Enantiomer Ordering and Separation

Enantiomer Ordering and Separation During Molecular Inclusion... 

When chiral, drugs and other molecules obtained from natural sources or by semisynthesis usually contain one of the possible enantiomeric forms. However, those obtained by total synthesis often consist of mixtures of both enantiomers. In order to develop commercially the isolated enantiomers, two alternative approaches can be considered (i) enantioselective synthesis of the desired enantiomer or (ii) separation of both isomers from a racemic mixture. The separation can be performed on the target molecule or on one of its chemical precursors obtained from conventional synthetic procedures. Both strategies have their advantages and drawbacks. 

The basis of separation in chiral HPLC is the formation of temporary diastereomeric complexes within the chiral stationary phase. This causes enantiomers, which normally exhibit identical partitioning into a non-chiral stationary phase, to partition to a different extent into the stationary phase. In order for separation to occur, the enantiomers must have three points of contact with the stationary phase. This is shown in Figure 12.22, where enantiomer 1 interacts with groups A, B and C. Its mirror image, enantiomer 2, is unable to interact in the same way with more than two of the groups on the chiral stationary phase no matter how it is positioned. 

However, in order to separate enantiomers via formation of diastereomers, the chiral selector (CDA) must be optically pure, e.g., 99.9% of ( )-SO, otherwise the separated diastereomeric reaction products will still be contaminated with the reaction products derived from (S)-SO, leading to optically impure reaction products (mixture of enantiomers) and false results when evaluating the optical purity data of the analyte. 

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. 

In order to install a benzophenone at the bicyclic scaffold we relied on the previously used oxazole linkage. To this end, the known amino-hydroxybenzophenone 37 (Aichaoui et al. 1990) was coupled to the free acid rac-38, which is available from Kemp s triacid in five synthetic steps. Remarkably, an 0-aeylation instead of the expected /V-acylalion was observed resulting in ester rac-39. As a consequence, oxazole formation was less straightforward but could eventually be achieved under more forceful conditions. The reaction sequence led to the racemic benzophenone rac-40, i.e. to a 1/1 mixture of the enantiomers (+)-40 and (-)-40, which was separated by chiral HPLC (Daicel Chiralpak AD). It is important to mention that a separation of enantiomers at an earlier stage is not sensible. While carboxylic acid 38 can be obtained in enantiomerically pure form, racemisation occurs upon activation, presumably due to a bridged symmetrical intermediate (Kirby et al. 1998) (Scheme 16). 

Typically, resolution depends on the conversion of enantiomers, which possess identical physical properties, into diastereoisomers, which do not, and then exploiting the difference in physical properties in order to separate the diastereoisomers. Finally, the diastereoisomers are reconverted to the component, and now separated, enantiomers. 

In the second scenario, target products and impurities are present in similar amounts. The separation of racemic mixtures exemplifies this scenario. The problem of racemic mixture formation often occurs during chemical synthesis, where 50% of the mixture consists of the wanted enantiomer (eutomer) and 50% is the unwanted enantiomer (distomer). In this case competitive adsorption and the elution order of the enantiomers are of special interest (Section 4.3.4). 

The requirement that a reagent be chiral in order to exert differential action upon a pair of enantiomers is normally met in one of two ways (1) treatment of the mixture with a conventional derivatizing agent and separating the products on a suitable chiral stationary phase (2) treatment of the mixture with a chiral derivatizing agent and separating the products on a conventional stationary phase. 

The enantiomers were successfully separated on Sumipax OA-2000 eluted with a mixture hexane/l,2-dichloroethane/EtOH (4 2 1). In all the series the (+) enantiomer was eluted first. These compounds are fluorescent except for the 2-MeO derivatives 458b and 458c. The optical rotation range in MeOH is 154—470. Compound 457a racemized very slowly in butan-l-ol at 70 °C fc (first-order rate constant) = 1.3510 s , AG = 125 kj mol . The other atropisomers did not racemize at that temperature. 

Now, assume that in order to separate a pair of enantiomers, a separation ratio of (a) is required. Assuming. and it... 

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