Enantiomers with

Figure A2.5.30. Left-hand side Eight hypothetical phase diagrams (A through H) for ternary mixtures of d-and /-enantiomers with an optically inactive third component. Note the syimnetry about a line corresponding to a racemic mixture. Right-hand side Four T, x diagrams ((a) tlirough (d)) for pseudobinary mixtures of a racemic mixture of enantiomers with an optically inactive third component. Reproduced from [37] 1984 Phase Transitions and Critical Phenomena ed C Domb and J Lebowitz, vol 9, eh 2, Knobler C M and Scott R L Multicritical points in fluid mixtures. Experimental studies pp 213-14, (Copyright 1984) by pennission of the publisher Academic Press.

Porcine liver esterase (PLE) gives excellent enantioselectivity with both dimethyl 3-methylglutarate [19013-37-7] (lb) and malonate (2b) diester. It is apparent from Table 1 that the enzyme s selectivity strongly depends on the size of the alkyl group in the 2-position. The hydrolysis of ethyl derivative (2c) gives the S-enantiomer with 75% ee whereas the hydrolysis of heptyl derivative (2d) results in the R-monoester with 90% ee. Chymotrypsin [9004-07-3] (CT) does not discriminate glutarates that have small substituents in the 3-position well. However, when hydroxyl is replaced by the much bulkier benzyl derivative (Ic), enantioselectivity improves significantly. 

Separation of enantiomers by physical or chemical methods requires the use of a chiral material, reagent, or catalyst. Both natural materials, such as polysaccharides and proteins, and solids that have been synthetically modified to incorporate chiral structures have been developed for use in separation of enantiomers by HPLC. The use of a chiral stationary phase makes the interactions between the two enantiomers with the adsorbent nonidentical and thus establishes a different rate of elution through the column. The interactions typically include hydrogen bonding, dipolar interactions, and n-n interactions. These attractive interactions may be disturbed by steric repulsions, and frequently the basis of enantioselectivity is a better steric fit for one of the two enantiomers. ... 

Another means of resolution depends on the difference in rates of reaction of two enantiomers with a chiral reagent. The transition-state energies for reaction of each enantiomer with one enantiomer of a chiral reagent will be different. This is because the transition states and intermediates (f -substrate... f -reactant) and (5-substrate... R-reactant) are diastereomeric. Kinetic resolution is the term used to describe the separation of enantiomers based on different reaction rates with an enantiomerically pure reagent. 

Erank H, G. J. Nicholson and E. Bayer, Rapid gas cliromatographic separation of amino acid enantiomers with a novel cliiral stationary phase , J. Chromatogr. Sci. 15 174-176(1977). 

The first partial chiral resolution reported in CCC dates from 1982 [120]. The separation of the two enantiomers of norephedrine was partially achieved, in almost 4 days, using (/ ,/ )-di-5-nonyltartrate as a chiral selector in the organic stationary phase. In 1984, the complete resolution of d,l-isoleucine was described, with N-dodecyl-L-proline as a selector in a two-phase buffered n-butanol/water system containing a copper (II) salt, in approximately 2 days [121]. A few partial resolutions of amino acids and dmg enantiomers with proteic selectors were also published [122, 123]. 

A different approach to making chiral drugs is asymmetric synthesis. An optically inactive precursor is converted to the drug by a reaction that uses a special catalyst, usually an enzyme (Chapter 11). If all goes well, the product is a single enantiomer with the desired physiological effect In 2001, William S. Knowles, Ryogi Noyori, and K. Barry Sharpless won the Nobel Prize in chemistry for work in this area. 

KR is the total or partial separation of two enantiomers from a racemic mixture [5]. KR is based on the different reaction rates of the enantiomers with a chiral molecule (a reagent, a catalyst, etc). In the ideal case, the difference in reactivity is large, and one of the enantiomers reacts very fast to give the product, whereas the other does not react at all (Figure 4.1). 

As outlined above, enantioconvergent processes require two separate reaction pathways in order to transform a racemic substrate into a single product enantiomer. This is accomplished by employing a catalyst, which transforms one of the substrate enantiomers to the product with retention of configuration. Concurrently, another catalyst, with opposite enantioselectivity and opposite regioselectivity, transforms the other substrate enantiomer with inversion of configuration (Figure 5.24). 

In 1996, Fu et al. reported the S3mthesis of the planar chiral heterocycles 64, formally DMAP fused with a ferrocene core [82]. While the original synthesis provided racemic 64a in only 2% overall yield requiring a subsequent resolution by preparative HPLC on a chiral stationary phase, a recently improved synthesis furnished the racemic complexes 64 in 32-40% yield over seven steps. A subsequent resolution with di-p-toluoyltartaric or dibenzoyltartaric acid gave access to the enantiomers with >99% ee (28 14% yield for each isomer in this step) [83]. 

Cycloamylose forms inclusion complexes stereoselectively with the enantiomers of isopropyl methylphosphinate (124) from which it was possible to isolate one enantiomer with an optical purity of 66%. The absolute configuration of menthyl methylphosphinate has been revised to the opposite of that previously assigned. 

Bis-(l-chloro-2-propyl)ether has two chiral centers, and exists in (R,R)-, (S,S)-, and a meso form. It is degraded by Rhodococcus sp. with a preference for the 5,5-enantiomer with the intermediate formation of l-chloro-propan-2-ol and chloroacetone (Garbe et al. 2006). 

Althongh the prodnct from the transformation of toluene by mntants of Pseudomonas putida lacking dehydrogenase activity is the cis-2R,3S dihydrodiol, the cis-2S,3R dihydrodiol has been synthesized from 4-iodotoluene by a combination of microbiological and chemical reactions. P. putida strain UV4 was used to prepare both enantiomers of the di-dihydrodiol, and iodine was chemically removed nsing H2 -Pd/C. Incubation of the mixtnre of enantiomers with P. putida NCIMB 8859 selectively degraded the 2R,3S componnd to prodnce toluene cis-2S,3R dihydrodiol (Allen et al. 1995). 

Kilar, F. and Fanali, S., Separation of tryptophan-derivative enantiomers with iron-free human serum transferrin by capillary zone electrophoresis, Electrophoresis, 16, 1510, 1995. 

Both quinine and dihydroquinine favored the required (S)-enantiomer. A small ee difference of the product might be due to inconsistent purity of the naturally obtained cinchona alkaloids. It was noted that quinidine (the pseudo-enantiomer of quinine) gave the (R)-enantiomer with a similar 55% ee. Since quinine was... 

Gotti et al. [42] reported an analytical study of penicillamine in pharmaceuticals by capillary zone electrophoresis. Dispersions of the drug (0.4 mg/mL for the determination of (/q-penicillaminc in water containing 0.03% of the internal standard, S -met hy I - r-cystei ne, were injected at 5 kPa for 10 seconds into the capillary (48.5 cm x 50 pm i.d., 40 cm to detector). Electrophoresis was carried out at 15 °C and 30 kV, with a pH 2.5 buffer of 50 mM potassium phosphate and detection at 200 rnn. Calibration graphs were linear for 0.2-0.6 pg/mL (detection limit = 90 pM). For a more sensitive determination of penicillamine, or for the separation of its enantiomers, a derivative was prepared. Solutions (0.5 mL, final concentration 20 pg/mL) in 10 mM phosphate buffer (pH 8) were mixed with 1 mL of methanolic 0.015% 1,1 -[ethylidenebis-(sulfonyl)]bis-benzene and, after 2 min, with 0.5 mL of pH 2.5 phosphate buffer. An internal standard (0.03% tryptophan, 0.15 mL) was added and aliquots were injected. With the same pH 2.5 buffer and detection at 220 nm, calibration graphs were linear for 9.3-37.2 pg/mL, with a detection limit of 2.5 pM. For the determination of small amounts of (L)-penicillamine impurity, the final analyte concentration was 75 pg/mL, the pH 2.5 buffer contained 5 mM beta-cyclodextrin and 30 mM (+)-camphor-10-sulfonic acid, with a voltage of 20 kV, and detection at 220 nm. Calibration graphs were linear for 0.5-2% of the toxic (L)-enantiomer, with a detection limit of 0.3%. 

An unusually extensive battery of experimental techniques was brought to bear on these comparisons of enantiomers with their racemic mixtures and of diastereomers with each other. A very sensitive Langmuir trough was constructed for the project, with temperature control from 15 to 40°C. In addition to the familiar force/area isotherms, which were used to compare all systems, measurements of surface potentials, surface shear viscosities, and dynamic suface tensions (for hysteresis only) were made on several systems with specially designed apparatus. Several microscopic techniques, epi-fluorescence optical microscopy, scanning tunneling microscopy, and electron microscopy, were applied to films of stearoylserine methyl ester, the most extensively investigated surfactant. 

The chiral sites which are able to rationalize the isospecific polymerization of 1-alkenes are also able, in the framework of the mechanism of the chiral orientation of the growing polymer chain, to account for the stereoselective behavior observed for chiral alkenes in the presence of isospecific heterogeneous catalysts.104 In particular, the model proved able to explain the experimental results relative to the first insertion of a chiral alkene into an initial Ti-methyl bond,105 that is, the absence of discrimination between si and re monomer enantiofaces and the presence of diastereoselectivity [preference for S(R) enantiomer upon si (re) insertion]. Upon si (re) coordination of the two enantiomers of 3-methyl-l-pentene to the octahedral model site, it was calculated that low-energy minima only occur when the conformation relative to the single C-C bond adjacent to the double bond, referred to the hydrogen atom bonded to the tertiary carbon atom, is nearly anticlinal minus, A- (anticlinal plus, A+). Thus one can postulate the reactivity only of the A- conformations upon si coordination and of the A+ conformations upon re coordination (Figure 1.16). In other words, upon si coordination, only the synperiplanar methyl conformation would be accessible to the S enantiomer and only the (less populated) synperiplanar ethyl conformation to the R enantiomer this would favor the si attack of the S enantiomer with respect to the same attack of the R enantiomer, independent of the chirality of the catalytic site. This result is in agreement with a previous hypothesis of Zambelli and co-workers based only on the experimental reactivity ratios of the different faces of C-3-branched 1-alkenes.105... 

Enantiomers with a particular orientation were randomly generated by the Monte Carlo method on the surface of 23a and 23x defined by the particular van der Waals radius using the reported technique of blowing up the atomic radii.212 Molecular-mechanics calculations between the molecules were then performed step by step. The results of these calculations were evaluated with the averaged interaction energy. 

A young Louis Pasteur observed that many salts of tartaric acid formed chiral crystals (which he knew was related to their ability to rotate the plane of polarization of plane-polarized light). He succeeded in solving the mystery of racemic acid when he found that the sodium ammonium salt of racemic acid could be crystallized to produce a crystal conglomerate. After physical separation of the macroscopic enantiomers with a dissecting needle, Pasteur... 

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