Epoxidation and conjugation

Synthesis The CO2H group spells trouble. We would certainly have to use an ester, but the a-bromoester is too reactive to use with an acetylene. Also there is a danger that the double bond in A will move into conjugation. We can get round all these problems with an epoxide and then oxidise at the end ... 

Epoxidation of conjugated dienes can be regioselective when one double bond is more electron-rich than the other otherwise mixtures of mono- and diepoxides will be obtained. When the alkene contains an adjacent stereocenter, the epoxidation can be diastereoselective [2]. Hydroxy groups can function as directing groups, causing the epoxidation to take place syn to the alcohol [2, 3]. 

Conjugated dienes can be epoxidized to provide vinylepoxides. Cyclic substrates react with Katsuki s catalyst to give vinylepoxides with high ees and moderate yields [17], whereas Jacobsen s catalyst gives good yields but moderate enantiose-lectivities [18]. Acyclic substrates were found to isomerize upon epoxidation (Z, )-conjugated dienes reacted selectively at the (Z)-alkene to give trans-vinylepoxides (Scheme 9.4a) [19]. This feature was utilized in the formal synthesis of leuko-triene A4 methyl ester (Scheme 9.4b) [19]. 

In terrestrial animals, the excreted products of PAHs are mainly conjugates formed from oxidative metabolites. These include glutathione conjugates of epoxides, and sulfate and glucuronide conjugates of phenols and diols. 

Studies conducted by Barenghi eta.1. (1990) and Lodge etal. (1993) independently have demonstrated the facile, multicomponent analysis of a wide range of PUFA-derived peroxidation products (e.g. conjugated dienes, epoxides and oxysterols) in samples of oxidized LDL by high-field H-NMR spectroscopy. Figure 1.9 shows the applications of this technique to the detection of cholesterol oxidation products (7-ketocholesterol and the 5a, 6a and 5/3,60-epoxides) in isolated samples of plasma LDL pretreated with added coppcr(Il) or an admixture of this metal ion with H2O2, an experiment conducted in the authors laboratories. 

In 2001, Ahn et al. introduced a Mn(salen) possessing a structurally related binaphthyl unit, and also achieved high enantioselectivity in the epoxidation of conjugated olefins.103... 

Besides ruthenium porphyrins (vide supra), several other ruthenium complexes were used as catalysts for asymmetric epoxidation and showed unique features 114,115 though enantioselectivity is moderate, some reactions are stereospecific and treats-olefins are better substrates for the epoxidation than are m-olcfins (Scheme 20).115 Epoxidation of conjugated olefins with the Ru (salen) (37) as catalyst was also found to proceed stereospecifically, with high enantioselectivity under photo-irradiation, irrespective of the olefmic substitution pattern (Scheme 21).116-118 Complex (37) itself is coordinatively saturated and catalytically inactive, but photo-irradiation promotes the dissociation of the apical nitrosyl ligand and makes the complex catalytically active. The wide scope of this epoxidation has been attributed to the unique structure of (37). Its salen ligand adopts a deeply folded and distorted conformation that allows the approach of an olefin of any substitution pattern to the intermediary oxo-Ru species.118 2,6-Dichloropyridine IV-oxide (DCPO) and tetramethylpyrazine /V. V -dioxide68 (TMPO) are oxidants of choice for this epoxidation. 

The epoxidation of nonconjugated olefins is slow123,124 and shows reduced enantioselectivity as compared with the epoxidation of conjugated olefins. For example, enantioselectivities from the epoxidation of (Z)-l-cyclohexyl-1-propene, 3,3-dimethyl-l-butene, and geranyl acetate are 82% (with (34)), 70% (with (34)),123 and 53% (6,7-epoxide, with (26)),124 respectively, and yields of the epoxides are modest. 

Reactive Metabolites of PAHs. A wide variety of products have been identified as metabolites of PAHs. These include phenols, quinones, trans-dihydrodiols, epoxides and a variety of conjugates of these compounds. Simple epoxides, especially those of the K-region, were initially favored as being the active metabolites responsible for the covalent binding of PAH to DNA. Little direct experimental support exists for this idea (62.63,64) except in microsomal incubations using preparation in which oxidations at the K-region are favored (65,66). Evidence has been presented that a 9-hydroxyB[a]P 4,5-oxide may account for some of the adducts observed in vivo (67.68) although these products have never been fully characterized. 

Due to conjugation, epoxides are less basic than linear ethers or larger saturated oxaheterocycles. Also, ring strain and conjugation render the two adjacent C-atoms markedly electrophilic, resulting in the characteristic alkylating activity of epoxides [3],... 

Oxidation reactions can be divided into two kinds those in which oxygen is incorporated into the drug molecule, and those in which primary oxidation causes part of the molecule to be lost The former include hydroxylations, epoxidations, and sulfoxidations. Hydroxylations may involve alkyl substituents (e.g., pentobarbital) or aromatic ring systems (e.g propranolol). In both cases, products are formed that are conjugated to an organic acid residue, e.g., glucuronic add, in a subsequent Phase 11 reaction. 

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