Epoxide enantiomers

The second system studied was the separation of the chiral epoxide enantiomers (la,2,7,7a-tetrahydro-3-methoxynaphth-(2,3b)-oxirane Sandoz Pharma) used as an intermediate in the enantioselective synthesis of optically active drugs. The SMB has been used to carry out this chiral separation [27, 34, 35]. The separation can be performed using microcrystalline cellulose triacetate as stationary phase with an average particle diameter greater than 45 )tm. The eluent used was pure methanol. A... 

The competitive adsorption isotherms were determined experimentally for the separation of chiral epoxide enantiomers at 25 °C by the adsorption-desorption method [37]. A mass balance allows the knowledge of the concentration of each component retained in the particle, q, in equilibrium with the feed concentration, < In fact includes both the adsorbed phase concentration and the concentration in the fluid inside pores. This overall retained concentration is used to be consistent with the models presented for the SMB simulations based on homogeneous particles. The bed porosity was taken as = 0.4 since the total porosity was measured as Ej = 0.67 and the particle porosity of microcrystalline cellulose triacetate is p = 0.45 [38]. This procedure provides one point of the adsorption isotherm for each component (Cp q. The determination of the complete isotherm will require a set of experiments using different feed concentrations. To support the measured isotherms, a dynamic method of frontal chromatography is implemented based on the analysis of the response curves to a step change in feed concentration (adsorption) followed by the desorption of the column with pure eluent. It is well known that often the selectivity factor decreases with the increase of the concentration of chiral species and therefore the linear -i- Langmuir competitive isotherm was used ... 

Pineschi and Feringa reported that chiral copper phosphoramidite catalysts mediate a regiodivergent kinetic resolution (RKR) of cyclic unsaturated epoxides with dialkylzinc reagents, in which epoxide enantiomers are selectively transformed into different regioisomers (allylic and homoallylic alcohols) [90]. The method was also applied to both s-cis and s-trans cyclic allylic epoxides (Schemes 7.45 and 7.46,... 

Studies using either molecular oxygen-18 or oxygen-18 water indicated that the 4R,5R-dihydrodiol is derived by water attack at the C-4 position of the metabolically formed 4,5-epoxide intermediate (15.21), These results established that 4S,5R-epoxide is formed as the metabolic precursor of the 4R,5R-dihydrodiol. Hydration studies of the optically pure BaP 4,5-epoxide enantiomers indicated that the 4S,5R-epoxide is hydrated exclusively at the S-center (C-4 position) whereas 85% of the 4R,5S-epoxide is hydrated at the S-center (C-5 position) (22 and Figure 4). 

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.

In contrast to the asymmetrization of meso-epoxides, the kinetic resolution of racemic epoxides by whole fungal and bacterial cells has proven to be highly selective (see above). These biocatalysts supply both the unreacted epoxide enantiomer and the corresponding vidnal diol in high enantiomeric excess. This so-called classic kinetic resolution pattern of the biohydrolysis is often regarded as a major drawback since the theoretical chemical yield can never exceed 50% based on the racemic starting material. As a consequence, methods... 

Table 17) with two substituents in position C3 the oxygen transfer by the chiral hydroperoxides occurred from the same enantioface of the double bond, while epoxidation of the (ii)-phenyl-substituted substrates 142c,g,i resulted in the formation of the opposite epoxide enantiomer in excess. In 2000 Hamann and coworkers reported a new saturated protected carbohydrate hydroperoxide 69b , which showed high asymmetric induction in the vanadium-catalyzed epoxidation reaction of 3-methyl-2-buten-l-ol. The ee of 90% obtained was a milestone in the field of stereoselective oxygen transfer with optically active hydroperoxides. Unfortunately, the tertiary allylic alcohol 2-methyl-3-buten-2-ol was epoxidized with low enantioselectivity (ee 18%) with the same catalytic system . 

The stereochemistry of the CPO-catalyzed epoxidation of indene has been reported [279]. In aqueous solution the initially formed epoxide is not stable and opens to form the ds-diols. When the reaction is carried out in the absence of water, the epoxide enantiomers were isolated, with the lS,2f -enantiomer being formed in 30% ee (Scheme 2.24). 

Weems, H.B., Mushtaq, M., and Yang, S.K., Resolution of epoxide enantiomers of polycyclic aromatic hydrocarbons by chiral stationary-phase high-performance liquid chromatography, Anal. Biochem., 148, 328, 1985. 

The epoxide enantiomers can also be resolved on chiral stationary phase HPLC columns as follows ... 

The epoxide formed by top-side attack of a peroxyacid on trans-4-octene has two chirality centers of R configuration. The epoxide formed by bottom-side attack has (S,S) configuration. The two epoxide enantiomers are formed in equal amounts and constitute a racemic mixture. 

The two epoxide enantiomers (i-) and (-) 7.71 were selected as chemical starting points for library generation Their synthesis from shikimic acid with reasonable overall yields was already known (248, 249), and they had a carboxylic acid handle for SPS. The other key intermediates were the three benzylnitrone carboxylic acids 7.72a-c, which were prepared from the corresponding benzyl alcohols (250,251) (Fig. 7.40). The two epoxycyclohexenols were supported onto a PEG-based resin, loaded with a photolabile linker, to give resin-bound 7.73a,b (from now on only one enantiomer will be shown in the figures, but the synthetic pathway was continued with both... 

The mechanism of the Jacobsen HKR and ARO are analogous. There is a second order dependence on the catalyst and a cooperative bimetallic mechanism is most likely. Both epoxide enantiomers bind to the catalyst equally well so the enantioselectivity depends on the selective reaction of one of the epoxide complexes. The active species is the Co(lll)salen-OH complex, which is generated from a complex where L OH. The enantioselectivity is counterion dependent when L is only weakly nucleophilic, the resolution proceeds with very high levels of enantioselectivity. 

Epoxidation of various olefins by cytochrome P-450 enzymes has been studied using rat liver microsomes [29,30] as well as using enzymes from microbial origin. For example, Ruettinger and Fulco [31] reported the epoxidation of fatty acids such as palmitoleic acid by a cytochrome P-450 from Bacillus megaterium. Their results indicate that both the epoxidation and the hydroxylation processes are catalyzed by the same NADPH-dependent monooxygenase. More recently, other researchers demonstrated that the cytochrome P-450cam from Pseudomonas putida, which is known to hydroxylate camphor at a non-activated carbon atom, is also responsible for stereoselective epoxidation of cis- -methylstyrene [32]. The (lS,2R)-epoxide enantiomer obtained showed an enantiomeric purity (ee) of 78%. This result fits the predictions based on a theoretical approach (Fig. 2). 

It is interesting that, while catalyst 24 (R = H) gives the (—)-(l S,2S) epoxide, when the catalyst contains an electron-withdrawing nitro or sulphone substituent (catalysts 34 and 36), a change is observed in the absolute configuration of the epoxide enantiomer formed preferentially, to the (I )-(lR,2R) epoxide, in every case. 

Marky, L.A., Rentzeperis, D., Luneva, N.P., Cosman, M., Geadntoy, N.E., and Kupke, D.W. (1996) Differential hydration thermodynamics of stereoiso-meric DNA-benzo[a]pyrene adducts derived from diol epoxide enantiomers with different tumorigenic potentials. 

The enantiomeric excess of the epoxide is determined by HPLC analysis using a Chiracel OB column (25 cm x 4.6 mm, Daicel) eluted with EtOH/hexanes (5 95) at 1 mUmin, while monitoring at 254 nm. The retention times of the epoxide enantiomers are 11.1 (1S,2R) and 15.3 (1R.2S) min. 

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