Epoxide arene

Epoxides/arene oxides have varying degrees of chemical reactivity and can be detoxified by hydrolysis to dihydrodiols as shown in Figure 6.8. This can occur either nonenzy-matically, if the epoxide is very reactive, or it can be catalyzed enzymatically by epoxide hydrolase (EH). 

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. 

The publication (70) in 1976 of the preparation of optically active epoxyketones via asymmetric catalysis marked the start of an increasingly popular field of study. When chalcones were treated with 30% hydrogen peroxide under (basic) phase-transfer conditions and the benzylammonium salt of quinine was used as the phase-transfer catalyst, the epoxyketones were produced with e.e. s up to 55%. Up to that time no optically active chalcone epoxides were known, while the importance of epoxides (arene oxides) in metabolic processes had just been discovered (71). The nonasymmetric reaction itself, known as the Weitz-Scheffer reaction under homogeneous conditions, has been reviewed by Berti (70). 

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. 

Glutathione conjugation Glutathione (GSH) GSH-S-transferase (cytosol, microsomes) Epoxides, arene oxides, nitro groups, hydroxylamines Acetaminophen, ethacrynic acid, bromobenzene... 

As has been stated before, oxirane derivatives are formed as intermediates during metabolic oxidations at carbon-carbon double bonds. These epoxides (arene oxides) undergo spontaneous isomerization to phenols, or enzymic hydration via epoxide hydrase to trans- dihydrodiols, or reaction with reduced glutathione (GSH) via specific GSH-transferases to the corresponding conjugates (Scheme 11), which eventually appear in urine... 

Such an attack could lead in step a either to an epoxide (arene oxide) or directly to a carbocation as shown in Eq. 18-47. Arene oxides can be converted, via the carbocation step b, to end products in which the NIH shift has occurred.438 The fact that phenylalanine hydroxylase also catalyzes the conversion of the special substrate shown in Eq. 18-48 to a stable epoxide, which cannot readily undergo ring opening, also supports this mechanism. 

The 2-oxoacid p-hydroxyphenylpyruvate is decar-boxylated by the action of a dioxygenase (Eq. 18-49). The product homogentisate is acted on by a second dioxygenase, as indicated in Fig. 25-5, with eventual conversion to fumarate and acetoacetate. A rare metabolic defect in formation of homogentisate leads to tyrosinemia and excretion of hawkinsin97 a compound postulated to arise from an epoxide (arene oxide) intermediate (see Eq. 18-47) which is detoxified by a glutathione transferase (Box 11-B). 

The epoxidation of aldrin to dieldrin is an example of the metabolic formation of a stable epoxide (Figure 10.1A), while the oxidation of naphthalene was one of the earliest understood examples of an epoxide (arene oxide) as an intermediate in aromatic hydroxylation (Figure 10.1B). The arene oxide can rearrange nonenzy-matically to yield predominantly 1-naphthol, can interact with the enzyme epoxide hydrolase to yield the dihydrodiol, or can interact with glutathione -transferase to yield the glutathione conjugate that ultimately is metabolized to a mercapturic acid. This reaction is also of importance in the metabolism of the insecticide carbaryl, which contains the naphthalene nucleus. 

In conjunction with work in natural products synthesis, the controlled installation of stereocenters alpha to indole C2 remains of significant interest. In their approach to Clausena alkaloids, e.g., (-)-(5R, 6S)-balasubramide, Wang and co-workers employed an intramolecular 8-CMc/o-epoxide-arene cyclization for installation of a C2-C3 8-membered lactam moiety with excellent enantioselectivity <07OL1387>. The Chen group has reported a diastereoselective reaction between 2-lithioindoles and chiral A -terf-but ane sulfinyl... 

FIGURE 16.5 Metabolism of bromobenzene (1) to a chemically reactive epoxide (arene oxide) metabolite (2) that can then either bind covalently to nearby macro-molecules, be scavenged by glutathione (GSH) (4) and be further metabolized 7), or be converted nonenzymatically or by epoxide hydrolase to stable hydroxylated metabolites 5, 8). 

In addition to the conversion of unactivated alkanes to alcohols, cytochrome P450 hemes transform alkenes to epoxides, arenes to phenols, and sulfides to sulfoxides to sulfones. Furthermore, they are involved in the biosynthesis and biodegradation of endogenous compounds such as steroids, fatty acids, prostaglandins and leukotrienes. Under anaerobic conditions, P450 will reductively dehalogenate haloalkanes to the corresponding alkanes. 

This chapter describes computational strategies for investigating the species in the catalytic cycle of the enzyme cjdochrome P450, and the mechanisms of its main processes alkane hydroxylation, alkene epoxidation, arene hydroxylation, and sulfoxidation. The methods reviewed are molecular mechanical (MM)-based approaches (used e.g., to study substrate docking), quantum mechanical (QM) and QM/MM calculations (used to study electronic structure and mechanism). 

Glutathion Cytosol Glutathion Epoxides, arene oxides... 

In some cases an insertion of the oxygen atom into a substrate leads to the formation of an unstable intermediate which stabilizes by electrophilic attack at molecules of the surrounding media e. g. semi-acetals formed by an insertion into the C—H bonds of OK rbons at heteroatoms undergo heterolytic cleavage yielding the corresponding aldehydes. If with epoxides, arene oxides or hydroxylamines the sta-... 

GSH conjugation GSH GSH-S-transferase (cytosol) Epoxides arene oxides halides nitro groups hydroxylamines, etc. 

D. Hydration Epoxide hydratase (EC 4.2.1.64), also called epoxide hydrase or hydrolase Epoxides (arene and alkene oxides) Epoxides are hydrated to dihydrodiols. Product glycols which are stereochemically fixed by a ring structure invariably have the /ra/i5-configuration... 

Akhatar, N.M., Boyd, D.R., Neill, J.D., and Jerina, D.M., Stereochemical and mechanistic aspects of sulfoxides, epoxides, arene oxides and phenol formation by photochemical oxygen atom transfer from aza-aromatic N-oxides,/. Chem. Soc., Perkin Trans. 1,1693, 1980. 

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