Electron asymmetric epoxidation

The asymmetric epoxidation of electron-poor cinnamate ester derivatives was highlighted by Jacobsen in the synthesis of the Taxol side-chain. Asymmetric epoxidation of ethyl cinnamate provided the desired epoxide in 96% ee and in 56% yield. Epoxide ring opening with ammonia followed by saponification and protection provided the Taxol side-chain 46 (Scheme 1.4.12). 

Better results for the porphyrin complex-catalyzed asymmetric epoxidation of prochiral olefins were achieved by Naruta et al.98 using iron complexes of chiral binaphthalene or bitetralin-linked porphyrin 128 as chiral catalysts. As shown in Scheme 4-45, asymmetric epoxidation of styrene or its analogs provided the product with good ee. Even better results were obtained with substrates bearing electron-withdrawing substituents. 

Subsequently, high chemoselectivity and enantioselectivity have been observed in the asymmetric epoxidation of a variety of conjugated enynes using fructose-derived chiral ketone as the catalyst and Oxone as the oxidant. Reported enantioselectivities range from 89% to 97%, and epoxidation occurs chemoselectively at the olefins. In contrast to certain isolated trisubstituted olefins, high enantioselectivity for trisubstituted enynes is noticeable. This may indicate that the alkyne group is beneficial for these substrates due to both electronic and steric effects. 

In the design of chiral sulfides for sulfur ylide-mediated asymmetric epoxidation of aldehydes, two factors are important. First, a single sulfur ylide should be produced. Otherwise, the diastereomeric sulfur ylides may react with aldehydes in different ways and thus cause a drop in stereoselectivity. This may be achieved by choosing a rigid cyclic structure to make one of the lone pairs more accessible than the other. Second, the structure should be amenable to structural modification in order to study the electronic and steric effects of the sulfur on the enantioselectivity of the epoxidation reaction. 

Figure 14.7. Electronic effects in asymmetric epoxidation of cinnamyl alcohols...

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). 

Next to the base-catalyzed asymmetric epoxidations of electron-deficient olefins with chiral hydroperoxides described above, a few examples of uncatalyzed epoxidations with... 

SCHEME 54. Zinc-mediated asymmetric epoxidation of electron-deficient olefins... 

Several methods for the asymmetric epoxidation of electron-poor alkenes rely on the use of metal peroxides associated with chiral ligands . Enders and coworkers reported that ( )-a,/ -unsaturated ketones may be epoxidized using stoichiometric quantities of diethylzinc and a chiral alcohol, in the presence of molecular oxygen (equation 33). The best enantioselectivities were found using (/ ,/ )-Af-methylpseudoephedrine 54 as R OH... 

Electron-deficient olefins, asymmetric epoxidation, 386-91 Electron diffraction dialkyl peroxides, 713 ozonides, 721, 723 1,2,4-trioxolanes, 740 see also Gas electron diffraction Electron-donating substituents ene reactions, 841 sulfonyl peroxides, 1005-7 Electronegative functional groups,... 

Efficient kinetic resolution of chiral unsaturated secondary alcohols by irreversible enzyme-mediated acylation (with vinyl acetate as acylating agent, a crude preparation of Pseudomonas AK, and hexane as solvent) is possible, provided one relatively large and one small substituent are attached to the carbinol carbon. However, the method can be used to resolve substrates that are not amenable to asymmetric epoxidation (see examples 23, 25, 27, 29, where the double bond is either deactivated by an electron-withdrawing substituent, or is of the propargyl alcohol type). Acylation of the / -enantiomer consistently proceeds faster than that of the 5-enantiomer. An example of an allenic alcohol was also reported248. 

The asymmetric epoxidation of several chalcones (39) and other electron-poor olefins in a triphase system (water/organjc solvent/chiral polyamino acid) afford optically active oxirans with optical yields of up to 96%. The influence of the molecular structure of the catalysts and substrates, the solvent, and the temperature on the stereochemistry was investigated by a group of chemists from Italy and Spain 77). 

For recent reviews on asymmetric epoxidation of electron deficient carbon-carbon double bonds, see Porter, M. J. and Skidmore, J. Chem. Commun. 2000, 1215. 

The Julia - Colonna asymmetric epoxidation of electron-deficient unsaturated ketones to the corresponding epoxides with high yields and high ee is well known. This technique produces chiral chemical entities from the clean oxidant, hydrogen peroxide, without the use of a toxic or water sensitive transition metal additive. 

Chiral (salen)Mn(III)Cl complexes are useful catalysts for the asymmetric epoxidation of isolated bonds. Jacobsen et al. used these catalysts for the asymmetric oxidation of aryl alkyl sulfides with unbuffered 30% hydrogen peroxide in acetonitrile [74]. The catalytic activity of these complexes was high (2-3 mol %), but the maximum enantioselectivity achieved was rather modest (68% ee for methyl o-bromophenyl sulfoxide). The chiral salen ligands used for the catalysts were based on 23 (Scheme 6C.9) bearing substituents at the ortho and meta positions of the phenol moiety. Because the structures of these ligands can easily be modified, substantia] improvements may well be made by changing the steric and electronic properties of the substituents. Katsuki et al. reported that cationic chiral (salen)Mn(III) complexes 24 and 25 were excellent catalysts (1 mol %) for the oxidation of sulfides with iodosylbenzene, which achieved excellent enantioselectivity [75,76]. The best result in this catalyst system was given by complex 24 in the formation of orthonitrophenyl methyl sulfoxide that was isolated in 94% yield and 94% ee [76]. 

The catalytic asymmetric epoxidation of electron-deficient olefins has been regarded as one of the most representative asymmetric PTC reactions, and various such systems have been reported (Scheme 3.12). Lygo reported the asymmetric epoxidation of chalcone derivatives through the use of NaOCl [30,31], while Shioiri and Arai used aqueous H202 as an oxidant, their results indicating hydrogen bonding between the catalyst and substrates because an OH functionality in the catalyst was essential... 

The catalytic asymmetric epoxidation of electron-deficient olefins, particularly a,P-unsaturated ketones, has been the subject of numerous investigations, and as a result a number of useful methodologies have been elaborated [44], Among these, the method utilizing chiral phase-transfer catalysis occupies a unique position in terms of its practical advantages. Moreover, it also allows the highly enantioselective epoxidation of trans-a,P-unsaturated ketones, particularly chalcone. 

H. Q. Tian, X. G. She, and Y. Shi, Electronic probing of ketone catalysts for asymmetric epoxidation. Search for more robust catalysis, Org. Lett. 2001, 3, 715-718. 

As summarized in Table 10.4, further studies by Armstrong et al. revealed that asymmetric epoxidation of trans-stilbene can also be effected by other bicydic ketones (25-28) carrying electron withdrawing substituents in both the a-position and on the 1-bridge [35],... 

Another method is to use poly-L-amino acids as catalysts in alkaline media (Julia-Colanna epoxidation) for the asymmetric epoxidation of chalcones and other electron-poor olefins with H202 [287]. SmithKline Beecham workers used this method (see Fig. 4.105) as a key step in the synthesis of a leukotriene antagonist, although it required 20 equivalents of H202 and 12 equivalents of NaOH, based on substrate [288]. The mechanism probably involves the asym-... 

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