Enantiomer direct

Two methods are used in practice to obtain enantiomerically pure amino acids. One way is to resolve the racemic mixture into its pure enantiomers (Section 9.8). A more direct approach, however, is to use an enantioselective synthesis to prepare only the desired 5 enantiomer directly. As discussed in the Chapter 19 Focus Oil, the idea behind enantioselective synthesis is to find a chiral reaction catalyst that will temporarily hold a substrate molecule in an unsymmetrical environment. While in that chiral environment, the substrate may be more... 

Direct analysis of the enantiomers in biological fluids is very important because it reduces both analysis time and sample preparation time. Indeed, when there is risk of the quick racemization of the enantiomer, direct analysis is essential. It has been observed that CD-based CSPs employ mobile phases that are generally compatible with biological samples, hence can be used for the direct analysis of the enantiomers in biological fluids [67,80]. Stalcup et al. [58] employed coupled column chromatography to isolate scopolamine from a plant extract and found that the extent of racemization depends on the isolation... 

A modification of this procedure was used by Cram, et al. who likewise obtained the (+)-BNP acid via Its cinchonine salt, but they isolated the (-) enantiomer directly from the more soluble salt, without using cinchonidine. In 59% and 46% respective yields. Both enantiomers, precipitated by 6 N hydrochloric acid from their cinchonine salt solutions, had to be purified by successive digestions with hot 6 N hydrochloric acid and water In order to decompose any remaining cinchonine salt. These purifications are avoided by using the procedure described herein. 

This method, based on the use of microbial cells or enzymes, exploits three important features of biocatalysts (1) directing a reaction exclusively toward one enantiomer, (2) transforming a prochiral center to a chiral product, and (3) carrying out transformations on nonfunctionalized centers. The traditional problem associated with the enzymatic method is the presumption that these reactions should, of necessity, be carried out in dilute aqueous solutions to mimic biological systems. This leads to problems such as expensive separations and sensitivity of fermentations to deactivating influences. Despite these limitations, the biochemical route offers an attractive alternative for synthesizing an enantiomer directly (Knowles, 1986 Sheldon, 1996). 

One area of chirotechnology which is undergoing rapid development is chiral HPLC, whereby the use of chiral stationary phases (CSPs) permits the direct separation of racemic compounds into constituent enantiomers. Despite the capital outlay required, for example, for columns costing upwards of 3000, the use of preparative chiral HPLC in drug discovery has a number of benefits. After development of an appropriate method based on a previously defined analytical separation has been carried out, rapid and quantitative separation of racemates can be achieved, with evaporation of solvent from column fractions affording pure enantiomers directly. Although preparative chiral HPLC is less amenable to scale-up than other resolution techniques, it may be ideal for preliminary screening of both enantiomers in circumstances where manipulation of small quantities of material, for example, by crystallization, is impractical and prone to contamination problems. 

Enantiomers. Two nonsuperimposable structures that are mirror images of each other are known as enantiomers. Enantiomers are related to each other in the same way that a right hand is related to a left hand. Except for the direction in which they rotate the plane of polarized light, enantiomers are identical in all physical properties. Enantiomers have identical chemical properties except in their reactivity toward optically active reagents. 

The optical activity of malic acid changes with dilution (8). The naturally occurring, levorotatory acid shows a most peculiar behavior in this respect a 34% solution at 20°C is optically inactive. Dilution results in increasing levo rotation, whereas more concentrated solutions show dextro rotation. The effects of dilution are explained by the postulation that an additional form, the epoxide (3), occurs in solution and that the direction of rotation of the normal (open-chain) and epoxide forms is reversed (8). Synthetic (racemic) R,.9-ma1ic acid can be resolved into the two enantiomers by crystallisation of its cinchonine salts. 

Integration of the peaks for the two diastereomers accurately quantifies the relative amounts of each enantiomer within the mixture. Such diastereometic derivatives may also be analy2ed by more accurate methods such as gc or hplc. One drawback to diastereometic detivatization is that it requites at least 15 mg of material, which is likely to be material painstakingly synthesized, isolated, and purified. The use of analytical chiral chromatographic methods allows for the direct quantification of enantiomeric purity, is highly accurate to above 99.8% ee, and requites less than one milligram of material. 

Use of D-amino acids in the synthesis of a hairpin loop portion from the CD4 receptor provides a stable CD4 receptor mimic, which blocks experimental allergic encephalomyelitis (144). This synthetic constmct is not simply the mirror image or enantiomer of the CD4 hairpin loop, but rather an aH-D-constmct in the reverse sequence, thus providing stereochemicaHy similar side-chain projections of the now inverted backbone (Fig. 11). This peptide mimetic, unlike its aH-L amino acid counterpart, is resistant to en2yme degradation. As one would expect, the aH-D amino acid CD4 hairpin loop, synthesi2ed in the natural direction, the enantiomer of the natural constmct, is inactive. 

An hplc assay was developed suitable for the analysis of enantiomers of ketoprofen (KT), a 2-arylpropionic acid nonsteroidal antiinflammatory dmg (NSAID), in plasma and urine (59). Following the addition of racemic fenprofen as internal standard (IS), plasma containing the KT enantiomers and IS was extracted by Hquid-Hquid extraction at an acidic pH. After evaporation of the organic layer, the dmg and IS were reconstituted in the mobile phase and injected onto the hplc column. The enantiomers were separated at ambient temperature on a commercially available 250 x 4.6 mm amylose carbamate-packed chiral column (chiral AD) with hexane—isopropyl alcohol—trifluoroacetic acid (80 19.9 0.1) as the mobile phase pumped at 1.0 mL/min. The enantiomers of KT were quantified by uv detection with the wavelength set at 254 nm. The assay allows direct quantitation of KT enantiomers in clinical studies in human plasma and urine after adrninistration of therapeutic doses. 

AGP columns have wide appHcation for the direct separation of enantiomers of many different classes of dmgs, amines, acids, and nonprotolytic compounds (18,23). Acidic dmgs resolved include ibuprofen [15687-27-17, C 2H g02, ketoprofen [22071 -15 ] and naproxen [22204-53-17,... 

Pure miantiomeric substances show rotations that are equal in magnitude but opposite in direction. Unequal mixtures of enantiomers rotate light in proportion to the composition. The relationship between optical purity and measured rotation is... 

Let s return to bromochlorofluoromethane as a simple example of a chiral molecule. The two enantiomers of BrCIFCH are shown as ball-and-stick models, as wedge-and-dash drawings, and as Fischer projections in Figure 7.6. Fischer projections are always generated the same way the molecule is oriented so that the vertical bonds at the chirality center are directed away from you and the horizontal bonds point toward you. A projection of the bonds onto the page is a cross. The chirality center lies at the center of the cross but is not explicitly shown. 

Hie use of chiral catalysts as an approach to enantiomer icaliy enriched products by means of coppet-mediated substitution reactions is covered in this chapter. Reactions in which a chiral auxiliary resides in the leaving group of the substrate w ill also he dealt with, since these reactions provide direct and efBcient routes to single enantiomers of the desired products. Most studies so far have been concerned with allylic substrates, with a new chiral center being produced in the course of a selec-... 

Drobuline (71) is a somewhat related cardiac-directed drug with antiarrhythmic action. Since both enantiomers have the... 

A. Walhagen and F.-E. Edholm, Coupled-column cliromatography of immobilized protein phases for direct separation and determination of dmg enantiomers in plasma , 7. Chromatogr. 473 371-379 (1989). 

A. Mosandl, U. Hener, U. Hagenauer-Hener and A. Kustertnann, Direct enantiomer separation of chiral y-lactones from food and beverages hy multidimensional gas chromatography , /. High Resolut. Chromatogr. 12 532-536 (1989). 

W. H. Pirkle and B. C. Hamper, The direct preparative resolution of enantiomers by liquid chromatography on chiral stationary phases in Preparative Liquid Chromatography, B. A. Bidling-meyer (Ed.), Journal Chromatography Library Vol. 38, 3 Edition, Elsevier Science Publishers B. V, Amsterdam (1991) Chapter 7. 

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