Enantiomeric epoxides

Dihydronaphthalene is often used as a model olefin in the study of epoxidation catalysts, and very often gives product epoxides in unusually high ee s. In 1994, Jacobsen discovered in his study on the epoxidation of 1,2-dihydronaphthalene that the ee of the epoxide increases at the expense of the minor enantiomeric epoxide.Further investigation led to the finding that certain epoxides, especially cyclic aromatically conjugated epoxides, undergo kinetic resolution via benzylic hydroxylation up to a krei of 28 (Scheme 1.4.9). 

Figure 3. Mechanism of microsomal EH-catalyzed hydration of the K-region epoxide enantiomers of BA, BaP, and DMBA. The percentages of the trans-addition product by water for each enantiomeric epoxide are indicated. The enantiomeric composition of the dihydrodiol enantiomers formed from the hydration of DMBA 5S,6R-epoxide was determined using 1 mg protein equivalent of liver microsomes from pheno-barbital-treated rats per ml of incubation mixture and this hydration reaction is highly dependent on the concentration of the microsomal EH (49). The epoxide enantiomer formed predominantly from the respective parent hydrocarbon by liver microsomes from 3-methylcho-lanthrene-treated rats is shown in the box.

An alternative method for the epoxidation of enones was developed by Jackson and coworkers in 1997 , who utilized metal peroxides that are modified by chiral ligands such as diethyl tartrate (DET), (5,5)-diphenylethanediol, (—)-ephedrine, ( )-N-methylephedrine and various simple chiral alcohols. The best results were achieved with DET as chiral inductor in toluene. In the stoichiometric version, DET and lithium tert-butyl peroxide, which was generated in situ from TBHP and n-butyllithium, were used as catalyst for the epoxidation of enones. Use of 1.1 equivalent of (-l-)-DET in toluene as solvent afforded (2/f,35 )-chalcone epoxide in 71-75% yield and 62% ee. In the substo-ichiometric method n-butyllithium was replaced by dibutylmagnesium. With this system (10 mol% Bu2Mg and 11 mol% DET), a variety of chalcone-type enones could be oxidized in moderate to good yields (36-61%) and high asymmetric induction (81-94%), giving exactly the other enantiomeric epoxide than obtained with the stoichiometric system (equation 37). 

Epoxidation of ( >2-butene gives a racemic mixture of two enantiomeric epoxides. 

With chiral ligands, the transition-metal catalyst-hydroperoxide complex yields optically active oxiranes. " One of the most significant advances in the formation of chiral epoxides from allyl alcohols has recently been reported by the Sharpless group. Using (-l-)-tartaric acid, ferf-butylhydroperoxide, and titanium isopropoxide, they were able to obtain chiral epoxides in very high enantiomeric excess. The enantiomeric epoxide can be obtained by employing (—)-tartaric acid (Eq. 33a). 

In recent years, there has been considerable interest in the stereochemical aspects of metabolic epoxidation, prompted by the recognition that the toxicity, metabolic formation, and further metabolism of epoxides can be highly stereoselective (211). As discussed earlier, when the epoxide formed is an arene oxide (i.e epoxidation of an aromatic double bond), it is often rapidly converted to dihydrodiols, and such hydroxyl compounds have been analyzed by the indirect resolution approach. However, when the metabolite epoxide is more stable, it is often possible to examine its stereochemistry. For this purpose, several methods for the chromatographic separation of enantiomeric epoxides have been developed, including some indirect methods. 

Among the reactions catalyzed by titanium complexes, the asymmetric epoxidation of allylic alcohols developed by Sharpless and coworkers [752, 807-810] has found numerous synthetic applications. Epoxidation of allylic alcohols 3.16 by ferf-BuOOH under anhydrous conditions takes place with an excellent enantioselectivity (ee > 95%) when promoted by titanium complexes generated in situ from Ti(0/ -Pr)4 and a slight excess of diethyl or diisopropyl (R,R)- or (iS, 5)-tartrates 2.69. The chiral complex formed in this way can be used in stoichiometric or in catalytic amounts. For catalytic use, molecular sieves must be added. Because both (RJ )- and (5,5)-tartrates are available, it is posable to obtain either enantiomeric epoxide from a single allylic alcohol. Cumene hydroperoxide (PhCMe20OH) can also be used in place of ferf-BuOOH. This method has been applied to industrial synthesis of enantiomeric glycidols [811, 812]. 

Diethyl D-tartrate (2b), treated similarly with 30% hydrobromic acid in acetic acid followed by acidic hydrolysis, is converted to diethyl 6 y /fro-(2R,3R)-2-bromo-3-hydroxysuccinate (824) in an overall yield of 73%. Sodium ethoxide cylization affords (2 S, 3 S)-2,3-epoxysuccinate (825), which is the enantiomeric epoxide of 821. Epoxide cleavage with lithium dimethylcuprate provides in 78% yield diethyl (2S,3R)- eo /zro-3-methylmalate (826), which is converted in eight steps to ( —)-(l S, 2 S, 4iS, 5R)-2,4-dimethyl-5-ethyl-6,8-dioxobicyclo-[3.2.1]octane or ( —)-(5-multistriatin (827), one of the eight possible stereoisomeric forms for this pheromone component responsible for the aggregation of the North American... 

Tit enantiomeric Epoxide from allylic Alcohol Ref Review A. Pfennjnger, Synthesis 89 (1986)... 

Using pure halohydrin dehalogenase (HheC), competing activities observed in whole-cell preparations were eUminated and halohydrins could be resolved via enantioselective ring-closure with excellent enantioselectivities yielding enantiomeric epoxides and nonreacted halohydrins (Scheme 2.237) [1846]. 

With optically active tartrate esters present in the reaction system, titanium alkoxides catalyze a very stereoselective oxidation of allylic alcohols. This method must depend on specific interactions in the transition state by which the hydroxyl group controls the relationship between the double bond and approaching reagent and the tartrate establishes a chiral environment at the metal atom. The (+) and (-) enantiomers of diethyl tartrate give enantiomeric epoxides, each in >90% yield." ... 

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