Resolution of a racemic mixture

The need for enantiomerically pure compounds has also led to the development of new methods for separating racemic mixtures into their enantiomeric components, a process called resolution. 

PROBLEM 5.25 Let us say that the (2R,3R) and 2S,3R) products in eq. 5.7 are formed in a 60 40 ratio. What products would be formed and in what ratio by adding HBr to pure (S)-3-chloro-l-butene By adding HBr to a racemic mixture of (R)- and (S)-3-chloro-l-butene  

We have just seen (eq. 5.5) that, when reaction between two achiral reagents leads to a chiral product, it always gives a racemic (50 50) mixture of enantiomers. Suppose we want to obtain each enantiomer pure and free of the other. The process of separating a racemic mixture into its enantiomers is called resolution. Since enantiomers have identical achiral properties, how can we resolve a racemic mixture into its components The answer is to convert them to diastereomers, separate the diastereomers, and then reconvert the now-separated diastereomers back to enantiomers. 

To separate two enantiomers, we first let them react with a chiral reagent. The product will be a pair of diastereomers. These, as we have seen earlier, differ in all types of 

The process of separating the two enantiomers of a racemic (50 50) mixture is called resolution. 

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The lipase from Pseudomonas sp. KIO has also been used to cleave the chloroacetate, resulting in resolution of a racemic mixture since only one enantiomer was cleaved. 

Four general methods have been used for obtaining chiral ligands resolution of a racemic mixture, use of a chiral naturally occurring product 33), and asymmetric homogeneous or heterogeneous hydrogenation. 

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. 

Resolution of a racemic mixture is still a valuable method involving fractional crystallization [113], chiral stationary phase column chromatography [114] and kinetic resolutions. Katsuki and co-workers demonstrated the kinetic resolution of racemic allenes by way of enantiomer-differentiating catalytic oxidation (Scheme 4.73) [115]. Treatment of racemic allenes 283 with 1 equiv. of PhIO and 2 mol% of a chiral (sale-n)manganese(III) complex 284 in the presence of 4-phenylpyridine N-oxide resulted... 

Carbonylative kinetic resolution of a racemic mixture of trans-2,3-epoxybutane was also investigated by using the enantiomerically pure cobalt complex [(J ,J )-salcy]Al(thf)2 [Co(CO)4] (4) [28]. The carbonylation of the substrate at 30 °C for 4h (49% conversion) gave the corresponding cis-/3-lactone in 44% enantiomeric excess, and the relative ratio (kre ) of the rate constants for the consumption of the two enantiomers was estimated to be 3.8, whereas at 0 °C, kte = 4.1 (Scheme 6). This successful kinetic resolution reaction supports the proposed mechanism where cationic chiral Lewis acid coordinates and activates an epoxide. 

Reactions catalyzed by enzymes or enzyme systems exhibit far greater specificities than more conventional organic reactions. Among these specificities which enzymatic reactions possess, stereospecificity is one of the most excellent. To overcome the disadvantage of a conventional synthetic process, i.e., the troublesome resolution of a racemic mixture, microbial transformation with enzymes possessing stereospecificities has been appHed to the asymmetric synthesis of optically active substances [1-10]. C3- and C4-synthetic units (synthons, building blocks), such as epichlorohydrin (EP), 2,3-dichloro-l-propanol (2,3-DCP), glycidol (GLD), 3-chloro-l,2-propanediol (3-CPD), 4-chloro-... 

Like other methods of asymmetric synthesis, the solid-state ionic chiral auxiliary procedure has an advantage over Pasteur resolution in terms of chemical yield. The maximum amount of either enantiomer that can be obtained by resolution of a racemic mixture is 50%, and in practice the yield is often considerably less [47]. In contrast, the ionic chiral auxiliary approach affords a single enantiomer of the product, often in chemical and optical yields of well over 90%. Furthermore, either enantiomer can be obtained as desired by simply using one optical antipode or the other of the ionic chiral auxiliary. 

There are several biochemical and chemical processes for the resolution of a racemic mixture of menthol. Many microbiological lipases hydrolyse men-... 

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. 

With few exceptions, enantiomers cannot be separated through physical means. When in racemic mixtures, they have the same physical properties. Enantiomers have similar cliemi cal properties as well. The only chemical difference between a pair of enantiomers occurs in reactions with other chiral compounds. Thus resolution of a racemic mixture typically takes place through a reaction with another optically active reagent. Since living organisms usually produce only one of two possible enantiomers, many optically active reagents can be obtained from natural sources. For instance muscle tissue and (S)-<-)-2-methyl-l-butanol, from yeast fermentation. 

A special case of host-guest inclusion is the resolution of a racemic mixture of chiral guests. This has important implications for the pharmaceutical industry, where the production of enantiomerically pure drugs has recently become increasingly important. A common method of chiral resolution is via the formation and separation of diastereomers. For example, a racemic acid AH may be treated with a chiral base B [21] ... 

In principle, three approaches may be adopted for obtaining an enantio-merically pure compound. These are resolution of a racemic mixture, stereoselective synthesis starting from a chiral building block, and conversion of a prochiral substrate into a chiral product by asymmetric catalysis. The last approach, since it is catalytic, means an amplification of chirality that is, one molecule of a chiral catalyst produces several hundred or a thousand molecules of the chiral product from a starting material that is optically inactive In the past two decades this strategy has proved to be extremely useful for the commercial manufacture of a number of intermediates for biologically active compounds. A few recent examples are given in Table 9.1. 

The other approach, resolution of a racemic mixture, is also used in many industrial processes. Here physical resolution (i.e., resolution by crystallization of a diastereomeric derivative) is in general the favored method. However, kinetic resolution in principle can also be used for separating out two enantiomers. Although kinetic resolution involving a soluble metal complex catalyst has yet to be widely practiced, the potential importance of such an approach is significant (see Section 9.3.5). 

Figure 9. Resolution of a racemic mixture of (+)-vincadifformine (250 mg) on a preparative 6-cyclodextrin polymer column (5x90 cm, pH 5.5 phosphate buffer, flow rate 300 ml/H, 20 °C).

Many procedures result in the incomplete resolution of a racemic mixture into the component enantiomers, and quantities have been defined, which are used to specify the degree of resolution. The enantiomeric purity (EP) of a substance will have values between 0 and 1, and for substances where the (R)-enantiomer is present in excess, the EP is given by... 

Resolution of a racemic mixture by converting it to a mixture of diastereomers... 

Optical resolution of a racemic mixture Not very economical, since 50% of the product is lost ... 

Molecules that are related as diastereoisomers have different melting points and solubilities, and have different rates of reaction. In some cases, these different rates of reaction can lead to a particular product being formed from a reaction of one diastereoisomer but not the other. Use is made of differences of, for example, solubility of diastereoisomers in the resolution of a racemic mixture (Section 3.6). 

Lonza is a major custom manufacturer of intermediates for the life science industries, and uses biocatalysis in many of its processes. Some of the products for which a biotransformation is used are achiral, however, an important characteristic of enzymes is their chirality, and this characteristic is used by Lonza to produce a number of chiral synthons. Biotransformations for the synthesis of asymmetric compounds can be divided into two types of reactions those where an achiral precursor is converted into a chiral product (true asymmetric synthesis) and those involving the resolution of a racemic mixture. Both types of reaction are used at Lonza, and several examples of each type of reaction are described for large-scale syntheses of chiral molecules that use a biotransformation in one or more of the steps. 

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