Epoxidation of arenes

Two extremely imponunt enzymatic reactions also aid in nentralizing the reactivity of arene oxides. The First of these involves the hydration (i.c.. nucleophilic attack of water on the epoxide) of arene oxides to yield inactive rra/i.v-dihy-drodiol metabolites (Fig. 4-5). This reaction is catalyzed hy... 

The first examples of syn stereoselective epoxidation of arene dihydro-diols have been reported with the preparation of (82) and (83) from the corresponding diolsThus unexpected -epoxidation has been interpreted as due to the exertion of steric control by the axial benzylic hydroxy-groups, whereas such control is usually exhibited by equatorial hydroxy-groups. 

Epoxidation of Arenes. Certain arenes (acenaphthylene, phenanthrene, and pyrene) are readily oxidized to the corresponding arene oxides by the peroxy intermediate (1) generated from sulfonyl chloride (3) in polar aprotic solvents such as MeCN and DME. Superoxide (4) is a strong base and reactions with (1) take place under mild and basic conditions. Acenaphthylene oxide (10) is unstable under acidic conditions but is more stable under basic conditions. Oxide (10) was obtained in 95% yield. ... 

E The writing has again been revised at the sentence level, streamlining the presentation, improving explanations, and updating a thousand small details. Several little-used reactions have been deleted (the alkali fusion of arene-sulfonic acids to give phenols, for instance), and a few new ones have been added (the Sharpless enantioselective epoxidation of alkene.s, for instance). 

Abstract In this review, recent developments of iron-catalyzed oxidations of olefins (epoxidation), alkanes, arenes, and alcohols are summarized. Special focus is given on the ligand systems and the catalytic performance of the iron complexes. In addition, the mechanistic involvement of high-valent iron-oxo species is discussed. 

Diol epoxides. Structural considerations. Because enzymatic hydration of arene oxides produces trans dihydrodiols in mammalian cells, there are two diastereomeric series of diol epoxides. In... 

Hydrolysis of epoxides and arene oxides Hydrolysis of amides and esters Hydrolysis of glycosides... 

It is sometimes assumed that every phenol metabolite indicates the formation of an arene oxide intermediate however, as discussed above, arene oxides are not obligate intermediates in the formation of phenols. This is an important distinction because arene oxides and other epoxides are reactive intermediates that can be toxic or even carcinogenic, e.g., epoxides of some polycyclic aromatic hydrocarbons. The question of whether their formation is obligatory is significant for drug design and development and has implications for toxicity as discussed in Chapter 8. 

In contrast, the primary role of microsomal EH appears to be in detoxifying the metabolically produced epoxides of drugs, e.g., carbamazepine epoxide, the arene oxide of diphenylhydantoin, and the epoxides of environmental contaminants like the polycyclic aromatic hydrocarbons, e.g., benzo[a]pyrene. 

The observation of a dihydrodiol has been taken as proof that an epoxide (arene oxide) is the precursor metabolite. Many epoxides, such as the 10,11-epoxide of carbamazepine shown above and even the arene oxide of benzene, which is quite reactive, have been directly observed. Others such as the epoxide of phenytoin are only inferred. It is conceivable that some dihydrodiols are formed by reaction of an intermediate with water in the active site of P450 without the formation of an epoxide. One clue to the origin of the dihydrodiol is the stereochemistry an exclusively tram-dihydrodiol suggests that it was formed via the EH-mediated hydrolysis of an epoxide or arene oxide. 

Conversion of epoxides (arene oxides) into phenols is spontaneous. The conversion of epoxides into dihydrodiols is catalyzed by EH (EC 4.2.1.63). Hydroxyl containing PAHs can act as substrates for conjugases (C) (UDP glucuronsyl transferase (EC 2.4.1.17) and phenol sulphotransferase (EC 2.8.2.1)). This pathway usually leads to inactive excretable products. Epoxides are scavenged by GSH and the reaction is catalyzed by GSHt (EC 2.5.1.18). When GSH is depleted and/or the other pathways are saturated, epoxides of dihydrodiols (particularly 7,8-diol-9,10-epoxides in the case of BP) and phenol metabolites react with cellular macromolecules such as DNA, RNA, and protein. If repair mechanisms are exceeded the detrimental effects of PAH may result. 

Jerina, D. M., Dansette, P. M., Lu, A. Y. H., and Levin, W. Hepatic microsomal epoxide hydrase a sensitive radiometric assay for hydration of arene oxides of carcinogenic aromatic hydrocarbons. Mol. Pharmacol. (1977) 13 342-351. 

In rearrangement reactions that lead to isomerization, an important discrimination must be made between epoxides of aromatic compounds, e.g., benzene oxide (10.1, Fig. 10.1), and epoxides of alkenes. As a class, epoxides of aromatic compounds (also known as arene oxides) are markedly un-... 

Another isomerization reaction of arene oxides is equilibrium with oxe-pins [5], Here, the fused six-membered carbocycle and three-membered oxirane merge to form a seven-membered heterocycle, as shown in Fig. 10.2. An extensive computational and experimental study involving 75 epoxides of monocyclic, bicyclic, and polycyclic aromatic hydrocarbons has revealed much information on the structural factors that influence the reaction rate and position of equilibrium [11], Thus, some compounds were stable as oxepins (e.g., naphthalene 2,3-oxide), while others exhibited a balanced equilibrium... 

In contrast, a number of alkene epoxides (10.3) are chemically quite stable, i.e., intrinsically less reactive than arene oxides. Examples of epoxide metabolites that have proven to be stable enough to be isolated in the absence of degrading enzymes include 1,2-epoxyoctane (10.4), 1,2-epoxycyclohex-ane (10.5), 1-phenyl-1,2-epoxy ethane (styrene oxide, 10.6), and cis- 1,2-diphenyl-1,2-epoxyethane (cfv-stilbene oxide, 10.7) [12], The same is true of alclofenac epoxide (10.8), hexobarbital epoxide (10.9), and a few other epoxides of bioactive compounds. 

Together with glutathione conjugation, hydration is a major pathway in the inactivation and detoxification of arene oxides. Exceptions to this rule will be treated when discussing polycyclic aromatic hydrocarbons. Arene oxides are good substrates for microsomal EH, as evidenced in Table 10.1, where hydration of selected arene oxides, alkene oxides, and cy-cloalkene oxides by purified rat liver epoxide hydrolase is compared. The hy- ... 

Detailed kinetic studies comparing the chemical reactivity ofK-region vs. non-K-region arene oxides have yielded important information. In aqueous solution, the non-K-region epoxides of phenanthrene (the 1,2-oxide and 3,4-oxides) yielded exclusively phenols (the 1-phenol and 4-phenol, respectively, as major products) in an acid-catalyzed reaction, as do epoxides of lower arenes (Fig. 10.1). In contrast, the K-region epoxide (i.e., phenanthrene 9,10-oxide 10.29) gave at pH < 7 the 9-phenol and the 9,10-dihydro-9,10-diol (predominantly trans) in a ratio of ca. 3 1. Under these conditions, the formation of this dihydrodiol was found to result from trapping of the carbonium ion by H20 (Fig. 10.11, Pathway a). At pH > 9, the product formed was nearly ex-... 

In other words, the non-K-region epoxides of phenanthrene react like epoxides of lower arenes (Fig. 10.1). In contrast, the K-region epoxide of phenanthrene, under alkaline conditions, hydrolyzes as does an olefin epoxide (i.e., as in Fig. 10.4), but seemingly faster. Under acidic conditions, however, it exhibits dual behavior, isomerizing mainly like an arene oxide (i.e.,... 

The data in Table 10.1 suggest that the reactivity of epoxide hydrolase toward alkene oxides is highly variable and appears to depend, among other things, on the size of the substrate (compare epoxybutane to epoxyoctane), steric features (compare epoxyoctane to cycloalkene oxides), and electronic factors (see the chlorinated epoxides). In fact, comprehensive structure-metabolism relationships have not been reported for substrates of EH, in contrast to some narrow relationships that are valid for closely related series of substrates. A group of arene oxides, along with two alkene oxides to be discussed below (epoxyoctane and styrene oxide), are compared as substrates of human liver EH in Table 10.2 [119]. Clearly, the two alkene oxides are among the better substrates for the human enzyme, as they are for the rat enzyme (Table 10.1). 

Some of the reagents used in olefin epoxidation can be applied in the direct oxidation of arenes to arene oxides. Benzene oxide, however, like other arene oxides, exists in equilibrium with oxepin, its valence tautomer, and has not been isolated. Existence of benzene oxides as intermediates can be concluded from observations like the NIH shift discussed above.752,753... 

In mammalian liver microsomes, cytochrome P-450 is not specific and catalyzes a wide variety of oxidative transformations, such as (i) aliphatic C—H hydroxylation occurring at the most nucleophilic C—H bonds (tertiary > secondary > primary) (ii) aromatic hydroxylation at the most nucleophilic positions with a characteristic intramolecular migration and retention of substituents of the aromatic ring, called an NIH shift,74 which indicates the intermediate formation of arene oxides (iii) epoxidation of alkenes and (iv) dealkylation (O, N, S) or oxidation (N, S) of heteroatoms. In mammalian liver these processes are of considerable importance in the elimination of xenobiotics and the metabolism of drugs, and also in the transformation of innocuous molecules into toxic or carcinogenic substances.75 77... 

NR = nonreactive toward hydrocarbons PO = oxidation of phosphines to phosphine oxides MF — peroxometallacyclic adduct formation with cyanoalkenes NSE — nonstereoselective epoxidation SE=stereoselective epoxidation AE = asymmetric epoxidation HA- hydroxylation of alkanes HB=hydroxylation of arenes OA = oxidation of alcohols to carbonyl compounds K = ketonization of Lermina 1 alkenes SO oxidation of S02 to coordinated S04 MO = metallaozonide formation with carbonyl compounds I = oxidation of isocyanides to isocyanates. 

Epoxidation of aromatic hydrocarbons is an important method for the preparation of arene oxides. m-Chloroperbenzoic acid (MCPBA) is used in a two-phase system that involves treating the hydrocarbon with a large excess ( 10-fold) of MCPBA in methylene chloride-aqueous sodium bicarbonate at room temperature. The yields are moderate (10-60%). Because the arene oxides are sensitive to acids, the presence of sodium bicarbonate buffer is necessary. A number of K-region (see Section VII for a definition) epoxides like phenanthrene 9,10-oxide (1, 59%), 9,10-dimethylphenanthrene 9,10-oxide (2,40%), 9-phenylphenanthrene 9,10-epoxide (3,50%), pyrene 4,5-oxide (4, 14%), and chrysene 4,5-oxide (5,9%) have been prepared by this method.9... 

The first example of syn stereoselective expoxidation of arene dihydrodiols was reported in 1981.11 The trans-dihydrodiols 11 and 12, when treated with a 10-fold excess of MCPBA in tetrahydrofuran (THF) at room temperature, gave stereoselectively the syn-diol epoxides 13 and 14, respectively. This stereoselectivity has been ascribed to the operation of steric control by the axial benzylic hydroxy group the equatorial hydroxy group does not exert such control. The isomeric 9,10-epoxides of 7,8-dihydroxy-7,8-dihydro-benzo[a]pyrene can be prepared by the same method.12... 

Conversion of arene oxides to dihydrodiols by mouse liver cytosol epoxide hydrolase and microsomal epoxide hydrolase has been compared, and it is found that the former is less active than the latter.200... 

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