene oxide.     

Insights into the reaction mechanism of soluble epoxide hydrolase from theoretical active site mutants

Density functional theory calculations of active site mutants are used to gain insights into the reaction mechanism of the soluble epoxide hydrolases (sEHs). The quantum chemical model is based on the X-ray crystal structure of the human soluble epoxide hydrolase. The role of two conserved active site tyrosines is explored through in silico single and double mutations to phenylalanine. Full potential energy curves for hydrolysis of (1S,2S)-beta-methylstyrene oxide are presented. The results indicate that the two active site tyrosines act in concert to lower the activation barrier for the alkylation step. For the wild-type and three different tyrosine mutant models, the regioselectivity of epoxide opening is compared for the substrates (1S,2S)-beta-methylstyrene oxide and (S)-styrene oxide. An additional part of our study focuses on the importance of the catalytic histidine for the alkylation half-reaction. Different models are presented to explore the protonation state of the catalytic histidine in the alkylation step and to evaluate the possibility of an interaction between the nucleophilic aspartate and the catalytic histidine.     

Synthesis of highly modular bis(oxazoline) ligands by Suzuki cross-coupling and evaluation as catalytic ligands

New bis(oxazoline) ligands (BOXs) containing biaryl substitutents at the C-4 position and H or CH₂OR substituents at the C-5 position have been synthesized using Suzuki cross-coupling as the main tool for structural diversity. Copper, zinc, and palladium complexes of the prepared BOXs have been evaluated in the following catalytic asymmetric processes: Acylation with kinetic resolution of trans-1,2-cyclohexanediol (Cu), enantioselective Friedel-Crafts alkylation of indole (Zn), and enantioselective alkylation of 3-acetoxy-1,3-diphenylpropene (Pd).     

Electrocyclic Ring Opening Reactions of Ethylene Oxides

Substituents capable of stabilizing negative charge endow ethylene oxides with the ability to undergo electrocyclic ring opening at the CC bond; heating or irradiation generates small equilibrium concentrations of carbonyl ylides which can engage in 1,3-dipolar cycloadditions. Apart from the normal conrotatory mode of ring opening, predicted by the Woodward-Hoffmann rules, the disrotatory process, forbidden by orbital symmetry, also appears to occur in the case of α-cyano-cis-stilbene oxide. Kinetic studies on α-cyano-trans -and -cis-stilbene oxide permit construction of the energy profile for electrocyclic ring opening to give the stereoisomeric carbonyl ylides and for their recyclization and rotation.     

Reactive properties of trans-dichlorooxirane in relation to the contrasting carcinogenicities of vinyl chloride and trans-dichloroethylen

Our objective in this work is to gain insight into the contrasting carcinogenic activities of vinyl chloride (definitely carcinogenic) and trans-dichloroethylene (apparently inactive). The initial metabolic step for each molecule is believed to be epoxidation of the double bond, and there is evidence indicating that for vinyl chloride, this epoxide (chlorooxirane) is its ultimate (direct-acting) carcinogenic form. This article presents the findings of a computational study of the reactive properties of trans-dichlorooxirane (the epoxide of trans-dichloroethylene). An ab initio SCF -MO procedure was used to determine the energy requirements for stretching the C? O and C? Cl bonds (S_N1 reactivity) and to study the epoxide's S_N2 interactions with ammonia, taken as a model nucleophile. The starting points were the oxygen- and chlorine-protonated forms of the epoxide. The structure of the system was reoptimized at each step along the various reaction pathways. The results of this work are compared to an analogous earlier study of the reactive properties of chlorooxirane. The chlorineprotonated C? Cl bonds are found to have much lower energy barriers to stretching than do the oxygen-protonated C? O bonds. In the S_N2 processes, intermediate complexes are formed with ammonia by both the oxygen- and the chlorine-protonated epoxides; the latter complexes are the more stable. Based on our results, we propose two mechanisms (one S_N1 and the other S_N2) whereby trans-dichlorooxirane can interact with N₇ of guanine to produce an adduct analogous to one formed by chlorooxirane, which has been found to be the primary in vivo DNA alkylation product of vinyl chloride and to which has been attributed the carcinogenicity of the latter. Overall, trans-dichlorooxirane is found to be chemically more reactive than chlorooxirane; this may help to account for the much lesser carcinogenic and mutagenic activities of trans-dichloroethylene, since the epoxide may be reacting with other cellular nucleophiles before it reaches the key site(s) at which the carcinogenic or mutagenic interaction would occur. We also offer some speculations concerning other possible factors related to the differing carcinogenicities of vinyl chloride and trans-dichloroethylene, such as ease of epoxide formation and the likelihood of oxygen protonation.     

Synthesis of adamantyl-containing 1,3-disubstituted diureas and thioureas,efficient targeted inhibitors of human soluble epoxide hydrolase

A series of adamantyl-containing 1,3-disubstituted diureas and thioureas containing different spacers between the ureylene group and the adamantyl substituent has been synthesized, their inhibitory activity against mammalian and human soluble epoxide hydrolase (sEH, E.C. 3.3.2.10) has been examined. The compounds synthesized were found to exhibit high inhibitory activity on the 0.4–2.8 nmol L^?1 level. The dependence between the inhibitor structure and its activity was established     

Electron transfer on cis- and trans-1,2-diphenylcyclopropane: stereoisomerization and formation of 1,3-diphenylpropene and 1,3-diphenylpropane

Reaction of cis- or trans-1,2-diphenylcyclopropane with Na/K leads to stereoisomerization and (after protonation) to 1,3-diphenylpropane and 1,3-diphenylpropene, the latter not being formed by H-migration.     

Bicyclo[3.2.1]octanone catalysts for asymmetric alkene epoxidation: the effect of disubstitution

A series of 2-fluoro-8-oxabicyclo[3.2.1]octan-3-ones are prepared and tested as catalysts for alkene epoxidation with Oxone^®. These catalysts provide trans-stilbene oxide with up to 83% ee, but the highest ee value is obtained with the monofluorinated ketone 2: both 2,2- and 2,4-disubstituted catalysts afford epoxide of lower ee.     

Chiral Ruthenium-Oxo Complexes for Enantioselective Epoxidation of trans-Stilbene

Two oxoruthenium(IV) complexes containing C₂ symmetric 1,1′-biisoquinoline (biqn) and (R,R)-3,3′-(1,2-dimethylethylenedioxy)-2,2′-bipyridine (diopy*) were prepared, and both are active oxidants for alkene epoxidations. The oxidation of styrene and cis- and trans-β-methylstyrenes by [(Cn)(diopy*)-Ru^IV(O)](ClO₄)₂ did not proceed enantioselectively, but the same oxidant can attain a moderate enantioselectivity of 33%ee for the trans-stilbene oxidation to trans-stilbene oxide. A head-on approach model, where the C=C is directed from the top to the O=Ru moiety, is proposed to account for the facial differentiation of the trans-stilbene oxidation.     

Reaction of Stereoisomers of 5-Isopropyl-4-methyl-1,3-dioxane with Esters of Monosubstituted Boric Acid

Gas-liquid chromatography was used to establish that the reactivity of the cis isomer in the reaction of 5-isopropyl-4-methyl-1,3-dioxane with the diisobutyl ester of isobutylboric acid leading to the corresponding 1,3,2-dioxaborinane is greater than for the trans isomer. An AM1 calculation for the energy of the intermediate ions in this reaction with model derivatives of boric acids: dioxyborane and the dimethyl ester of methylboric acid showed that one of the probable reasons for the observed behavior is the lower barrier for conversion of the intermediate bipolar structure of the cis derivative in the step involving formation of the endocyclic B-O bond.     

Synthesis and Properties of <Emphasis Type="Italic">N</Emphasis>-[R-Adamantan-1(2)-yl]-<Emphasis Type="Italic">N</Emphasis>′-(2-fluorophenyl)ureas—Target-Oriented Soluble Epoxide Hydrolase Inhibitors

2-Fluorophenyl isocyanate reacted with adamantan-1(2)-amines and their homologs in DMF to give 31–92% of the corresponding N,N′-disubstituted ureas that are target-oriented human soluble epoxide hydrolase (sEH) inhibitors. Introduction of a fluorine atom increases the sEH inhibitory activity by a factor of 4.5.     

Novel optically active pyrazole ligands derived from (+)-3-carene

Reactions of chiral β-diketone with racemic hydrazines as well as reaction of chiral pyrazole with cyclohexene epoxide and trans-stilbene epoxide have been examined as the routes to optically active pyrazolylethanols. Diastereomerically pure products have been isolated by crystallization or column chromatography in good yields.     

Unusually large deuterium isotope effects on one-bond 13C, 1H coupling constants in trans-stilbene challenged

The reported apparent large decrease in ¹J(C-α, H-α) by 1.75±0.20 Hz on replacement of one of the olefinic protons by deuterium in trans-stilbene is due to improper first-order analysis of the ¹H-coupled ¹³C spectrum of the parent compound. Consequently, the implied conformational difference between trans-stilbene and α-deuterio-trans-stilbene, which was used to explain the result, is not substantiated.     

Synthesis and transformations of metallacycles

The Cp₂ZrCl₂-catalyzed reaction of arylolefins (styrene,o- andp-methylstyrenes,trans-stilbene, 1,4-diphenyl-1,3-butadiene) with AlEt₃ resulting in mono- and disubstituted alumacyclopentanes and substituted alumacyclopropanes was studied. The yield and ratio of cyclic organoaluminum compounds depend on the structure of the initial arylolefins and conditions of cycloalumination.     

Angular Alkylation of cis-Decalin Epoxides with C-nucleophiles: Mechanism,scope, and limitations of a novel bridgehead functionalisation

The angular alkylation of cis-decalin epoxides like 5 or 7 can be achieved at C(8a)

1 For convenience, the arbitrary numbering given for 5 (Scheme I) is used throughout the General Part; for systematic names, see Exper. Part.

in good yield by using CuI and a large excess of Grignard reagents without an sp³ centre at C(2). The reaction proceeds via a carbenium-ion intermediate which is stabilised by homoconjugative interaction with the adjacent double bond. Due to 1,3-diaxial strain in the alkoxides resulting from alkylation or reduction at C(4a) of the epoxides 5 or 7 , the nucleophile is delivered selectively to C(8a). Grignard reagents possessing H-atoms at C(β), transfer a hydride to the epoxide yielding the trans-decalol 11 (Grignard reduction). The angular alkylation of 5 with allylic and benzylic Grignard reagents proceeds with good yield.     

Diastereoselective ring opening of limonene oxide with water catalysed by β-ketophosphonate complexes of molybdenum(VI)

In the presence of catalytic quantities of [MoO₂Cl₂L] (L=β-ketophosphonate derived from camphor), water initiates the selective ring opening of cis (+) or (−)-limonene oxide to give the trans-diaxial diol. The trans isomer of the limonene oxide remains almost completely unreacted, thus providing a method for the kinetic separation of the trans diastereomer. ¹H and ¹³C NMR studies of the interaction of the epoxide with the molybdenum complex show that the metal coordinates to the epoxide oxygen atom and that the diastereo-discriminating step is attack of MoO onto the tertiary carbocation formed by cleavage of a C–O bond in the epoxide.     

Enantioconvergent Biohydrolysis of Racemic Styrene Oxide to R-phenyl-1, 2-ethanediol by a Newly Isolated Filamentous Fungus Aspergillus tubingensis TF1

An effort was made to isolate biocatalysts hydrolyzing epoxides from various ecological niches of northeast India, a biodiversity hot spot zone of the world and screened for epoxide hydrolase activity to convert different racemic epoxides to the corresponding 1, 2-vicinal diols. Screening of a total of 450 microorganisms isolated was carried out using NBP colorimetric assay. One of the strains TF1, after internal transcribed spacer sequence analysis, identified as Aspergillus tubingensis, showed promising enantioconvergent epoxide hydrolase activity. The hydrolysis of unsubstituted styrene oxide (1) occurred to give 97 % ee of R-(?)-1-phenylethane-1, 2-diol (6) with more than 99 % conversion within 45 min incubation. It is shown to be a cheap and practical biocatalyst for one step asymmetric synthesis of chiral R-diol. The other representative substrates (2–5), although underwent hydrolysis with more than 99 % conversion beyond 15 h, exhibited poor enantioselectivity.     

Enantioselective Syntheses and Fragrance Properties of the Four Stereoisomers of Magnolione® (Magnolia Ketone)

Enantioselective total syntheses of the four stereoisomers of the fragrance Magnolione® ( 1 ) are described. Key step is a Pd‐catalyzed asymmetric allylic alkylation displaying enantiomer excess of ≥ 99% (Scheme 2). The resultant methyl α‐acetyl‐2‐pentylcyclopent‐2‐ene‐1‐acetate) was subjected to demethoxycarbonylation, carbonyl protection by acetalization, and epoxidation (Schemes 2 and 3). Subsequent Lewis acid catalyzed epoxide/ ketone rearrangement followed by deprotection gave cis/trans mixtures of Magnolione® in 28% overall yield (Scheme 3). The cis/trans isomers were separated by prep. HPLC, and fragrance properties as well as odor threshold values were determined (Table 2).