Isolating enantiomers

The recognition of differences in the pharmacological activity of enantiomeric molecules has created the need to administer them - and therefore to obtain them -as isolated enantiomers. However, nowadays this problem affects not only the pharmaceutical industry, but also the agrochemical industry and food additive producers, both of which are increasingly concerned by this subject. 

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. 

Among the various methods proposed to produce selectively isolated enantiomers, the use of enantioselective catalysis is by far the most attractive one. The control of stereochemistry by use of a minute amount of an asymmetric catalyst offers clear advantages. Therefore, the design and development of catalytic enantioselective organic reactions is considered as one of the most attractive and challenging frontiers in synthetic organic chemistry. 

The isolated enantiomers S (M ) and R (Mr) of a chiral molecule M exhibit the same spectral features since their physical properties are identical. However, their aggregation with a chiral chromophore of defined configuration (Cr/s) leads to the formation of two diastereomeric complexes with different spectral properties, i.e., and [C /yM ]. The lcR2PI spectroscopy is able to discriminate between Mj and by measuring the spectral shift of the diastereomeric [C /yM ] and [Cj5/5-Mj ] complexes with respect to that of the bare chromophore Cr/s- It is convenient to define the diastereomeric clusters as homochiral when the chromophore and the solvent have the same configuration, and heterochiral in the opposite case. 

The stability of both the racemate and isolated enantiomer was re-investigated, and although the materials were stable at ambient temperature, at >40 °C care would be required as epimerizahon could occur. This finding highlighted the importance of temperature control and monitoring during the isolation, but also indicated that it might be possible to introduce a simple procedure to effect racemization of the unwanted enantiomer. 

This assignment was at odds with that obtained by the octant rule but was later confirmed also by chiroptical evidence (cf. cited references in Schurig and Leyrer, 1990). Thus the absolute configuration of (+)-l-chloro-2,2-dimethylaziridine was assigned as (S). The results show that the assignment of absolute configuration can be aided by semipreparative GC via the determination of the sign of the specific rotation of isolated enantiomers. 

The recommendations of the European Community Working Party on drug quahty, safety and efficacy, take into account two situations. For already well-established racemates the clinical use can continue as such, no specific study of the isolated enantiomers is required. For newly introduced chiral drugs both enantiomers have to be prepared and studied separately with regard to their activity as well as their disposition in vivo. However the final decision to introduce the drug on the market as enantiomer or as racemate belongs to the producer. 

In this case the ee value of the monoester P (or ent-P) depends on the extent of the conversion of the diester S to the monoesters P and ent-P and of the conversion of the latter to the achiral diol Q, and thus on all four rate constants. From the fact that a hydrolase usually retains the (R)- or (S)-group preference of the enantiotopos differentiation in the enantiomer-differentiating hydrolysis, i. e. the hydrolysis of the faster formed monoester P to the diol Q is slower than the hydrolysis of the slower formed monoester ent-P to the diol Q (fci > k2 and fc4 > k) or vice versa), it follows that the ee value of the monoester P (or mt-P) can be raised upon carrying the hydrolysis further to the diol Q, at the expense of the yield. This can be advantageously used to raise the ee value of the monoester to the point where it can be isolated enantiomer-ically pure (for practical purposes). The diol can in most cases be converted to the diester. A mathematical model for the prediction of the ee value of the monoester and the quantity of the individual products in such a combined enantiotopos- and enantiomer-differentiating hydrolysis, which allows one to find the optimum in regard to the ee value and the yield, has been developed on the basis of an irreversible reaction and the absence of product inhibition (Scheme 11.1-11) I8, s7 691. Required are the kinetic constants a, Ei and E2, which can be derived from a determination of... 

The incorporation of arenes in small cyclophanes hinders rotation around certain bonds and can afford isolable enantiomers with appropriately substituted backbones, e.g., planar-chiral 11 (Liittringhaus) or helical-chiral 12 (Vogtle). Studies of the dynamic properties of small cyclophanes with intraannular substituents X (13) provided insight into the space occupancy of atoms or functional groups. ... 

The 3,3 -5,5 isomer of the compound just shown has a chirality axis, but its separation into isolable enantiomers would be extremely difficult. Why ... 

Generally, better chromatographic performance is found with chiral separations in the normal phase for most column manufacturers. It is also likely that the easier solvent removal after collecting the isolated enantiomer, is what drove the industry to normal phase chromatography for chiral applications. It is advantageous to the chiral chromatographer that the majority of the commercially available normal phase LC CSPs and modifiers can be used on both LC and SFC instrumentation. This flexibility allows methods developed using one mode to be transferred to the other... 

Only the low loadability of GC constitutes a limitation. Thus, applicability in GC is restricted to analytical purposes. Therefore, when the final aim is to obtain isolated enantiomers from the mixture, although GC may be adequate to the physicochemical characteristics of the considered compound, HPLC conditions have the advantage of being adequate as a starting point in the scale-up of the separation. 

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