Epoxides chemical reactivity

In searching for a relationship between antijuvenile hormone activities and epoxide chemical reactivity, we attempted to apply as a chemical probe the m-chloroperoxybenzoic-alkaline fluoride system, a reagent developed in this laboratory for preparation of acid labile epoxides (20). However, formation of hemiesters of 3,4-dihydroxy precocene, was the predominant reaction in the case of activated chro-mene structures. 

This kind of chemical reactivity of epoxides is rather general Nucleophiles other than Gng nard reagents react with epoxides and epoxides more elaborate than ethylene oxide may be used All these features of epoxide chemistry will be discussed m Sections 16 11-16 13... 

A large number of methods have been used to prepare perfluoroepoxides (5). AH of these methods must contend with the great chemical reactivity of the epoxide product, especially with subsequent ionic and thermal reactions which result in the loss of the desired epoxide. 

The scope and direction of these biological investigations have been largely determined by the development of methods for the synthesis of the PAH metabolites. The diol epoxides are not isolable as products of metabolism due to their exceptional chemical reactivity. 

For the alternant PAH that have been studied extensively, bay-region diol epoxides are important metabolically activated forms. Studies of the chemical and biological activity of a variety of diol epoxides have provided insight into the factors related to reactivity and biological activity. Chemical reactivity, as measured by spontaneous hydrolysis, correlated well with calculated quantum chemical parameters that estimate ir-electron stabilization upon conversion of the epoxide to a benzylic carbocation, provided... 

The rates of hydrolysis and binding to DNA of anti-DE-I, syn-DE-I, anti-DE-II, syn-DE-II, and anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydrochrysene (anti-chrysene-DE) were studied in order to relate the chemical reactivity of these dihydrodiol epoxides to their biological activities. The half-lives of the dihydrodiol epoxides in cacodylate buffer at pH 7.0 and 37°C are summarized in Table III and their relative extents of binding to DNA in Table IV. It is clear that the rates of hydrolysis of the dihydrodiol epoxides do not correlate with their DNA binding properties. 

This procarcinogen undergoes metabolic conversion to benzo[a]pyrene diol epoxides, BPDEs (5,28-31), which have been the focus of structural and conformational studies by theoretical and experimental methods. These chemically reactive BPDEs are involved in covalent binding to DNA (13-22). 

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 chemical reactivity of epoxides varies widely depending on chemical structure and conditions, and that reactivity is often of toxicological significance [2], From a metabolic and toxicological viewpoint, it is customary to distinguish three classes of epoxides, namely ... 

This chapter begins, thus, with a short introduction to the chemical reactivity of epoxides. We continue with a description of the epoxides hydrolases and their biochemistry, and devote most of its length to a systematic discussion of the substrates hydrated by these enzymes. Arene oxides and diol epoxides will be presented first, followed by a large variety of alkene and cy-cloalkene oxides. 

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-... 

Epoxide metabolites can be generated from a variety of aromatic systems. Anticonvulsants are a class of drug whose side-effects, such as hepatic necrosis and aplastic anaemia, are thought to be mediated by chemically reactive epoxide metabolites formed by cytochrome P450 oxidation. For instance phenytoin (Figure 8.6) toxicity is correlated with oxidation and the inhibition of epoxide hydrolase [8]. 

The chemistry of saturated heterocyclic compounds is characteristic of their functional group. For example, nitrogen compounds are amines, oxygen compounds arc ethers, sulfur compounds are sulfides. Differences in chemical reactivity are observed for three-membered rings, e.g., epoxides, whose enhanced reactivity is driven by the relief of their severe ring strain. This chapter discusses heterocycles that are aromatic and have unique chemical properties. 

An example of the second type of chiral effect in metabolism is afforded by benzofa]-pyrene, also discussed in more detail in chapter 7. This carcinogenic polycyclic hydrocarbon is metabolized stereos elec lively by a particular cytochrome P-450 isozyme, CYP1A1, to the (+)-7R,8S oxide (chap. 7, Fig. 5.2), which in turn is metabolized by epoxide hydrolase to the (—)-7R,8S dihydrodiol. This metabolite is further metabolized to (- -)-benzo[aIpyrene, 7R,8S dihydrodiol, 9S,10R epoxide in which the hydroxyl group and epoxide are trans and which is more mutagenic than other enantiomers. The (—)-7R,8S dihydrodiol of benzo[aIpyrene is 10 times more tumorigenic than the (+)-7R,8S enantiomer. It was reported that in this case the configuration was more important for tumorigenicity than the chemical reactivity. 

Gervasi, P.G., Citti, L., Del Monte, M.. Longo, V. Benetti, D. (1985) Mutagenicity and chemical reactivity of epoxidic intermediates of the isoprene metabolism and other structurally related compounds. Mutat. Res., 156. 77-82... 

Asymmetric epoxidation of ailylic alcohols.1 Epoxidation of allylic alcohols with r-bulyl hydroperoxide in the presence of titanium(lV) isopropoxide as the metal catalyst and either diethyl D- or diethyl L-tartrate as the chiral ligand proceeds in > 90% stereoselectivity, which is independent of the substitution pattern of the allylic alcohol but dependent on the chirality of the tartrate. Suggested standard conditions are 2 equivalents of anhydrous r-butyl hydroperoxide with 1 equivalent each of the alcohol, the tartrate, and the titanium catalyst. Lesser amounts of the last two components can be used for epoxidation of reactive allylic alcohols, but it is important to use equivalent amounts of these two components. Chemical yields are in the range of 70-85%. 

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