Ketone-Mediated Epoxidation

However, it was the development of the fructose-derived ketone catalyst 5, reported by Shi in 1996, that offered the most useful organocatalyst for asymmetric epoxidations [12-14]. Now commercially available, the catalyst 5 can be produced 

This model also offers an explanation for the poor selectivities achieved in the epoxidations of as- and terminal alkenes, where R = H. With these substrates either enantiotopic face of the alkene can approach the dioxirane oxygen with a hydrogen placed in the spirocycUc acetonide region (R and R interchanged in 

13aX= NBoc 13bX = NTol 13cX= N(4-EtCeH4) 

The development of the oxazolidinone catalyst has allowed Shi to further increase the scope of the epoxidation to a range of new substrates. Using ketone catalyst 5 styrene is epoxidized with 24% ee, while the use of oxazolidinone 13a for the same transformation gave 86% ee, with further improvement in enantioselectivity seen with the inclusion of electron-donating substituents on the aromatic ring of the styrene substrates [43]. ds/tra s-Dienes and trienes were epoxidized regioselectivity at the ds-alkene and no isomerization or further epoxidation of the products were observed [44], while epoxidation of conjugated dx-enynes resulted in chemoselective epoxidation of the alkene [45]. 

Several novel carbohydrate-derived ketones have been reported. Arabinose-derived ketone catalyst 16a has been shown to provide good enantioselectivities for the epoxidation of trans-aliphatic alkenes but offered poor enantioselectivity for cis-alkenes [69-71]. Studies found that increased enantioselectivities could be achieved for the epoxidation of dx-alkenes with decreased size of the acetal blocking groups. The best results for the epoxidation of ds-alkenes were found with methoxy catalyst 16b, which was successfully used in the synthesis of the side chain of Taxol [72]. 

Owing to their electron-poor nature, enoates present challenging substrates for asymmetric oxidation using the electrophiUc dioxirane reagents previously 

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Mechanistic studies103 revealed that chiral ketone-mediated asymmetric epoxidation of hydroxyl alkenes is highly pH dependent. Lower enantioselectivity is obtained at lower pH values at high pH, epoxidation mediated by chiral ketone out-competes the racemic epoxidation, leading to higher enantioselectivity. (For another mechanistic study on ketone-mediated epoxidation of C=C bonds, see Miaskiewicz and Smith.104)... 

Proceeding via a similar reaction mechanism to the ketone-mediated epoxidation reactions, iminium salts offer an alternative source of catalysts for asymmetric organocatalytic epoxidations. The first example of the appHcation of iminium salts to asymmetric epoxidations used dihydroisoquinolinium-based catalyst 20 (Figure 19.9), affording a 33% ee for the epoxidation of ( )-stilbene [81]. 

Discovering highly enantioselective ketone catalysts for asymmetric epoxidation has proven to be a challenging process. As shown in Scheme 3.62, quite a few processes are competing with the catalytic cycle of the ketone mediated epoxidation, including racemization of chiral control elements, excessive hydration of the carbonyl, facile... 

Until this work, the reactions between the benzyl sulfonium ylide and ketones to give trisubstituted epoxides had not previously been used in asymmetric sulfur ylide-mediated epoxidation. It was found that good selectivities were obtained with cyclic ketones (Entry 6), but lower diastereo- and enantioselectivities resulted with acyclic ketones (Entries 7 and 8), which still remain challenging substrates for sulfur ylide-mediated epoxidation. In addition they showed that aryl-vinyl epoxides could also be synthesized with the aid of a,P-unsaturated sulfonium salts lOa-b (Scheme 1.4). 

Epoxy Esters, Amides, Acids, Ketones, and Sulfbnes 1.2.3.1 Sulfur Ylide-mediated Epoxidation... 

Following their success with chiral ketone-mediated asymmetric epoxidation of unfunctionalized olefins, Zhu et al.113 further extended this chemistry to prochiral enol silyl ethers or prochiral enol esters. As the resultant compounds can easily be converted to the corresponding a-hydroxyl ketones, this method may also be regarded as a kind of a-hydroxylation method for carbonyl substrates. Thus, as shown in Scheme 4-58, the asymmetric epoxidation of enol silyl... 

B. Lygo, P. G. Wainwright, Asymmetric Phase-Transfer Mediated Epoxidation of a,p-Unsaturated Ketones using Catalysts Derived from Cinchona Alkaloids , Tetrahedron Lett. 1998,39,1599-1602. 

In recent years, dioxiranes have become workhorses for a variety of selective transformations in organic synthesis, from epoxidation of alkenes to the conversion of alcohols into fee corresponding ketones <99CJC308>. Dioxirane-mediated epoxidation continues to be the method of choice for complex substrates wife acid-sensitive functionality. Thus, fee dimethyl-dioxirane (DMD)-mediated epoxidation of the silylated stilbene lactam 159 has been reported as a key step in fee synthesis of protoberberines <99JOC877>. 

Polymer-bound trifluoromethyl aryl ketone 42 was prepared by attaching 4-(trifluoroacetyl)benzoic acid to a suitably functionalized resin and used as a catalyst in Oxone-mediated epoxidations.64 The reactions proceed by in situ generation of the polymer-supported (trifluoromethyl)-dioxirane. A series of epoxides was formed in good to excellent yield. 

Lygo and Wainwright recently reported a detailed study of the asymmetric phase-transfer mediated epoxidation of a variety of acyclic a,P-unsaturated ketones of the chalcone type. The third-generation cinchona-derived quats (8c and 7c), related to those discussed earlier in the alkylation section and Scheme 10.4, gave the best inductions (89% ee, 88 to 89, Scheme 10.13 and 86% ee for the pseudoenantiomeric catalyst 7c to give, as product, the enantiomer of 89). 

Sello et al. have reviewed recent developments in oxirane preparation including metal- and ketone-mediated methods, the synthesis of epoxides from carbonyls, and enzymatic reactions <2006CSY457>. 

In the realm of epoxidations without the use of transition metals, dioxirane-mediated processes are among the most versatile. While the use of stoichiometric amounts of even the simplest dioxiranes can still be experimentally cumbersome, novel catalytic systems eontinue to emerge. For example, the PEG-immobilized trifluoroacetophenone 17 is a convenient dioxirane precursor that is highly active, soluble in both water and organic solvents, and easily recoverable and reusable. In the presence of Oxone, this ketone mediates the efficient epoxidation of sensitive substrates, such as the BOC-protected aminostyrene 18 04TL6357>. 

The ability of non-C2 symmetric ketones to promote a highly enantioselective dioxirane-mediated epoxidation was first effectively demonstrated by Shi in 1996 [114]. The fructose-derived ketone 44 was discovered to be particularly effective for the epoxidation of frans-olefins (Scheme 17 ). frans-Stilbene, for instance, was epoxidized in 95% ee using stoichiometric amounts of ketone 44, and even more impressive was the epoxidation of dialkyl-substituted substrates. This method was rendered catalytic (30 mol %) upon the discovery of a dramatic pH effect, whereby higher pH led to improved substrate conversion [115]. Higher pH was proposed to suppress decomposition pathways for ketone 44 while simultaneously increasing the nucleophilicity of Oxone. Shi s ketone system has recently been applied to the AE of enol esters and silyl enol ethers to provide access to enantio-enriched enol ester epoxides and a-hydroxy ketones [116]. Another recent improvement of Shi s fructose-derived epoxidation reaction is the development of inexpensive synthetic routes to access both enantiomers of this very promising ketone catalyst [117]. 

Reagents involved in the oxidation of alcohols to aldehydes-ketones by oxygen under fluorous biphasic conditions are TEMPO, CuBr-SMe2, and 4,4 -bis[heptadecafluoro)-dodecyl]-2,2 -bipyridyl. The Mn(salen) complexes that mediate epoxidation of alkenes have been modified to bear polyfluoroalkyl substituents in the aromatic rings. Oxyfunc-tionalization of unactivated C—H sites is achieved with perfluorinated oj-2-butyl-3-propyloxaziridine. "... 

Attack of the oxygen atom of NO2 anion at Pd-coordinated alkene ligand afforded metallacycle compounds (Scheme 8.32) [53]. The X-ray structure determination of the product from dicylopentadiene complex of Pd(II) established the cis oxypalladation. The metallacycle thus formed can be regarded as an intermediate in Pd-catalyzed oxidation of alkenes to ketones or epoxides with the use of NO2 ligand as a mediator and O2 as an oxidant. 

Further examples of selective oxidations using O2 include the oxidation of -xylene to terephthalic acid, Baeyer-Villiger oxidations of cyclic ketones to lactones using molecular oxygen and benzaldehyde as a sacrificial aldehyde and catalytic epoxidation via a free radical route (rather than the electrophilic oxidation proposed for hydrogen peroxide mediated epoxidation over TS-1). ... 

The group of Carreira reported the synthesis of various human-derived epoxyisoprostanes with anti-inflammatory properties enabled by a chemoselective Sml2-mediated epoxide opening. Reduction of a,p-epo)q ketones 69 with Sml2 was found to be the only method able to... 

Fluorine-containing ketones have proven to be one of the most successful types of catalyst for dioxirane-mediated epoxidation [27]. Demnark has shown that good to excellent enantioselectivities can be achieved with catalyst 9 for tra 5-olefins (Scheme 1.10). However, catalyst loadings are high (30 mol%) [28]. 

A breakthrough in dioxirane-mediated epoxidation was achieved by Shi in the late 1990s. He reported excellent ees for a wide variety of snbstrates nsing the frnctose-derived ketone 10 [32], This catalyst is easily prepared in two steps, and typical enantioselectivities range from 80% to 95% ee. However, the chiral ketone decomposes under the reaction conditions (pH 7-8), presnmably throngh Baeyer-VUliger oxidation, and initially a large excess of the mediator had to be nsed (3 equivalents, with respect to the snbstrate) (Scheme 1.12). 

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