Racemic Mixtures and the Resolution of Enantiomers

Which of the following structures represent meso compounds  

Which of the following have a meso form (Recall that the -ol suffix refers to an alcohol, ROH.) 

Does the following structure represent a meso compound If so, indicate the symmetry plane. 

To end this discussion of stereoisomerism, let s return for a last look at Pasteur s pioneering work, described in Section 5.4. Pastern took an optically inactive tartaric acid salt and found that he could crystallize from it two optically active forms having what we would now call the 2R,3R and 2S,3S configurations. But what was the optically inactive form he started with It couldn t have been meso-tartaric acid, because meso-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 racemate (raa-suh-mate), or racemic mixture, and is denoted by either the symbol ( ) or the prefix d,l to indicate an equal mixture of dextrorotatory and levorotatory forms. Racemates show no optical rotation because the (+) rotation from one enantiomer exactly cancels the (-) rotation from the other. Through luck, Pasteur was able to separate, or resolve, racemic tartaric acid into its (+) and (-) enantiomers. Unfortunately, the fractional crystallization technique he used doesn t work for most racemates, so other methods are needed. 

The most common method of resolution uses an acid-base reaction between a racemic mixture of chiral carboxylic acids (RC02H) and an amine base (RNH2) to yield an ammonium salt. 

To understand how this method of resolution works, let s see what happens when a racemic mixture of chiral acids, such as (+)- and (-)-lactic acids, reacts with an achiral amine base, such as methylamine, CH3NH2. Stereochemically, the situation is analogous to what happens when left and right hands (chiral) pick up a ball (achiral). Both left and right hands pick up the ball equally well, and the products—ball in right hand versus ball in left hand—are mirror images. In the same way, both ( H- and (-)-lactic acid react with methylamine equally 

FIGURE 5.12 Reaction of racemic lactic acid with achiral methylamine leads to a racemic mixture of ammonium salts. 

FIGURE 5.13 Reaction of racemic lactic acid with (R)-i-phenylethylamine yields a mixture of diastereomeric ammonium salts, which have different properties and can be separated. 

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The resolution of ( ) amino acids isn t really a synthetic method, but it s certainly useful in the production of a particular amino acid from a racemic mixture. In the resolution of ( ) amino acids, an enzyme (a biological catalyst) interacts with only one enantiomer. (Why, you ask Because enzymes are stereoselective.) The enzyme leaves one enantiomer unchanged and modifies the other into a different compound, which makes it possible to separate the enantiomer from the other compound by a number of techniques. After the enantiomer has been separated, all that s left is to reverse the process induced by the enzyme. 

Conduritols and inositols are cyclic polyalcohols with significant biological activity. The presence of four stereogenic centers in the stmcture of conduritols allows the existence of 10 stereoisomers. Enzymatic methods have been reported for the resolution of racemic mixtures or the desymmetrization of meso-conduritols. For example, Mucor miehei lipase (MML) showed enantiomeric discrimination between all-(R) and all-(S) stereoisomers ofconduritol E tetraacetate (Figure 6.52). Alcoholysis resulted in the removal of the four acetyl groups ofthe all-(R) enantiomer whereas the all-(S) enantiomer was recovered [141]. 

Synthesis of Phosphoric Acids and Their Derivatives. - The individual Rp-and Sp- isomers of the organophosphate triesters (1-6) were synthesized and isolated on a preparative scale through the kinetic resolution of racemic mixtures via the hydrolysis of a single enantiomer by the bacterial phosphotriesteraze (PTE).i... 

Finally, a completely new use of planar-chiral ferrocenes has been recently disclosed by Fu and co-workers [24]. Compounds of type 25 and 26 were prepared as racemic mixtures and obtained as pure enantiomers via semipreparative HPLC. Derivatives 25, analogues of 4-(dimethylamino)pyridine, were used as nucleophilic catalysts in the kinetic resolution of chiral secondary alcohols [24a,b]. The ami-noalcohol system 26, on the other hand, is an effective chiral ligand for the asymmetric addition of dialkylzinc reagents to aldehydes (up to 90% ee) [24c]. 

Two examples of enzymatic resolutions with selectivities of = 5 and = 20 are depicted in Fig. 2.4. The curves show that the product (P -E Q) can be obtained in its highest optical purities before 50% conversion, where the enzyme can freely choose the weU-fitting enantiomer from the racemic mixture. So, the well-fitting enantiomer is predominantly depleted from the reaction mixture during the course of the reaction, leaving behind the poor-fitting counterpart. Beyond 50% conversion, the enhanced relative concentration of the poor-fitting counterpart leads to... 

Of the methods to prepare single enantiomers, resolution by preparation of the diastereomers from the racemic mixture and then separation of the diastereomers followed by regeneration of the single enantiomer might be the most common. If the racemic mixture has either acidic or basic functionality, this can be accomplished by salt formation. For example, in the synthesis of levothyroxine, used to treat hypothyroidism, the chiral center is resolved at an intermediate stage. The intermediate is a racemic mixture and has a carboxylic acid fimctionality. When the racemic mixture is treated with a chiral amine to form the ammonium carboxylate, two diastereomers are formed. These can be separated and then the carboxylic acid of the single enantiomer regenerated by treatment with acid. 

Crystallization Method. Such methods as mechanical separation, preferential crystallisation, and substitution crystallisation procedures are included in this category. The preferential crystallisation method is the most popular. The general procedure is to inoculate a saturated solution of the racemic mixture with a seed of the desired enantiomer. Resolutions by this method have been reported for histidine (43), glutamic acid (44), DOPA (45), threonine (46), A/-acetyl phenylalanine (47), and others. In the case of glutamic acid, the method had been used for industrial manufacture (48). 

Synthetic chiral adsorbents are usually prepared by tethering a chiral molecule to a silica surface. The attachment to the silica is through alkylsiloxy bonds. A study which demonstrates the technique reports the resolution of a number of aromatic compoimds on a 1- to 8-g scale. The adsorbent is a silica that has been derivatized with a chiral reagent. Specifically, hydroxyl groups on the silica surface are covalently boimd to a derivative of f -phenylglycine. A medium-pressure chromatography apparatus is used. The racemic mixture is passed through the column, and, when resolution is successful, the separated enantiomers are isolated as completely resolved fiactions. Scheme 2.5 shows some other examples of chiral stationary phases. 

Most of the chiral membrane-assisted applications can be considered as a modality of liquid-liquid extraction, and will be discussed in the next section. However, it is worth mentioning here a device developed by Keurentjes et al., in which two miscible chiral liquids with opposing enantiomers of the chiral selector flow counter-currently through a column, separated by a nonmiscible liquid membrane [179]. In this case the selector molecules are located out of the liquid membrane and both enantiomers are needed. The system allows recovery of the two enantiomers of the racemic mixture to be separated. Thus, using dihexyltartrate and poly(lactic acid), the authors described the resolution of different drugs, such as norephedrine, salbu-tamol, terbutaline, ibuprofen or propranolol. 

The synthesis of key intermediate 12, in optically active form, commences with the resolution of racemic trans-2,3-epoxybutyric acid (27), a substance readily obtained by epoxidation of crotonic acid (26) (see Scheme 5). Treatment of racemic 27 with enantio-merically pure (S)-(-)-1 -a-napthylethylamine affords a 1 1 mixture of diastereomeric ammonium salts which can be resolved by recrystallization from absolute ethanol. Acidification of the resolved diastereomeric ammonium salts with methanesulfonic acid and extraction furnishes both epoxy acid enantiomers in eantiomerically pure form. Because the optical rotation and absolute configuration of one of the antipodes was known, the identity of enantiomerically pure epoxy acid, (+)-27, with the absolute configuration required for a synthesis of erythronolide B, could be confirmed. Sequential treatment of (+)-27 with ethyl chloroformate, excess sodium boro-hydride, and 2-methoxypropene with a trace of phosphorous oxychloride affords protected intermediate 28 in an overall yield of 76%. The action of ethyl chloroformate on carboxylic acid (+)-27 affords a mixed carbonic anhydride which is subsequently reduced by sodium borohydride to a primary alcohol. Protection of the primary hydroxyl group in the form of a mixed ketal is achieved easily with 2-methoxypropene and a catalytic amount of phosphorous oxychloride. 

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