Racemic Mixtures and Their Resolution

9S Molecules with More Than Two Chirality Centers 

Problem 9.17 How many chirality centers does morphine have How many stereoisomers of morphine are possible in principle  

To conclude this discussion of stereoisomerism, let s return for a final look at Pasteur s pioneering work. Pasteur took an optically inactive tartaric acid salt and found that he could crystallize from it two optically active forms having the 2R,3R and 2S.3S configurations. But what was the optically inactive form he started with It couldn t have been me.vo-tartaric acid, because me.so-tartaric acid is a different chemical compound and can t interconvert with the two chiral enantiomers without breaking and re-forming chemical bonds. 

The answer is that Pasteur started with a 50 50 mixture of the two chiral tartaric acid enantiomers. Such a mixture is called a racemic (ray-see-mic) mixture, or racemate, and is denoted either by the symbol ( ) or by 

The most common method of resolution uses an acid-base reaction between a racemic mixture of chiral carboxylic acids (RCOOHJ and an amine (RNHa) to yield an ammonium salt  

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Use of DMAP to accelerate coupling reactions is another cause of racemization. DMAP has been most often used to accelerate coupling of the first protected annino acid to hydroxymethyl resins without catalysis, this reaction is often unacceptably slow. Use of an equivalent amount of DMAP in this situation can cause extensive racennization, especially of phenylalanine only a catalytic amount of the DMAP additive should be used.h l As a precautionary measure, optical purity of purchased amino acid derivatives should be ascertained before use by measuring their optical rotation. Optical purity of naturally occurring L-amino acids should not be a problem, since they are generally prepared biologically. However, o-amino acids are prepared chemically by resolution of racemic mixtures, and there are examples of suppliers mistakes in optical purity. 

Biocatalytic processes have become very important in the chemical industry [1-4], Of particular importance is one property of enz3unes— their stereoselectivity—which enables either of the two enanhomers to be reacted or formed preferentially in chemical reactions with chiral or prochiral compounds. Thus, resolution of racemic mixtures and more importantly the direct synthesis of enantiomerically pure products can be achieved without the need to protect group chemistry. Biocatalytic reactions are usually carried out under mild conditions, thus avoiding xmwanted side reactions [5,6]. Particularly in combination with enz)me immobilization, which enables easy workup of the product and reusability of the catalyst, biocatalysis is a promising approach in green chemistry. Moreover, the availability of protein engineering techniques also makes evolved or tailor-made biocatalysts more suitable for meeting the requirements of industrial applications. 

The resolution of the racemates of 2-arylpropionic acids (or their esters) is a very convenient alternative to the stereoselective synthesis, because fairly easy and cheap conventional methodologies can be employed to obtain the racemic mixtures. Thus, several resolution procedures can be found in the literature ... 

Microorganisms and their enzymes have been used to functionalize nonactivated carbon atoms, to introduce centers of chirahty into optically inactive substrates, and to carry out optical resolutions of racemic mixtures (1,2,37—42). Their utifity results from the abiUty of the microbes to elaborate both constitutive and inducible enzymes that possess broad substrate specificities and also remarkable regio- and stereospecificities. 

The optical activity of biologically-active chemicals is important to their activity and toxicology. Pure enantiomers, or optical isomers, of pharmaceuticals and agrochemicals can in many cases be made by enantiospecific synthesis. An alternative method is to use a less complicated synthesis followed by chromatographic resolution of the racemic mixture into its enantiomers. 

These reflections are of special interest in the case of industrial syntheses in which the economic aspects are important. In these syntheses there is another factor to be kept in mind that may be illustrated by considering the industrial syntheses of steroids developed by Velluz and his coworkers in 1960 [18]. In contrast with other syntheses in which the intermediates are racemates and are only resolved into their optical active forms in the last step, the industrial syntheses require the resolution of the racemic mixture at the first possible opportunity, in order to exclude the unwanted isomer and thus avoiding the expenses of its processing. For recent advances in enantioselective synthesis see Heading 9.3. 

Enantiopure epoxides and vicinal diols are important versatile chiral building blocks for pharmaceuticals (Hanson, 1991). Their preparation has much in common and they may also be converted into one another. These chirons may be obtained both by asymmetric synthesis and resolution of racemic mixtures. When planning a synthetic strategy both enzymic and non-enzymic methods have to be taken into account. In recent years there has been considerable advance in non-enzymic methods as mentioned in part 2.1.1. Formation of epoxides and vicinal diols from aromatics is important for the break down of benzene compounds in nature (See part 2.6.5). 

Despite the fact that solvent effects on enzyme enantioselectivity appear to resist our efforts to rationalize their outcome using commonly accepted solvent descriptors, the effects are certainly there. An impressive example is provided in a report on the successful resolution of ds/trans-( 1 R,5 R)-bicyclo[3.2.0]hept-6-ylidene-acetate ethyl esters, intermediates in the synthesis of GABA (y-aminobutyric acid) analogs, by the Pfizer Bio transformations and Global R D groups (Scheme 2.2) [136]. From a screening protocol, CaLB was identified as a reactive catalyst for the hydrolysis of the racemic mixture of / //-os lor enantiomers with approximately equal activity for the ds- and tmns-isomers and a rather modest (E = 2.7) preference for the /Z-(lR,5R)-enantiomers. Application of medium engineering resulted in a phenomenal increase in the enantioselectivity (addition of 40% acetone, E > 200), while the ds- and trans-isomers were still converted at an almost equal rate. 

Apart from their obvious utility in separating mixtures of cations,68 crown ethers have found much use in organic synthesis (see the discussion on p. 363). Chiral crown ethers have been used for the resolution of racemic mixtures (p. 121). Although crown ethers are most frequently used to complex cations, amines, phenols, and other neutral molecules have also been complexed69 (see p. 133 for the complexing of anions).70... 

In the resolution of a racemic acid, a solution of (R)-phenylcthylamine is reacted with a racemic mixture of phenylchloroacetic acid to form the corresponding salts. The salts are then separated by careful fractional crystallization. Hydrochloric acid is added to the separated salts, and the respective acids are precipitated from their solutions. 

An equimolar mixture of two enantiomers is called a racemate. The separation of two enantiomers that constitute a racemate is called optical resolution or resolution. Their crystalline forms best characterize types of racemates. A racemic mixture is a crystal where two enantiomers are present in equal amounts. A conglomerate is a case where each enantiomer has its own crystalline form. Sometimes their crystals have so-called hemihedral faces, which differentiate left and right crystals. For over a hundred years, crystallization processes have been used for the separation and purification of isomers and optical resolution, both in the laboratory and on an industrial scale. 

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