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.     

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.     

Regiodivergent epoxide opening: a concept in stereoselective catalysis beyond classical kinetic resolutions and desymmetrizations

An approach to highly regiodivergent epoxide openings (REOs) is presented. The very popular kinetic resolutions of epoxides and openings of meso-epoxides constitute subclasses of such REOs. REOs are attractive for parallel resolutions, double asymmetric reactions of enantiomerically enriched epoxides, and for semisynthetic applications in the functionalization of natural products. They have been notoriously difficult to realize by means of SN2 mechanisms. Our titanocene-catalyzed radical REO addresses this issue by decoupling epoxide opening and radical trapping and is firmly based on a mechanistic study of the reductive epoxide opening.     

Mechanical relaxations in episulfide network polymers

A variety of condensation network polymers have been prepared by the reaction between amine, episulfide, and epoxide monomers. The mechanical relaxations occurring in these systems have been examined using a torsion pendulum and the role of hydrogen bonding in the mechanism of the β relaxation is shown to be insignificant. The chemical reaction between amine and episulfide groups has been investigated by IR spectroscopy and is shown to parallel the reaction between amine and epoxide groups. However, steric and electronic factors are suggested to decrease the extent of reaction when aromatic amines are involved. In the case of networks prepared from blends of episulfide and epoxide monomers, measurements of the gel time, together with the mechanical behavior around the glass transition, indicate that either interpenetrating or two-phase networks are formed. This is postulated to be a consequence of the high reactivity of the episulfide ring compared to the epoxide ring. The blending of small amounts of episulfide monomer with the epoxide monomer prior to curing may provide an effective method for lowering gel times without reducing the crosslink density and its dependent physical properties.     

Total Synthesis of Resveratrone and iso-Resveratrone

The first total synthesis of resveratrone and iso-resveratrone based on an epoxide olefination approach is described. The pivotal reaction proceeds by insertion of the lithiated epoxide into a boronic ester and subsequent syn-elimination. Resveratrone has been described to have remarkable photophysical properties, including two-photon absorption. Therefore, an azide derivative has been prepared to allow for use as a biological label.     

Electrostatic potential mapping of polycyclic aromatic hydrocarbon diol epoxides using a dipole

Electrostatic potential maps of benz(a)anthracene diol epoxide, benzphenanthrene diol epoxide, chrysene diol epoxide, and tryphenylene diol epoxide, which are ultimate carcinogens derived from the corresponding polycyclic aromatic hydrocarbons, have been studied using a dipole of length 1 Å and strength 1 Debye. The net charge distributions in the molecules were obtained using the MNDO molecular orbital method. The maps were drawn for two closest distances of approach between the charged ends of the dipole and atoms of the molecules. Using the electric field directions and values of electrostatic potentials, reactive sites and relative reactivities of these molecules have been examined. Existence of a bay region appears to be important for the carcinogenic activity of a diol epoxide in this class of carcinogens.     

On the interaction between supercritical CO2 and epoxides combining infrared absorption spectroscopy and quantum chemistry calculations

The nature and strength of the interactions occurring between epoxides and CO(2) have been investigated by combining infrared spectroscopy with quantum chemistry calculations. A series of infrared absorption experiments on four model epoxide molecules highly diluted in supercritical CO(2) have been performed at constant temperature T = 40 °C for various CO(2) pressures varying from 1 to 30 MPa. Then, we carried out a theoretical analysis based on quantum chemistry calculations using Density Functional Theory (B3PW91 and CAM-B3LYP) and ab initio (MP2) computational methods. A very good agreement between experimental and calculated vibrational frequency shifts of the epoxide ring vibrations group was obtained using the CAM-B3LYP functional, hence validating the calculated optimized geometries of the epoxide-CO(2) complexes. Whatever the epoxide considered, CO(2) is found to be on average above the oxygen atom of the epoxy ring and interacts with the carbon atom of CO(2) through a Lewis acid-Lewis base type of interaction. The substituents on the epoxide ring are found to influence the stability of the epoxide-CO(2) complexes mainly because of the partial charge on the oxygen atom that is sensitive to the nature of the substituent.     

High-throughput selection system for assessing the activity of epoxide hydrolases

Crucial to the success of directed evolution of enantioselective enzymes for use as catalysts in synthetic organic chemistry is the availability of high-throughput assays for determining the enantiopurity of thousands of samples. Although several such ee-assays are available, they entail time and effort, which means that pre-tests for activity have been developed to eliminate non-active mutants prior to ee-screening. Pre-selection systems may be even more efficient and simple to perform. In the present paper an efficient pre-selection test for assessing the activity of epoxide hydrolases has been developed. The bacterial (E. coli) growth on agar plates is shown to be directly related to the presence of active epoxide hydrolases which catalyze the detoxicating hydrolysis of the epoxide substrates. Visual inspection of agar plates is all that is necessary to identify positive (active) hits in large libraries of mutant epoxide hydrolases.     

Tandem base-promoted ring-opening/Brook rearrangement/allylic alkylation of O-silyl cyanohydrins of beta-silyl-alpha,beta-epoxyaldehyde: scope and mechanism

Metalated O-silyl cyanohydrins of beta-silyl-alpha,beta-epoxyaldehyde have been found to serve as functionalized homoenolate equivalents by a tandem sequence involving base-promoted ring opening of the epoxide, Brook rearrangement, and alkylation of the resulting allylic anion. On the basis of mechanistic studies involving competitive experiments using the diastereomeric cyanohydrins, we propose a reaction pathway involving a silicate intermediate 36 formed by a concerted process via an anti-opening of the epoxide followed by the formation of an O-Si bond.     

Divergent synthesis of D-erythro-sphingosine,L-threo-sphingosine,and their regioisomers

Starting from a vinyl epoxide, a divergent synthesis of four sphingosine isomers is described. The remaining four isomers can easily be synthesized using the same methodology. Although numerous syntheses of sphingosine have been published, this is the first general route leading to all eight isomers in this important compound class. The synthetic strategy relies on regioselective opening of a vinyl epoxide and a vinylaziridine in the allylic position.     

A theoretical examination of the acid-catalyzed and noncatalyzed ring-opening reaction of an oxirane by nucleophilic addition of acetate. Implications to epoxide hydrolases

Ab initio and density functional calculations have been performed to gain a better understanding of the epoxide ring-opening reaction catalyzed by epoxide hydrolase. The S(N)2 reaction of acetate with 1S,2S-trans-2-methylstyrene oxide to provide the corresponding diol acetate ester was studied with and without general-acid catalysis. MP2 and DFT (B3LYP) calculations predict, for the noncatalyzed reaction, a central barrier of approximately 20-21 kcal/mol separating the reactants from products depending on which carbon center in the epoxide is undergoing attack. From these gas-phase reactions the immediate alkoxide products are not energetically far below their associated transition states such that the reaction is predicted to be endothermic. Inclusion of aqueous solvation effects via a polarizable continuum model predicts the activation barrier to increase by almost 10 kcal/mol due to the solvation of the acetate ion nucleophile. The activation barrier for the epoxide ring-opening reaction is reduced to approximately 10 kcal/mol when phenol, as the general-acid catalyst, is included in the gas-phase calculations. This is due to the immediate product being the neutral ester rather than the corresponding alkoxide. The transition state in the general-acid-catalyzed reaction is earlier than that for the noncatalyzed reaction and the reaction is highly exothermic. Molecular mechanics calculations of 1S,2S-trans-2-methylstyrene oxide in the active site of murine epoxide hydrolase show two possible binding conformations. Both conformers have the epoxide oxygen forming hydrogen bonds with the acidic hydrogens of the catalytic tyrosines (Tyr381 and Tyr465). These two conformations likely lead to different products since the nucleophile (Asp333-CO(2)(-)) is positioned to react with either carbon center in the epoxide.     

Total synthesis of the quinone epoxide dimer (+)-torreyanic acid: application of a biomimetic oxidation/electrocyclization/Diels-Alder dimerization cascade

An asymmetric synthesis of the quinone epoxide dimer (+)-torreyanic acid (48) has been accomplished employing [4 + 2] dimerization of diastereomeric 2H-pyran monomers. Synthesis of the related monomeric natural product (+)-ambuic acid (2) has also been achieved which establishes the biosynthetic relationship between these two natural products. A tartrate-mediated nucleophilic epoxidation involving hydroxyl group direction facilitated the asymmetric synthesis of a key chiral quinone monoepoxide intermediate. Thermolysis experiments have also been conducted on a model dimer based on the torreyanic acid core structure and facile retro Diels-Alder reaction processes and equilibration of diastereomeric 2H-pyrans have been observed. Theoretical calculations of Diels-Alder transition states have been performed to evaluate alternative transition states for Diels-Alder dimerization of 2H-pyran quinone epoxide monomers and provide insight into the stereocontrol elements for these reactions.     

Polarizability of the Si<Subscript>60</Subscript>H<Subscript>60</Subscript> Derivatives Containing Epoxide Moieties (Si<Subscript>60</Subscript>H<Subscript>60−2n</Subscript>O<Subscript>n</Subscript> with n up to 30): A DFT Study

We have applied density functional theory calculations to study polarizability of the Si₆₀H₆₀ derivatives with epoxide moieties (Si₆₀H_60?2nO_n with n up to 30). The results show that mean polarizability, α, of oxygen-containing silicon fullerene derivatives is higher than that of Si₆₀H₆₀. The mean polarizabilities of the isomers slightly depend on the positional relationship of the epoxide moieties, and are determined mainly by the number of epoxide moieties. Mean polarizabilities of Si₆₀H_60?2nO_n linearly increase with n, and are characterized by the depression of polarizability. The formula describing the mean polarizability as a function of the number of epoxide groups has been obtained, which may be important for the design of silicon-containing nanostructures with regulated polar parameters.     

Octafluoroisobutylene epoxide derivatives

Octafluoroisobutylene epoxide (OFIBO) reacts with alkoxides in a manner similar to hexafluoropropylene epoxide (HFPO). Higher oligomers of OFIBO than previously reported have been prepared, but no difunctional polymers with molecular weights as high as obtained with HFPO could be made.Unsaturated ethers derived from OFIBO dimer and from a potassium pentafluorophenoxide-OFIBO adduct have been incorporated into perfluorinated polymers. The unsaturated ether, perfluoro(2-phenoxypropene), affords a crosslinking site for the nucleophilic vulcanization of a tetrafluoro-ethylene-perfluoro (methyl vinyl ether) perfluoroelastomer.     

Simultaneous hydrosilation and ring-opening polymerization as a route to novel polymer architectures

Typical platinum, rhodium and cobalt hydrosilation catalysts have been found to catalyze the ring-opening polymerization of many different types of heterocyclic monomers. In particular, epoxide monomers undergo especially rapid polymerization with these catalysts. Investigations have shown that in the case of platinum and rhodium catalysts these polymerizations proceed at the surface of the metal colloids by means of a novel cationic mechanism. In contrast, polymerizations with octacarbonyldicobalt take place by a homogeneous cationic mechanism. In all cases, polymerization appears to proceed by the formal attack of a positively charged silicon species on the heteroatom with the formation of a silicon-oxygen bond. Interesting comb, graft, block and network polymers can be prepared by carrying out simultaneous epoxide ring-opening and hydrosilation reactions using these catalysts.     

Modification of photoinitiated cationic epoxide polymerizations by sulfides

The addition of sulfides has a marked effect on the rates of onium salt induced photoinitiated cationic ring‐opening polymerizations of epoxide monomers. Various behaviors have been observed that depend on the structure of the sulfide. Dialkyl sulfides strongly inhibit the photopolymerizations of these monomers, whereas diaryl sulfides have a retarding effect on the photopolymerizations. Real‐time infrared spectroscopy and optical pyrometry have been employed as analytical methods to probe the kinetic effects of the addition of a variety of sulfides on cationic epoxide ring‐opening photopolymerizations. A mechanism is proposed that involves the formation of sulfonium salts as intermediates. The observations made in this study have important implications for cationic photopolymerizations in general and for photoinitiated cationic ring‐opening polymerizations of epoxides in particular. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 2504–2519, 2005     

Effects of tertiary amine accelerators on curing of epoxide resins

The effects of seven tertiary amine accelerators on curing of bisphenol-type epoxide resins using azelaic acid as a curing agent have been investigated. The structure of the cured resins is characterized and reaction and structure schemes are proposed. The reaction mechanism and the resulting structure of the resin depend on the basicity of the accelerator. With increasing accelerator basicity crosslinking in the cured resin increases. Characterization results indicate that the network structure consists of ether bonds or a mixture of ether and ester bonds; the linear structure consists of only ester bonds. The structure and, therefore, the properties of the cured epoxide resin may thus be regulated by selection of the amine basicity.     

Conformation of bicyclo [n.1.0] Derivatives: Part 3. Dioxa- and trioxa-bicyclo[5.1.0] octanes

The conformational geometries and possible interconversion paths for some oxa derivatives of bicyclo[5.1.0] octane have been studied by the molecular mechanics method. The theoretical results are compared with the experimental data for the molecular geometry of bicyclo[5.1.0] octane and 3,5,8-trioxabicyclo[5.1.0] octane, the free energy of activation for cycloheptene epoxide and 3,5-dioxabicyclo[5.1.0] octane, the dipole moments and molar Kerr constants in solution for cycloheptene epoxide, 3,5-dioxa- and 3,5,8-trioxabicyclo[5.1.0] octane.     

Synthesis of carba analogs of 6-O-(benzyl)-d-allal- and -d-galactal-derived allyl epoxides and evaluation of the regio- and stereoselective behavior in nucleophilic addition reactions

The new racemic diastereoisomeric epoxides 6α and 6β, the carba analogs of the corresponding d-galactal- and d-allal-derived allyl epoxides have been synthesized and their regio- and stereoselective behavior examined in addition reactions with model O-, C-, N-, and S-nucleophiles. The results have indicated that epoxide 6β has a pronounced tendency toward anti-1,2-addition, whereas epoxide 6α shows interesting levels of syn- and/or anti-1,4-addition processes. A chiral recognition process found with epoxide 6β, turned out to be consistently reduced in epoxide 6α. All the results have been rationalized on the basis of conformational, steric, and stereoelectronic effects.     

Design and synthesis of two epoxide derivatives from 3-ethynylaniline

For several years ago, several epoxide derivatives have been prepared using different methods; however, some protocols use reagents which could be expensive and require specials conditions. The aim of this investigation was to prepare two new epoxide-derivatives from 3-ethynylaniline using some reactions such as oximation, acetylation, 2 + 2 addition, functionalized chloroamides, and epoxidation via Darzens reaction. The chemical characteristics of epoxide derivatives were determinate through a spectroscopic and spectrometric analysis. In conclusion, it is noteworthy that the reactions used in this study do not involve expensive reagents or special conditions for the synthesis of epoxide derivatives.