Resolution of racemic compounds

A minor chemical use for many of the commoner alkaloids is the resolution of racemic compounds (often acids) into their optically active enantiomorphs. 

E. Erancotte, Chromatography as a separation tool for the preparative resolution of racemic compounds in Chiral separations, applications and technology, S. Ahuja (Ed.), American Chemical Society, Washington (1997) Chapter 10. 

Erancotte E. (1996) Chromatography as a Separation Tool for the Preparative Resolution of Racemic Compounds, in Chiral Separations. Applications and Technology, Ahuja S. (ed.), American Chemical Society, p. 271-308. 

The polymer of high molecular weight in the solid stage exhibited high crystallinity under a polarized microscope and insoluble in common organic solvents. When the polymer with high optical rotation was used as stationary phase or sorbent for the chromatographic resolution of racemic compounds, it showed the ability of resolution for many kinds of compounds, such as alcohols, amines, esters, and even hydrocarbons (28). 

The chromatographic methods use gas or liquid separately as the mobile phase, hence the terms gas chromatography (GC) and liquid chromatography (LC). Gas chromatography could not be accepted as the method of choice for the chiral resolution of racemic compounds mainly because of its requirement for the conversion by derivatization of the racemic compound into a volatile species. Besides, the separated enantiomers cannot be collected for further pharmacological and other studies. Moreover, GC cannot be used at the preparative scale. 

It is not easy to determine the differences in structural selectivity among all possible derivatives. A rationalization based on an electronic effect [18] and the length of the acyl substituent on cellulose were attempted [42]. CTA-I (micro-crystalline cellulose triacetate) is very specific and can be used for resolution of racemic compounds both having aromatic rings and carbonyl groups. On the other hand, a CTA-II (cellulose triacetate) CSP has a different selectivity. Both... 

Cyclodextrin-based CSPs are among the most popular materials used for the chiral resolution of racemic compounds. These CSPs have a wide range of applications because they can be used successfully in all three mobile phase modes normal, reversed, and polar organic. There are numerous examples of chiral separations on CDs and CSPs based on their derivatives. Some of the important chiral separations are discussed herein. 

TABLE 11 The Enantiomeric Resolution of Racemic Compounds on Cyclodextrin-Based CSPs by Means of Subcritical and Supercritical Fluid Chromatography... 

The Pirkle-type chiral stationary phases are quite stable and exhibit good chiral selectivities to a wide range of solute types. These CSPs are also popular for the separation of many drug enantiomers and for amino acid analysis. Primarily, direct chiral resolution of racemic compounds were achieved on these CSPs. However, in some cases, prederivatization of racemic compounds with achiral reagents is required. The applications of these phases are discussed considering re-acidic, re-basic, and re-acidic-basic types of CSP. These CSPs have also been found effective for the chiral resolution on a preparative scale. Generally, the normal phase mode was used for the chiral resolution on these phases. However, with the development of new and more stable phases, the reversed phase mode became popular. 

TABLE 5 Enantiomeric Resolution of Racemic Compounds on Pirkle-Type CSPs Using Sub-FC and SFC... 

TABLE 9 Enantiomeric Resolution of Racemic Compounds Using Ligand-Exchange TLC... 

With the development of the chiral ligand exchange chromatography by Davan-kov, this technique has been used frequently for the chiral resolution of racemic compounds containing electron-donating atoms. It is useful for providing the basic information on the chiral resolution and, hence, is still in use. In spite of this, there are some limitations with this chiral resolution technique. The most... 

CCE-based CSPs have limited application in the chiral resolution of racemic compounds using HPLC. There is only one report on the use of these CSPs in... 

When a chiral host compound includes one enantiomer of racemic guest compound selectively, optical resolution of the guest can be accomplished. In this chapter, efficient resolutions of racemic compounds by the complexation with various artificial chiral hosts are described. All the data described in this chapter are those obtained in the author s research group. 

The third method used in the resolution of racemates is the kinetic resolution. The success of this method is depending on the fact that the two enantiomers react at different rates with a chiral entity. The chiral entity should be present in catalytic amounts it may be a biocatalyst (enzyme or a microorganism) or a chemocatalyst (chiral acid or base or even a chiral metal complex). Kinetic resolution of racemic compounds is by far the most common transformation catalyzed by lipases, in which, the enzyme discriminate between the two enantiomers of racemic mixture, so that one enantiomer is readily transferred to the product faster than the other.1"18 (cf. fig 3)... 

Optical resolution of racemic compounds by biocatalysts has been a useful method as shown in this review. For this purpose, two types of biocatalysts are mainly used hydrolytic enzymes and oxidoreductases. 

To evolve useful enzymes, genetic engineering technology has been applied increasingly to improve stability of enzymes, enantioselectivity, extension of substrate specificity for kinetic resolution of racemic compounds. Novel enzymes created by this technique will be available in large quantities and varieties within a next few years. In the near future, a lot of useful enzymes will be on the market and expanding number of chemists can use enzymes more freely than present due to the improvement in the simplification of experimental procedures. 

L. Oliveros, C. Minguillon, B. Desmazieres, and P.-L. Desbene, Preparation and evaluation of chiral HPLC stationary phases of mixed character for the resolution of racemic compounds, J. Chromatogr., 543 211 (1991). 

H. Yuki, Y. Okamoto, and I. Okamoto, Resolution of racemic compounds by optically active poly (triphenylmethyl methacrylate), J. Am. Chem. Soc., 702 6356 (1980). 

The resolution of racemic compounds through the formation of reversible diastereomer complexes is certainly an example of the generation of chirality upon association of an achiral solute (the racemate to be resolved) and a chiral solute (the resolving agent). Such interactions are normally considered solely from the separations point of view [11], and only rarely is CD used to follow the association mechanism. It is evident, however, that the spectroscopic method would be of great value to characterize the associated species. 

The resolution of racemic compounds mediated by enzymes has become a valuable tool for the synthesis of chiral intermediates. In most cases, however, only one enantiomer of the intermediate is required for the next step in the synthesis thus, the unwanted isomer must be either discarded or racemized for reuse in the enzymatic resolution process. Dynamic kinetic resolution is one way of avoiding this problem the unwanted enantiomer is racemized during the selective enzymatic process and serves as fresh starting material in the resolution. 

Kinetic resolution of racemic compounds is by far the most common transformation catalyzed by lipases, in which the enzyme discriminates between the two enantiomeric constituents of a racemic mixture. It is important to note that the maximum yield of a kinetic resolution is restricted to 50% for each enantiomer based on the starting material. The prochiral route and transformations involving meso compounds, the meso-trkk, have the advantage of potentially obtaining a 100% yield of pure enantiomer. A theoretical quantitative analysis of the kinetics involved in the biocatalytic processes described above has been developed. - The enantiomeric ratio ( ), an index of enantioselectivity, can be calculated from the extent of conversion and the corresponding enantiomeric excess (ee) values of either the product or the remaining substrate. The results reveal that for an irreversible process. 

Preparative Uses of MTPA Derivatives. Resolution of racemic compounds on a preparative scale is always a challenging endeavor. Conversion of the enantiomeric mixture into a mixture of diastereomers, each with unique physical properties, makes it possible to separate the components by a variety of physical methods, such as fractional recrystallization, distillation, or chromatography. One of the earliest uses of MTPA was the resolution of racemic alcohols via the separation of diastereomeric MTPA esters by preparative gas-liquid chromatography, followed by alcohol regeneration with Lithium Aluminum Hydride (eq 2). More frequently, diastereomeric MTPA esters have been separated by high performance liquid chromatography (HPLC), followed by al-... 

In the intervening years since the first resolution of a racemate by Pasteur, many chromatographic and nonchromatographic methods have been developed for the resolution of racemic compounds. These methods are the subjects of many of the other chapters in this book. 

Cinchona-Based Organocatalysts for Desymmetrization of meso-Compounds and (Dynamic) Kinetic Resolution of Racemic Compounds... 

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