Chiral alkenes dioxirane epoxidation

Development of chiral, nonracemic dioxiranes for the catalytic enantioselective epoxidation of alkenes 99SL847. 

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 diastereomeric epoxides, for which the diastereoselectivity depends on the alkene and on the dioxirane structure. A comparative study on the diastereoselectivity for the electrophihc 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 DMD . ... 

The results of the dioxirane epoxidation of some 3-alkyl-substituted cyclohexenes and of 2-menthene indicate that the diastereoselectivity control is subject to the steric interactions of the dioxirane with the substituents of the substrate, while the size of the dioxirane substituents has only a minimal effect . In the favored transition structure, the alkyl groups of the dioxirane cannot interact effectively with the substituents at the stereogenic center of the chiral alkene . ... 

The dioxirane epoxidation of a prochrral alkene will produce an epoxide with either one new chirality center for terminal alkenes, or two for internal aUcenes. When an optically active dioxirane is nsed as the oxidant, expectedly, prochiral alkenes should be epoxi-dized asymmetrically. This attractive idea for preparative purposes was initially explored by Curci and coworkers in the very beginning of dioxirane chemistry. The optically active chiral ketones 1 and 2 were employed as the dioxirane precursors, but quite disappointing enantioselectivities were obtained. Subsequently, the glucose-derived ketone 3 was used, but unfortunately, this oxidatively labile dioxirane precursor was quickly consumed without any conversion of the aUcene . After a long pause (11 years) of activity in this challenging area, the Curci group reported work on the much more reactive ketone... 

The breakthrough came already in 1996, one year after Curd s prediction, when Yang and coworkers reported the C2-symmetric binaphthalene-derived ketone catalyst 6, with which ee values of up to 87% were achieved. A few months later, Shi and coworkers reported the fructose-derived ketone 7, which is to date still one of the best and most widely employed chiral ketone catalysts for the asymmetric epoxidation of nonactivated alkenes. Routinely, epoxide products with ee values of over 90% may be obtained for trans- and trisubstituted alkenes. Later on, a catalytic version of this oxygen-transfer reaction was developed by increasing the pH value of the buffer. The shortcoming of such fructose-based dioxirane precursors is that they are prone to undergo oxidative decomposition, which curtails their catalytic activity. 

Denmark, S. E. Wu, Z. The Development of Chiral, Nonracemic Dioxiranes for the Catalytic Enantioselective Epoxidation of Alkenes, Synlett 1999, 847-859. 

Enantioselective epoxidation of pro-chiral alkenes with dioxiranes generated from optically active ketones affords optically active epoxides with enantiomeric excesses (ee) in the 9-12.5% range <84CC155>. In the late 1980s values up to 24% have been observed when employing 4,4,4-trifluoro-3-phenyl-3-methoxybutan-2-one as the ketone <89ACR205>. 

The development of solid-supported chiral oxidants is a challenging area that has yielded interesting results in the development of a chiral supported dioxiran precursor. The preparation of non-racemic epoxides has been extensively studied in recent years since they are important building blocks in stereoselective synthesis. A supported dioxirane precursor based on a-fluorotropinones was shown to promote the epoxidation of alkenes [28, 29]. The reactant was anchored on meso-porous MCM-41 and amorphous silicas. It has shown comparable activity to its homogenous counterpart and good stability on recycling. The enantiomerically enriched version efficiently promotes the enanhoselective epoxidation of alkenes, with ee values up to 80% (Scheme 4.4). 

A number of chiral ketones have been developed that are capable of enantiose-lective epoxidation via dioxirane intermediates.104 Scheme 12.13 shows the structures of some chiral ketones that have been used as catalysts for enantioselective epoxidation. The BINAP-derived ketone shown in Entry 1, as well as its halogenated derivatives, have shown good enantioselectivity toward di- and trisubstituted alkenes. 

The epoxidation of nonfunctionalized alkenes may also be effected by chiral dioxiranes. These species, formed in situ using the appropriate ketone and potassium caroate (Oxone), can be formed from C-2 symmetric chiral ketones (29)[93], functionalized carbohydrates (30)[94] or alkaloid derivatives (31)[95]. One example from the laboratories of Shi and co-workers is given in Scheme 19. 

Among many other methods for epoxidation of disubstituted E-alkenes, chiral dioxiranes generated in situ from potassium peroxomonosulfate and chiral ketones have appeared to be one of the most efficient. Recently, Wang et /. 2J reported a highly enantioselective epoxidation for disubstituted E-alkenes and trisubstituted alkenes using a d- or L-fructose derived ketone as catalyst and oxone as oxidant (Figure 6.3). 

Epoxidation of alkenes can be effected by potassium persulphate. When the oxidation is conducted in the presence of chiral trifluoroketones, chiral oxiranes (ee 12-22%) are produced [14]. The chirality appears to be achieved via the initial reaction of the persulphate with the ketone to generate chiral dioxiranes, which then interact with the alkenes. 

Asymmetric epoxidation of olefins is an effective approach for the synthesis of enan-tiomerically enriched epoxides. A variety of efficient methods have been developed [1, 2], including Sharpless epoxidation of allylic alcohols [3, 4], metal-catalyzed epoxidation of unfunctionalized olefins [5-10], and nucleophilic epoxidation of electron-deficient olefins [11-14], Dioxiranes and oxazirdinium salts have been proven to be effective oxidation reagents [15-21], Chiral dioxiranes [22-28] and oxaziridinium salts [19] generated in situ with Oxone from ketones and iminium salts, respectively, have been extensively investigated in numerous laboratories and have been shown to be useful toward the asymmetric epoxidation of alkenes. In these epoxidation reactions, only a catalytic amount of ketone or iminium salt is required since they are regenerated upon epoxidation of alkenes (Scheme 1). 

From this series of calculations it is noted that the gas-phase reactivity of TFDO is substantially greater than that of DMDO. This rate difference has been ascribed largely to the inductive effect of the CF3 group. Fluoro-substituted dioxiranes have also played a unique role in the chiral epoxidation of alkenes. Flouk and coworkers have identified a novel stereoelectronic effect that increases the rate of epoxidation when the fiuorine substituent is anti to the oxygen of the developing C=0 group in the TS for epoxidation. 

The epoxidation of unfunctionalized alkenes by dioxiranes was investigated mainly for mechanistic purposes P . Some representative cases are collected in Scheme 3. Although such unfunctionalized alkenes have not been studied as intensively as the other olefin types, the recent asymmetric epoxidations by dioxirane were performed mainly on this substrate class (vide infra) J P. For this purpose, in-situ-generated dioxiranes in carefully buffered aqueous solutions had to be used, since the chiral dioxiranes cannot be readily isolated. Fortunately, the epoxides of unfunctionalized alkenes are more resistant to... 

Curd, R., Fiorentino, M. and Serio, M. R. Asymmetric Epoxidation of Unfunctionahzed Alkenes by Dioxirane Intermediates Generated from Potassium Peroxomonosulphate and Chiral Ketones. J. Chem. Soc., Chem. Commun. 1984, 155-156. 

Chiral dioxiranes, generated in situ from chiral ketones and Oxone , are promising reagents for the asymmetric epoxidation of unfunctionalized alkenes. Chiral ketone catalysts that are easily accessible in both enantiomers are targets for development. 

One highly attractive feature of ketone-catalyzed epoxidation via chiral dioxir-anes is that reliable models can be developed to rationalize the observed enantio-selectivities. For the reaction of a dioxirane with an alkene, two extreme transition states can be envisaged the so-called spiro and planar modes (Fig. 12.3). 

One of the most important advances in the past decade has been the development of asymmetric epoxidation methods for unfunctionalized alkenes using dioxiranes generated from chiral ketone precursors (Scheme 23) <1995TL5831, 1997JOC8964>. 

The epoxidation of alkenes is accelerated in fluorinated alcohol solvents the factors responsible for this rate acceleration have been examined <2006JA8421, 2006JA13412>. Chiral dioxiranes can now be used in a catalytic sense for the synthesis of vinyl m-epoxides <2006AGE4475>. 

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