Indirect resolutions

Since all the physical properties of two given enantiomers are the same in the absence of a chiral, or optically active, medium, their chromatographic resolution needs a different approach from the relatively simple separation of geometrical isomers, stereoisomers or positional isomers. Two methods are used. The older technique of indirect resolution, requires conversion of the enantiomers to diastereoisomers using a suitable chiral reagent, followed by separation of the diastereoisomers on a non-chiral GC or LC stationary phase. This technique has now been largely superseded by direct resolution, using either a chiral mobile phase (in LC) or a chiral stationary phase. A variety of types of chiral stationary phase have been developed for use in GC, LC and SFC(21 23). 

TLC has also been used for the separation of diastereomeric derivatives of enantiomers, but this form of chromatography has not attained widespread use in indirect resolutions. Other chromatographic techniques, for example, supercritical fluid chromatography, capillary electrophoresis, countercurrent chromatography, etc., have not received much attention in indirect enantioseparation. 

In this section, applications of the indirect-resolution approach to compounds of primarily pharmaceutical, pharmacological, or toxicological interest will be reviewed. Because a fundamental aspect of the method is the chemical reaction between the analyte and the CDA, it is convenient to divide the applications according to the drug functional groups involved in the derivatization,... 

The above-mentioned antiarrhythmic agent tocainide has also been resolved with (R)-(-)-0-methylmandeIic acid chloride, [10], using normal-phase LC in a study of the stereoselective disposition of the drug (58). In the assay, CDA [10] was dissolved in the organic solvent used for the extraction of tocainide from urine (58). The S form of this CDA was used by Helmchen and Strubert in early studies on indirect resolutions of chiral amines using LC (59). Both enantiomers of the parent acid of [10] are commercially available. 

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. 

Kleidemigg, O.P. Posch, K, Lindner, W. Synthesis and application of a new isothiocyanate as a chiral derivatizing agent for the indirect resolution of chiral amino alcohols and amines. J.ChromatognA,... 

A general point to note is that the number of steps involved in any resolution process must be kept to the minimum. The actual number of steps depends on whether the resolution leads directly to the desired enantiomer or some intermediate steps are present. Figure 9.2 illustrates schemes for direct and indirect resolution involving two and four steps, respectively (Sheldon, 1996). 

The most popular thin layer chromatography (TLC) techniques for separation of enantiomers are described here 1) use of non-chiral phases for indirect resolution of optical isomers after derivatization to obtain the corresponding diastereoisomers and 2) direct resolution of enantiomers using chiral stationary phases or chiral mobile phases. Advantages and limits of all reported techniques are discussed. 

Many experimental methods may be distinguished by whether and how they achieve time resolution—directly or indirectly. Indirect methods avoid the requirement for fast detection methods, either by detemiining relative rates from product yields or by transfonuing from the time axis to another coordinate, for example the distance or flow rate in flow tubes. Direct methods include (laser-) flash photolysis [27], pulse radiolysis [28]... 

Indirect or scalar coupling of nuclear spins through covalent bonds causes the splitting of NMR signals into multiplets in high-resolution NMR spectroscopy in the solution state. The direct or... 

Investigations based on equation (a) are indirect. Direct structural studies using diffraction techniques (X-ray or neutron), or electron microscopy, while they cannot detect the low concentrations of defects present in NiO or CoO are indispensible to the study of grossly non-stoichiometric oxides like FeO, TiOj, WOj etc., and particularly electron microscopes with a point-to-point resolution of about 0.2 nm are widely used. The first direct observation of a point defect (actually a complex of two interstitial metal atoms, and two oxygen atoms in Nb,2029) was made" using electron microscopy. 

Two recent reports described addition of nitrogen-centered nucleophiles in usefully protected fonn. Jacobsen reported that N-Boc-protected sulfonamides undergo poorly selective (salen) Co-catalyzed addition to racemic epoxides. However, by performing a one-pot, indirect kinetic resolution with water first (HKR, vide infra, Table 7.1) and then sulfonamide, it was possible to obtain highly enantiomer-ically enriched addition products (Scheme 7.39) [71]. These products were transformed into enantioenriched terminal aziridines in straightforward manner. 

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