Resolution can be used to separate enantiomers

How do carbenes react 1013 Resolution can be used to separate enantiomers 1106... 

Sharpless epoxidations can also be used to separate enantiomers of chiral allylic alcohols by kinetic resolution (V.S. Martin, 1981 K.B. Sharpless, 1983 B). In this procedure the epoxidation of the allylic alcohol is stopped at 50% conversion, and the desired alcohol is either enriched in the epoxide fraction or in the non-reacted allylic alcohol fraction. Examples are given in section 4.8.3. 

Chiral stationary-phase HPLC (high-performance liquid chromatography) columns can be used to separate the enantiomers of anft -cryptophanes, or CTV derivatives however, it is not an ideal technique owing to its sensitivity to conditions, high expense, and inability to separate large quantities of material. A better approach for the resolution of chiral CTVs and cryptophanes is to attach a resolved chiral moiety onto the CTV or cryptophane framework. The... 

As mentioned earlier, enantiomers have the same physical properties (boiling point, melting point, solubility, etc.). Since traditional separation techniques generally rely on differences in physical properties, they cannot be used to separate enantiomers from each other. The resolution (separation) of enantiomers can be achieved in a variety of other ways. 

In practise, if using one of these reagents to follow the course of a chiral separation, it is essential to determine whether resolution is possible, by performing a test experiment either on a sample of racemate, or at least a sample known to contain significant quantities of both enantiomers. Once useable resolution has been established, the technique can be used to monitor solutions of unknown enantiomer ratios with reasonable accuracy, down to normal NMR detection limits. 

The fundamentals of structure and stereochemistry have been considered in previous chapters in some detail. There are, however, practical aspects of stereochemistry that have not yet been mentioned, particularly with regard to chiral compounds. How, for instance, can a racemic mixture be separated into its component enantiomers (resolution) what methods can be used to establish the configuration of enantiomers how can we tell if they are pure and how do we synthesize one of a pair of enantiomers preferentially (asymmetric synthesis) In this chapter, some answers to these questions will be described briefly. 

Optically active diisopinocamphenylborane can be used to resolve racemic olefins. The reagent adds to one enantiomer, and the other is unchanged. Optical purities on the order of 37-65% are possible. Chiral ally lie alcohols can be resolved with chiral epoxidizing agents derived from tartrate complexes of titanium. One enantiomer is epoxidized and the other is not. Thus, die two alcohol enantiomers can be separated, one as the unsaturated alcohol and one as the epoxy alcohol. Use of die other tartrate isomer reverses die stereoselectivity. Selectivities on die order of >100 are possible with this method. As in any kinetic resolution, however, only one enantiomer can be recovered. The other is converted to a different chiral product. 

Even a few seed crystals, mechanically separated, can be used to produce larger quantities of resolved enantiomerically pure material. A second method of resolution by direct crystallization involves the localized crystallization of each enantiomer from a racemic, supersaturated solution. With the crystallizing solution within the metastable zone, oppositely handed enantiomerically pure seed crystals of the compound are placed in geographically distant locations in the crystallization vessel. These serve as nuclei for the further crystallization of the like enantiomer, and enantiomerically resolved product grows in the seeded locations. 

The combination of the chromatographic separation of enan-tiopure p-hydroxysulfoximine diastereomers and reductive elimination results in a method of ketone methylenation with optical resolution. The technique is illustrated in the synthesis of the ginseng sesquiterpene (—)-p-panasinsene and its enantiomer (eq 5). The addition of the enantiopure lithiosulfoximine to prochiral enones or the diastereoface selective addition to racemic enones results in the formation of two diastereomeric adducts. The hydroxy group in these adducts can be used to direct the Simmons-Smith cyclopropanation (eq 6 and eq 7). Catalytic osmylation of such adducts is directed by the anti effect of the hydroxy augmented by chelation by the methylimino group (eq 7). ... 

Resolution by entrainment can sometimes be used to separate racemic mixtures when there are distinct differences in the rates of crystallization of the two optical isomers. This preferential crystallization is initiated by seeding with the crystals of one enantiomer. This technique has been shown to be effective in the production of thiamphenicol (21). 

Conglomerate solids are characterized by the presence of a single enantiomer within the unit cell of the crystal, even when the solid is obtained through crystallization of a racemic or partially resolved mixture. These solids consist of separate crystals, each of which consists entirely of one enantiomer or the other, which may be separated entirely on the basis of their physical properties. Compounds known to crystallize as conglomerates can be quite easily resolved, since the resolution step takes place spontaneously upon crystallization. The key to a successful resolution by direct crystallization lies in the means used to separate physically the crystals containing the opposite enantiomers. Jacques and coworkers have provided extensive summaries of the methods whereby direct crystallization can be used to effect the resolution of a racemic mixture [10,32]. 

There are two procedures used by chemists that imitate the natural pathway. In one, actual microorganisms are used in fermentation reactions that can directly produce some L-amino acids. In the other, enzymes are used to react with one enantiomer of a racemic pair. As you might guess, it is usually the L isomer that is eaten by the enzyme, because enzymes have evolved in an environment of L isomers. So it is usually the D isomers that are ignored by enzymes. In an extraordinarily clever procedure, this preference for natural, L, enantiomers can be used to achieve a kinetic resolution (Fig. 23.15). The mixture of enantiomers is first acetylated to create amide linkages. An enzyme, hog-kidney acylase, then hydrolyzes the amide linkages of only L-amino acids. So, treatment of the pair of acetylated amino acids leads to formation of the free L-amino acid. The acylat-ed D enantiomer is unaffected by the enzyme, which has evolved to react only with natural L-amino acids. The free L-amino acid can then easily be separated from the residual D acetylated material. 

The difference in physical properties of diastereoisomers suggests a route that we might use to separate enantiomers (a process described as resolution)—vte will convert them, by some reversible process, into separable diastereoisomers. If we consider the reduction of 7.55 using sodium borohydride (weTl meet this reaction in Chapter 14), the ketone is planar and can be approached from either face by Na[BHj. These approaches are equally likely, so the product obtained will be racemic. If this alcohol is then reacted with a chiral carboxylic acid (Equation 7.3), then two distinct esters will be formed, with R,R- and R,S-stereochemistries. The two esters are diastereoisomers, which may be separated by physical techniques. Once the esters have been separated, then they can be hydrolyzed to obtain the separated alcohols and recover the chiral acid ... 

Comparisons of LC and SFC have also been performed on naphthylethylcar-bamoylated-(3-cyclodextrin CSPs. These multimodal CSPs can be used in conjunction with normal phase, reversed phase, and polar organic eluents. Discrete sets of chiral compounds tend to be resolved in each of the three mobile phase modes in LC. As demonstrated by Williams et al., separations obtained in each of the different mobile phase modes in LC could be replicated with a simple CO,-methanol eluent in SFC [54]. Separation of tropicamide enantiomers on a Cyclobond I SN CSP with a modified CO, eluent is illustrated in Fig. 12-4. An aqueous-organic mobile phase was required for enantioresolution of the same compound on the Cyclobond I SN CSP in LC. In this case, SFC offered a means of simplifying method development for the derivatized cyclodextrin CSPs. Higher resolution was also achieved in SFC. 

MDGC is useful for separating compounds of an essential oil using two columns in line with different polarities. Through column-switching techniques, selected impure compounds in the first column can be diverted to the second column to ensure their complete separation. If the second column is chiral, then enantiomers potentially can be separated. The selected chiral stationary phase affects the resolution and separation drastically [73]. 

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