Resolution of a racemic compound

Resolution of a racemic compound, 503 of Mc.-octyl alcohol, 505 P-Reeorcylaldehyde, 690,702 P Reeorcylie acid, 754, 775 Rimmi test, 420 ... 

Kinetic resolution may be used to determine [Oq] in two ways [23,24]. The results of two kinetic resolutions of a racemic compound, allowed to go to different (known) extents of conversion, can be used to calculate the specific rotation of the enantiomerically pure compound. Alternatively, one may use two reciprocal kinetic resolutions racemic A is resolved by B and racemic B is resolved by A. If the racemate is used in large excess in both cases, and the stereoselectivities of the resolutions are not too high, [Oq] for A may be calculated if [tto] for B is known, or vice versa. 

We will see later that, while in most cases racemization is an inconvenience that destroys what the chemist has spent much time in achieving, it can be put to use in the resolution of a racemic compound to obtain one enantiomer in a yield close to one. 

Our strategy consisted of the following steps A mixture of potential chiral selectors is immobilized on a solid support and packed to afford a complete-library column , which is tested in the resolution of targeted racemic compounds. If some separation is achieved, the column should be deconvoluted to identify the selector possessing the highest selectivity. The deconvolution consisted in the stepwise preparation of a series of sublibrary columns of lower diversity, each of which constitute a CSP with a reduced number of library members. 

Enantioenriched alcohols and amines are valuable building blocks for the synthesis of bioactive compounds. While some of them are available from nature s chiral pool , the large majority is accessible only by asymmetric synthesis or resolution of a racemic mixture. Similarly to DMAP, 64b is readily acylated by acetic anhydride to form a positively charged planar chiral acylpyridinium species [64b-Ac] (Fig. 43). The latter preferentially reacts with one enantiomer of a racemic alcohol by acyl-transfer thereby regenerating the free catalyst. For this type of reaction, the CsPhs-derivatives 64b/d have been found superior. 

A fourth method is a chromatographic resolution of a racemic mixture of organotin compounds for instance on a chiral matrix such as microcrystalline cellulose triacetate. 

Enzymes may be used either directly for chiral synthesis of the desired enantiomer of the amino acid itself or of a derivative from which it can readily be prepared, or for kinetic resolution. Resolution of a racemate may remove the unwanted enantiomer, leaving the intended product untouched, or else the reaction may release the desired enantiomer from a racemic precursor. In either case the apparent disadvantage is that the process on its own can only yield up to 50% of the target compound. However, in a number of processes the enzyme-catalyzed kinetic resolution is combined with a second process that re-racemizes the unwanted enantiomer. This may be chemical or enzymatic, and in the latter case, the combination of two simultaneous enzymatic reactions can produce a smooth dynamic kinetic resolution leading to 100% yield. 

A number of compounds exist as racemic mixtures ( ), i.e. a mixture of equal amounts of two enantiomers, (—) and (+). Often, one enantiomer shows medicinal properties. Therefore, it is important to purify the racemic mixture so that active enantiomer can be obtained. The separation of a mixture of enantiomers is called the resolution of a racemic mixture. 

Resolution of a racemic mixture can also be achieved by using an enzyme. An enzyme selectively converts one enantiomer in a racemic mixture to another compound, after which the unreacted enantiomer and the new compound are separated. For example, lipase is used in the hydrolysis of chiral esters as shown above. 

The separation of a racemic compound into its enantiomers is called resolution. Various methodologies have been used for the resolution of the enantiomers on both analytical and preparative scales. The different techniques may be categorized into two classes the classical approach, using enzymatic degradation of one of the enantiomers, and preferential crystallization. Modem technologies include spectroscopic, electrophoretic, and chromatographic methods. 

The properties of partially acetylated cellulose for the separation of enantiomers were recognized in 1966 by Luttringhaus and Peters [14]. But the full potential of cellulose acetate was developed by Hesse and Hagel in 1973 [15]. Since then, this stationary phase has been frequently used for the resolution of various racemic compounds. Native cellulose acetylated heterogeneously yields a crystallographic form of cellulose triacetate (CTA) known as CTA-I, which corresponds to its source, an indication that the original supramolecular structure of the starting... 

Although about 20 polysaccharide-based CSPs have been commercialized and much work on enantioresolution has been carried out on these phases, it remains very difficult to predict the best CSP for the chiral resolution of a particular compound. It has been observed that most of the resolved racemic compounds contain aromatic rings or groups such as carbonyl, sulfinyl, nitro, amino, and benzoyl. However, some reports have been published on the chiral resolution of nonaromatic racemates on polysaccharide CSPs [61]. As in the case of other CSPs, polysaccharide-based CSPs do not require a certain combination of functional groups. However, only one group can afford a satisfactory separation. Presumably some chiral space (e.g., a concavity or ravine existing on a polysaccharide derivative) could enable such a separation [62],... 

A single CSP cannot be used for the chiral resolution of all racemic compounds. Therefore, different CSPs were used for the chiral resolution of different racemates. To make this part easy and clear, Table 1 includes the names of 20 CSPs and their most frequent applications. However, some other interesting applications are possible. Upon screening about 510 racemic compounds described in the literature, we observed that 229 of them resolved completely and 86 partially on cellulose tris(3,5-dimethylphenylcarbamate), and the rest not at all. For amylose tris(3,5-dimethylphenylcarbamate) CSP, we screened 384 racemic compounds and observed that 107 resolved completely and 102 partially. Clearly, cellulose and amylose tris(3,5-diphenylcarbamate) CSPs have the ability to resolve about 80% of the racemic compounds investigated. 

In 1978, Harada et al. [17] used polymerized CD with gel support for the chiral resolution of mandelic acid and its derivatives. Later Zsadon et al. [18-21] used cyclodextrin-based CSPs for the chiral resolution of indole alkaloids, with aqueous buffers as the mobile phases. Today CD-based CSPs have a good reputation. In separate studies, Fujimura [22] and Kawaguchi [23] and their colleagues resolved the enantiomers of aromatic compounds in the reversed-phase mode. Armstrong et al. [29,30,33,34,41,44 46,48,54-63] carried out extensive and remarkable work on the chiral resolution of various racemic compounds using CD-based CSPs. 

In 1998, Machida et al. [45] and Hyun et al. [46] developed a new CCE-based CSP (covalently bonded to silica gel see Sect. 8.2). This CSP was used successfully for the chiral resolution of certain racemic compounds using a variety of mobile phases. The most important applications of this CSP are for the resolution of amino acids, amino esters, amino alcohols, amines, amides, quinolone antibacterials, and other drugs having primary amino groups [46-51,64,65]. The typical chromatograms of the chiral resolution of amino acids on (+)-(18-crown-6)-2,3,ll,12-tetracarboxylic acid CSP are shown in Figure 4. The enantiomeric resolution of the racemic compound on CCE-based CSPs are listed in Table 2. There is no report available on the chiral separations at the preparative scale using these CSPs. 

Because the steric effect contributes to the complex formation between guest and host, the chiral resolution on these CSPs is affected by the structures of the analytes. Amino acids, amino alcohols, and derivatives of amines are the best classes for studying the effect of analyte structures on the chiral resolution. The effect of analyte structures on the chiral resolution may be obtained from the work of Hyun et al. [47,48]. The authors studied the chiral resolution of amino alcohols, amides, amino esters, and amino carbonyls. The effects of the substituents on the chiral resolution of some racemic compounds are shown in Table 6. A perusal of this table indicates the dominant effect of steric interactions on chiral resolution. Furthermore, an improved resolution of the racemic compounds, having phenyl moieties as the substituents, may be observed from this Table 6. ft may be the result of the presence of n—n interactions between the CCE and racemates. Generally, the resolution decreases with the addition of bulky groups, which may be caused by the steric effects. In addition, some anions have been used as the mobile phase additives for the improvement of the chiral resolution of amino acids [76]. Recently, Machida et al. [69] reported the use of some mobile phase additives for the improvement of chiral resolution. They observed an improvement in the chiral resolution of some hydrophobic amino compound using cyclodextrins and cations as mobile phase additives. 

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