Arene diols, formation

CYPs are good at epoxidizing aikenes and alkynes as well, which is probably one reason why more drugs don t contain these groups. Then again, just because a reaction can happen doesn t mean that it will. For carbamazepine (Figure 9.18), epoxidation followed by diol formation is the major metabolic route, but for tamoxifen, metabohc epoxidation of the central double bond hardly happens, and other CYP-catalyzed reactions, including arene epoxidation and N-demethylation (discussed in a later section) are much more in evidence. 

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-... 

This mechanism also holds for the photochemical osmylation of arenes through irradiation of a preformed arene/0s04 CT complex. This reaction finally results in the formation of vic-diols [88]. 

To date, the only natural product containing a benzene dioxide moiety is the antibiotic 149. In addition to this cis dioxide, there is evidence that trans naphthalene dioxide 152 may be an intermediate in the hepatic metabolism of naphthalene. The reactivity of the cis (153) and trans (152) naphthalene dioxides with nucleophiles and the relative stereochemistry of the adducts has been determined. The possibility that arene dioxide intermediates form during metabolism of PAHs has been discussed frequently. Indeed, the detection of a rrans-diol epoxide such as that derived from arene oxide 25, or the isolation of a rra s-diol oxepin (e.g., 165) is mechanistically consistent with the formation of two epoxides on either the same or different rings. However, presently available evidence would suggest that it is most unlikely that either diol metabolite was derived from an arene dioxide intermediate. Involvement of dioxide intermediates in the metabolism of PAHs will require further experimental verification. 

The pH-independent reaction of cyclopentadiene oxide 12 in water is clearly different from that of 13.97 This reaction yields 33% of 3-cyclopentenone, 35% of cis-2,4-pentadienal and 35% of a mixture of cis and trans 1,2- and 1,4-diols (Scheme 28). When the reaction is carried out in D20 instead of H20, no deuterium is incorporated into the ketone product. Thus, 1,2-hydrogen migration is required for this reaction just as it is in the rearrangement of arene oxides to phenols. The mechanisms of product formation in this reaction are not fully understood. The observation that the diol mixture is similar to that from the acid-catalyzed hydrolysis of 12 suggests that an allylic carbocation may be involved in the diol-forming reaction. Ketone (96) and dienal (97) products are potentially formed either by stepwise or concerted mechanisms, and there is insufficient evidence to rule out either one. There is a significant normal salt effect on this pH-independent... 

Estrogens induce tumors in animals, a fact that probably depends on the formation of catechol-type A rings. Arene oxides and/or semiquinones may then be formed, which react as cross-linkers in the same way as polycyclic hydrocarbons, such as benzopyrene, which is oxidized in the body to a diol-epoxide. Electroreduction of the corresponding ortho-quimm to the semiquinone radical, the same product that would be formed upon oxygen oxidation of the catechol, in the presence of adenine, does indeed produce a covalent adduct in 14% yield (Scheme 3.4.5)... 

Photoinduced Charge Transfer Osmylation. The reaction of osmium tetroxide with benzenoid derivatives can only be accomplished by irradiation of the mixture. This reaction had previously been shown to work (with stoichiometric osmium tetroxide) by promotion of charge transfer between the two reactants to form an ion-pair this can then collapse to form an osmate ester of benzene diol. Subsequent dihydroxylation of this intermediate appears to follow a more conventional (and stereoselective) course. The use of catalytic osmium tetroxide (in conjunction with barium perchlorate as a reoxidant) for this reaction is noteworthy, as is the formation of both inositol and conduritol derivatives in one-pot (eq SS). The photoinduced osmylation of mono-substituted arenes was possible although the yields were lower and the amount of cyclitol-type products reduced. 

Many of the first crown ethers to be prepared were benzo or dibenzo derivatives. These were often amenable to arene substitution reactions that made the products lariat ethers in the current sense but, unlike later examples, the intention was not to enhance guest binding. The first report of a true lariat ether was from Gokel in 1980 whose group reacted epichlorohydrin with several phenols and alcohols resulting in the formation of diols. These... 

Nucleophilic. In view of the ability of epoxides to become hydrated to the diol under aqueous alkaline conditions, the analogous addition of water to epoxides by enzymes will be considered in this section. The en mes responsible for epoxide hydration (epoxide hydrases) in animal liver systems have been purified, assayed using [7- H]styrene oxide,and tested for substrate and inhibitor -ass specificity. The current interest in these epoxide hydrases is mainly due to their close association with aryl monooxygenase enzymes and thus the total metabolism of olefinic and arene substrates via epoxides) in animals. The isolation of the antibacterial compounds aeroplysinin-1 (358) and aeroplysinin-2 (359) from the sponge Verongia aerophoba might be explained by the initial enzymatic formation of the unstable arene oxide (357), which can subsequently be hydrated by an epoxide hydrase enzyme, to form what the authors consider... 

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