In epoxide hydrolysis

Many enzymes form covalent bonds with their substrates during catalysis, such as the acyl-enzyme intermediate in carboxyl ester hydrolysis (Scheme 2.1) or the glycol monoester intermediate in epoxide hydrolysis (Scheme 2.85). Despite the covalent enzyme-substrate bond, such species are metastable and should be regarded as activated intermediates . Some enzymes utilize cofactors, such as... 

Alkenes are reduced by addition of H2 in the presence of a catalyst such as platinum or palladium to yield alkanes, a process called catalytic hydrogenation. Alkenes are also oxidized by reaction with a peroxyacid to give epoxides, which can be converted into lTans-l,2-diols by acid-catalyzed epoxide hydrolysis. The corresponding cis-l,2-diols can be made directly from alkenes by hydroxylation with 0s04. Alkenes can also be cleaved to produce carbonyl compounds by reaction with ozone, followed by reduction with zinc metal. 

Gomez GA, Morisseau C, Hammock BD, Christianson DW. Structure of human epoxide hydrolase reveals mechanistic inferences on bifunctional catalysis in epoxide and phosphate ester hydrolysis. Biochemistry 2004 43 4716-23. 

Diols are applied on a multimilhon ton scale as antifreezing agents and polyester monomers (ethylene and propylene glycol) [58]. In addition, they are starting materials for various fine chemicals. Intimately coimected with the epoxidation-hydrolysis process, dihydroxylation of C=C double bonds constitutes a shorter and more atom-efficient route to 1,2-diols. Although considerable advancements in the field of biomimetic nonheme complexes have been achieved in recent years, still osmium complexes remain the most efficient and reliable catalysts for dihydroxylation of olefins (reviews [59]). 

Arene oxides and diol epoxides are generally unstable in aqueous, especially acidic media (103-105). and in addition, several groups have noted that DNA has a marked catalytic effect upon diol epoxide hydrolysis (106.107). However, in cells there appears to be sites, probably lipid in nature, in which these compounds can have much longer half-lives. 

Fig. 10.6. Simplified representation of the postulated catalytic cycle of microsomal and cytosolic epoxide hydrolases, showing the roles played by the catalytic triad (i.e., nucleophile, general base, and charge relay acid) and some other residues, a) Nucleophilic attack of the substrate to form a /3-hydroxyalkyl ester intermediate, b) Nucleophilic attack of the /Thydroxyal-kyl ester by an activated H20 molecule, c) Tetrahedral transition state in the hydrolysis of the /f-hydroxyalkyl ester, d) Product liberation, with the enzyme poised for a further catalytic... 

Fig. 10.11. Chemical mechanisms in the hydrolysis ofK-region epoxides. Pathway a characteristic proton-catalyzed hydrolysis under acidic conditions Pathway b nucleophilic hydrolysis by H2C) Pathway c HO"-catalyzed hydrolysis under basic conditions. Pathways b and c form the trans-diol. In the case of Pathway a, partial configurational inversion may occur at the carbonium ion, resulting in a mixture of the trans- and cw-diols. 

Interestingly, there is a marked species difference in the in vitro hydrolysis of carbamazepine 10,11-epoxide, such that the reaction was observed only in liver microsomes from humans but not in liver microsomal or cytosolic preparations from dogs, rabbits, hamsters, rats, or mice [181][196], Thus, carbamazepine appears to be a very poor substrate for EH, in analogy with the simpler analogues 10.129 (X = RN, RCH, or RCH=C). The human enzyme is exceptional in this respect, but not, however, in the steric course of the reaction. The diol formed (10.131, X = H2NCON) is mostly the trans-(10.S, 11. S )-enaniiomer [196], In other words, the product enantioselectivity of the hydration of carbamazepine epoxide catalyzed by human EH is the same as that of di benzol a,oxide catalyzed by rabbit microsomal EH, discussed above. 

A further remarkable finding in the hydrolysis of aflatoxin B1 exo-8,9-epoxide is the relative instability of the dihydrodiol, which under basic conditions exists in equilibrium with an aflatoxin dialdehyde, more precisely a furofuran-ring-opened oxy anionic a-hydroxy dialdehyde (10.134, Fig. 10.30). The dihydrodiol is the predominant or exclusive species at pH < 7, whereas this is true for the dialdehyde at pH >9, the pK value of the equilibrium being 8.2 [204], The dialdehyde is known to form Schiff bases with primary amino groups leading to protein adducts. However, the slow rate of dialdehyde formation at physiological pH and its reduction by rat and human aldo-keto reductases cast doubts on the toxicological relevance of this pathway [206]. 

The exceptional reactivity of aflatoxin B1 exo-8,9-epoxide raises the question of its potential detoxification by EHs. Despite the short half-life, the epoxide does react with DNA (toxification) and glutathione 5-transferases (detoxification), but a role for EH appeared dubious [207], Rat liver or recombinant rat EH has since been shown to provide a modest enhancement of up to 22% in the hydrolysis rate of aflatoxin B1 exo-S,9-epoxide, and to decrease somewhat the genotoxicity of aflatoxin B1 when the ratio of EH to cytochrome P450 is high (ca. 50-fold). Purified human EH provided no such enhancement in hydrolysis, nor did it have a clear effect on genotoxicity. Thus, little evidence exists to support a role for EH in the detoxification of aflatoxin B1 [208],... 

Reaction in organic solvent can sometimes provide superior selectivity to that observed in aqueous solution. For example, Keeling et al recently produced enantioenriched a-trifluoromethyl-a-tosyloxymethyl epoxide, a key intermediate in the synthetic route to a series of nonsteroidal glucocorticoid receptor agonist drug candidates, through the enan-tioselective acylation of a prochiral triol using the hpase from Burkholderia cepacia in vinyl butyrate and TBME (Scheme 1.59). In contrast, attempts to access the opposite enantiomer by desymmetrization of the 1,3-diester by lipase-catalysed hydrolysis resulted in rapid hydrolysis to triol under a variety of conditions. 

Kedderis, GL. Batra, R. (1993) Species differences in the hydrolysis of 2-cy anoethylene oxide, the epoxide metabolite of acrylonitrile. Carcinogenesis, 14, 685-689... 

In conclusion, the chiral salen Co(III) complexes immobilized on Si-MCM-41 colud be synthesized by multi-grafting method. The asymmetric synthesis of diols from terminal olefins was applied with success using a hybrid catalyst of Ti-MCM-41/chiral Co(III) salen complexes. The olefins are readily oxidized to racemic epoxides over Ti-MCM-41 in the presence of oxidants such as TBHP, and then these synthesized diols are generated sequentially by epoxide hydrolysis on the salen Co(lll) complexes. This catalytic system may provide a direct approach to the synthesis of enantioselective diols from olefins. 

The furan (450) is also formed on photolysis of 1,3-diphenylindenone epoxide (449) in ethanol. Hydrolysis of the epoxide (449) in acetic acid with hydrogen chloride was also... 

In contrast to the copolymerization of cyclic carbonates, the molecular weights are lower in the epoxide copolymerization 6,41 43). We assume that this is due to the presence of proton donors in the reaction mixture. They occur as impurities in epoxides 19,20) or anhydrides, moisture in all components of the copolymerization system, or their presence is a consequence of the high rate of hydrolysis of cyclic anhydrides 21). Proton donors added to the monomer feed remarkably decrease the molecular weight42 even in the copolymerization of ethylene glycol carbonate at 200 °C. Under these conditions, when recyclization of phthalic acid takes place 64) and the released C02 can tear off moisture to the gas phase, the molecular weight Mv decreases without proton donors from 45200 to 7100 in the presence of 5% phthalic acid or ethylene glycol or to 9300 in the presence of 15% water42,54. ... 

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