Electrophiles epoxides

It should be noted that epoxidation of a dienone with mCPBA or other electrophilic epoxidation reagents proceeds with complementary regioselectivity, yielding y,8-epoxy enones instead of the ot,P-epoxy ketones discussed above. This feature has been utilized in several natural product syntheses Scheme 9.8 demonstrates... 

Guengerich, F.P. (2003) Cytochrome P450 oxidations in the generation of reactive electrophiles epoxidation and related reactions. Archives of Biochemistry and Biophysics, 409, 59-71. 

Posner and coworkers proposed that the highly electrophilic epoxide could not be isolated due to its inherent instability but was a potent alkylating agent responsible for parasite death. However, Wu and coworkers have isolated a small quantity (1-2% yield) of the epoxide 16 in their iron(II) degradations of artemisinin using iron(II) sulphate in aqueous acetonitrile s. These authors conclude that it is not the active killing species since any external nucleophiles would have to compete with the in-built nucleophile (the OH moiety). Moreover, Avery and coworkers also concluded that the epoxide could not... 

As already mentioned, the dioxirane epoxidation of an alkene is a stereoselective process, which proceeds with complete retention of the original substrate configuration. The dioxirane epoxidation of chiral alkenes leads to diasteieomeric epoxides, for which the diasteieoselectivity depends on the alkene and on the dioxirane structure. A comparative study on the diasteieoselectivity for the electrophilic epoxidants DMD versus mCPBA has revealed that DMD exhibits consistently a higher diastereoselectivity than mCPBA however, the difference is usually small. An exception is 3-hydroxycyclohexene, which displays a high cis selectivity for mCPBA, but is unselective for DMD65. 

Michael-type addition of a suitable nucleophile, e.g. thiols, on to the a,f)-unsaturated lactone. Such alkylation reactions are believed to explain biological activity, and, indeed, activity is typically lost if either the double bond or the carbonyl group is chemically reduced. In some structures, additional electrophilic centres offer further scope for alkylation reactions. In parthenolide (Figure 5.31), an electrophilic epoxide group is also present, allowing transannular cyclization and generation of a... 

A concise and practical synthesis of HIV-1 protease inhibitor 2 was developed by Askin and coworkers, using the rigid tricyclic aminoindanol acetonide as a chiral platform.11 The diastereo-selective alkylation of (Z)-lithium enolate of amide 48 with amino epoxide 49 gave intermediate 50 in >90% yield and >98% de (Scheme 24.9). Lithium carbamate salt of 49 presumably activated the epoxide toward electrophilic epoxide opening, and alkylation of the (Z)-enolate occurred from the less hindered (3-face. The amino alcohol was deprotected by treatment with camphorsulfonic acid and gave 2 in good yield. 

High dilutions reduced the amount of oligomers formed. Preliminary experiments on enantio-enriched hydroxyl esters 20.6 and 20.7, using distannoxane transesterification catalyst, produced stereochemically diverse homo- and heterodimers 20.8-20.10. Functionalization of the macrodiolides was investigated in an effort to create additional structural diversity. Electrophilic epoxidation of macrodiolide 20.9 afforded bis-epoxide 20.11. Further diversification was achieved by treating the macrodiolide bis-epoxide with DBU, which resulted in epoxide ring opening to afford a,P-unsaturated macrolide 20.12. 

Capsaicin and capsaicinoids undergo Phase I metabolic bioconversion to catechol metabolites via hydroxylation of the vanillyl ring moiety (Lee and Kumar, 1980 Miller et al, 1983). Metabohsm involves oxidative, in addition to non-oxidative, mechanisms. An example of oxidative conversion involves the liver mixed-function oxidase system to convert capsaicin to an electrophilic epoxide, a reactive metabolite (Olajos, 2004). Surh and Lee (1995) have also demonstrated the formation of a phenoxy radical and quinine product the quinine pathway leads to formation of a highly reactive methyl radical (Reilly et al, 2003). The alkyl side chain of capsaicin also undergoes rapid oxidative deamination (Wehmeyer et al, 1990) or hydroxylation (Surh et al, 1995 Reilly et al, 2003) to hydroxycapsaicin as a detoxification pathway. An example of nonoxidative metabolism of capsaicin is hydrolysis of the acid-amide bond to yield vanillylamide and fatty acyl groups (Kawada et al, 1984 Oi et al, 1992). 

The mechanism of concerted electrophilic epoxidation is still a matter of debate. Two exemplary transition-state structures, (a) and (b), for symmetric oxygen transfer from peroxy compounds (or oxaziridines) to the C-C double bond are the most generally accepted. In (a) the double bond is located in the plane of the breaking bonds of the transferred oxygen in (b) it is perpendicular to the plane of the breaking bonds of the transferred oxygen. 

In the case of 5-hydroxy-2-hexanone shown below, Umpolung of the polarity in the acceptor synthon is accomplished by using the electrophilic epoxide as the corresponding SE. 

R = alkyl, aryl R = 1° or 2 alkyl, allyl, benzyl, activated aryl, acyl X - Cl, Br, I, OTs electrophile epoxide, dialkyl sulfate, alkyl sulfonate, alkyl nitrate base = NaOR NaH base = KOf-Bu, cone. NaOEt, NaH solvent = R OH, f-BuOH, benzene, ether, DMF... 

The high selectivity of catalyst lb toward terminal unfunctionalized alkenes is highlighted by the experiments reported in Fig. 2.2. As a typical example, czs-l,4-hexadiene bears both terminal and cis C=C bonds and in the presence of a stoichiometric amount of m-chloroperbenzoic acid (m-CPBA) leads mainly to czs-4,5-epoxy-l-hexene due to the electrophilic epoxidation of the more electron-rich internal double bond. On the contrary, when the epoxidation is performed with catalyst lb and one equivalent of H2O2, the regioselectivity of the reaction is completely inverted, favoring the product with the terminal oxirane ring. The same applies to frflns-l,4-hexadiene or dienes bearing substituents in the... 

Scheme 4.20 Oxidation of aromatic substructures leads, via an electrophilic epoxide, to the formation of phenols. The so-called NIH shift in haloarenes involves 1,2 migration of the halogen substituent [52].

The electrophilic epoxidizing agents such as m-CPBA, which you met in Chapter 20, are less good with electron-deficient alkenes we need a nucleophilic epoxidizing agent instead. There is another sig-... 

Though it requires vigorous conditions and is less common than nucleophilic epoxidation, electrophilic epoxidation of aperfluoroalkene is possible with the potent combination of chromic oxide and fluorosulfonic acid, providing another route to hexafluoropropylene oxide (1). As a further example of electrophilic attack, hexa-fluoro Dewar benzene (3) is transformed into either a mono- or a diepoxide by the powerful hypofluorous acid-acetonitrile complex.The fact that the much weaker electrophile MCPBA readily epoxides such electron-deficient alkenes as ethyl pentafiuoromethacrylate (4) suggests that it actually reacts via nucleophilic attack at the [3-carbon. 

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