Arene oxide intermediate

Phenolic compounds are commonplace natural products Figure 24 2 presents a sampling of some naturally occurring phenols Phenolic natural products can arise by a number of different biosynthetic pathways In animals aromatic rings are hydroxylated by way of arene oxide intermediates formed by the enzyme catalyzed reaction between an aromatic ring and molecular oxygen... 

The first step in any of the degradation pathways is the formation of 2-quinolinone/2-hydroxyquinoline/2-oxo-l, 2-dihydroquinoline and quinoline2-oxidoreductase has been shown to be responsible for this initial metabolic reaction [318], When the oxidation is carried out by a dioxygenase, it resulted in the formation of ds-hydrodiol derivatives and when oxidation is carried out by a monooxygenase monohydroxilated derivatives are formed, via the arene oxide intermediates [323],... 

FIGURE 4.78 Mechanistic pathways for aromatic hydroxylation by concerted addition of oxene, pathway 1, or by stepwise addition of oxene, pathway 2. Pathways 2, 3, and 4 describe the formation of phenol that bypasses the arene oxide intermediate. 

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. 

The metabolism of 1,4-dichlorobenzene could involve the formation of an arene oxide intermediate, as has been proposed to occur in the oxidative metabolism of many halogenated aromatic hydrocarbons (Jerina and Daly 1974). 1,4-Dichlorobenzene has not been shown to be mutagenic in microbial or mammalian systems, a result that may be viewed as further suggestive evidence that an arene oxide intermediate is not involved in its metabolism. 

HYDRATION WATER a-L-ARABINOFURANOSIDASE d-ARABINOKINASE ARABINONATE DEHYDRATASE ARABINOSE ISOMERASE ARABINOSE-5-PHOSPHATE ISOMERASE Arachidonate 5-lipoxygenase, 5-LIPOXYGENASE ARACHIDONYL-CoA SYNTHETASE Arene oxide intermediate,... 

Sulfur nucleophiles such as thiolate anion generally appear near the top of the nucleophi-licity scale and thus readily attack oxepins (Scheme 20). While adduct formation between oxepin (7) and thiols occurs spontaneously upon mixing (74JA6929), a similar reaction between the naturally occurring tripeptide thiol, glutathione, and oxepin-arene oxide intermediates formed during mammalian metabolism is catalyzed by a glutathione epoxide transferase. 

NADH-dependent reductase, thus allowing the biopterin cofactor to function catalytically (72JBC(247)6082). That the conversion of phenylalanine to tyrosine involves an arene oxide intermediate is suggested by the observation of the so-called NIH shift phenomenon (i.e. migration and retention of the para substituents such as deuterium, tritium, methyl and bromine when these para-substituted phenylalanines are enzymatically hydroxylated) <66BBR(24)720, 67MI11000). 

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). 

Aromatic hydrocarbons are mainly hydroxylated to phenolic products. Complex (12) hydroxylated benzene in MeCN at 20 °C into phenol in ca. 55% yield, and no isotope effect was found for this reaction. Hydroxylation of toluene mainly occurs at the ring positions, with minor amounts of benzylic oxidation products. Hydroxylation of 4-deuterotoluene by (12) occurred with 70% retention and migration of deuterium in the formation of p-cresol. This high NIH shift value is in the same range as that found for liver microsome cytochrome P-450 hydroxylase, and suggests the transient formation of arene oxide intermediates. 

Polynuclear aromatic compounds such as naphthalene or anthracene are oxidized by chromyl reagents mainly into quinones, with a significant NIH shift, providing evidence for the intermediacy of arene oxide intermediates.306,54... 

No metabolism has been demonstrated for the decachlorobiphenyl (NI0SH, ref. 136, p. 29). This and other highly chlorinated PCBs not readily metabolized may persist in the tissues for years following exposure. Some PCBs lacking the adjacent hydrogens required for rapid metabolism can be slowly metabolized by hydroxylation and oxidative dechlorination. Since arene oxide intermediates may also be involved, there is the risk of chronic exposure to compounds of high carcinogenic activity (ref. 136, p. 30). 

Use of transition metal catalysts opens up previously unavailable mechanistic pathways. With hydrogen peroxide and catalytic amounts of methyl trioxorhe-nium (MTO), 2-methylnaphthalene can be converted to 2-methylnaphtha-l,4-qui-none (vitamin K3 or menadione) in 58 % yield and 86 % selectivity at 81 % conversion (Eq. 10) [43, 44]. Metalloporphyrin-catalyzed oxidation of 2-methylnaphtha-lene with KHSOs can also be used to prepare vitamin K3 [45]. The MTO-catalyzed process can also be applied to the synthesis of quinones from phenols [46, 47]. In particular, several benzoquinones of cardanol derivatives were prepared in this manner [48], The oxidation is thought to proceed through the formation of arene oxide intermediates [47]. 

Aromatic hydrocarbons are subject to cytochrome P-450-catalyzed hydroxylation in a process that is similar to olefin epoxidation. As discussed in Section IV. G, halogen migration observed during the hydroxylation of 4-ClPhe and similar substrates, led to the discovery of a general mechanism of oxidation that invokes arene oxide intermediates and the NIH shift. Arene oxides and their oxepin tautomers have not been isolated as products of metabolism of benzenoid compounds, but their presence has been inferred by the isolation of phenols, dihydrodiols and dihydrophenolic GSH conjugates derived therefrom262. 

Detoxification of PCBs by Phase I conjugation produces hydroxylated PCBs (OH-PCBs) through either direct hydroxide insertion or via arene oxide intermediates [7]. The latter can... 

Many aromatic drugs are hydroxy la ted either directly through asymmetrical oxygen transfer or through an unstable arene oxide intermediate, as shown in Scheme 11.9. 

The major metabolite of phenytoin is para-hydroxyphenytoin, formed through an arene epoxide intermediate as shown in Scheme 11.11. Microsomal epoxide hydrolase (HYEl) is widely distributed in tissues and serves a protective role in converting longer lasting arene oxide intermediates to diols. The arene epoxide of phenytoin is detoxified through HYEl to form the dihydrodiol (20). 

---