Covalent diastereomers

Preparative chromatographic resolution procedures have overall freed chemists from the constraint of dependency on crystallization. They are most often performed with covalent diastereomer mixtures but ionic salts can also be separated. Recently, it was found that the lipophilicity of TRISPHAT anion 8 profoundly modifies the chromatographic properties of the cations associated with it and the resulting ion pairs are usually poorly retained on polar chromatographic phases (Si02, AI2O3) [131]. Using enantiopure TRISPHAT anion. 

The distinction between enantio- and diastereoselectivity in a reaction is usually, but not generally, evident. Clearly, an enantioselective reaction must proceed via diastereomeric transition states and often diastereomeric intermediates can be demonstrated. In order to narrow the overlap area as far as possible it is demanded that a diastercoselective reaction must yield covalent diastereomers, as distinct from salts, coordination compounds etc., as reaction products. 

As mentioned, asymmetrically pure compounds are important for many applications, and many different strategies are pursued. However, in spite of many methods being developed, the classic resolution technique of diastereomeric crystallization is still preferentially used to prepare optically active pure compounds in bulk quantity. Crystallization is commonly used in the last purification steps for solid compounds because it is the most economic technique for purification and resolution. Attempts to achieve crystallization after completed reaction without workup and extraction is called a direct isolation process. This technique can be cost-effective even though the product yield obtained is lower. Special conditions may be needed in this case, and the diastereomers can be classified into two types diastereomeric salts and covalent diastereomeric compounds, respectively. Diastereomeric salts can, for example, be used in the crystallization of a desired amine from its racemic mixture using a chiral acid. Covalent diastereomers can, on the other hand, be separated by chromatography, but are more difficult to prepare. Another advantage of crystallization is the possibility of combining in situ racemi-zation reactions and diastereomeric formation reactions to get the desired pure compounds. This crystallization-induced resolution technique is still under development because of its requirements for optimized conditions [55, 56],... 

Direct enantiomer separation methodologies circumvent the rather laborious formation of covalent diastereomers, but instead exploit subtle energetic differences of reversibly formed, noncovalent diastereomeric complexes for chiral recognition. Direct chromatographic enantiomer separation may be achieved in two different modes, the chiral mobile phase additive and the chiral stationary phase mode. 

The resulting covalent diastereomeric compounds possessing different free energies may be resolved based on their different physico-chemical properties and then be transformed back to the optically pure starting material. The technique of covalent diastereomer formations is very laborious and time-consuming, and sometimes needs to be performed under conditions where a racemization may occur. Therefore, for preparative purposes this technique represents just a theoretical interest. However, it is still used in analytical-scale enantioseparations where the enantiomers must not necessarily be collected after the separation. 

An enantioseparation in this mode is based on the formation of non-covalent diastereomer-ic complexes between the enantiomers of an analyte and the chiral additive in the mobile phase (CAMP). Compared with indirect enantioseparations, the CAMP technique has advantages such as the absence of a derivatization step or a higher flexibility (easier change of a chiral additive than a chiral or an achiral packing material). As documented by Davan-kov [105], the enantiomer migration order with CAMP most likely will be opposite to that observed with the same chiral selector as the stationary phase. The complementary enantio-selectivity of enantioseparation with CAMP compared with CSPs is a significant advantage. 

Racemate resolution methods via diastereomeric salt formation may be classified into the following categories 1) resolution by formation of noncovalent diastereomers (diastereomeric salt formation, diastereomeric complex formation, etc.) and 2) resolution by formation of covalent diastereomers. 

It is worthwhile emphasising that the abovementioned syntheses using chiral auxiliaries covalently bound to the substrate bearing the prochiral center prior to the creation of the new asymmetric centre mean converting the problem of enantiofacial recognition into a problem of diastereofacial selectivity i.e. the pair of enantiomers 41 and 42 are actually obtained from hydrolysis of two different diastereomers 39 and 40. In fact, "direct enantioselectivity" can only be attained by using an external chiral catalyst,23 as shown in Figure 9.1 [26]. 

A second method requires the formation of diastereomeric salts or covalent derivatives, which are in a mobile equilibrium in solution ( First-Order Asymmetric Transformation"). Again, one of the diastereomers crystallizes ( Second-Order Asymmetric Transformation ). 

As discussed earlier, the concepts of chiral chromatography can be divided into two groups, the indirect and the direct mode. The indirect technique is based on the formation of covalently bonded diastereomers using an optically pure chiral derivatizing agent (CDA) and reacting it with the pair of enantiomers of the chiral analyte. The method of direct enantioseparation relies on the formation of reversible quasi diastereomeric transient molecule associates between the chiral selector, e.g., i /t)-SO, and the enantiomers of the chiral selectands, [R,S)-SAs [(Ry SA + (S)-SA] (Scheme 1). 

As stated earlier, this technique relies essentially on the formation of covalently bonded diastereomers derived from a pair of chiral analytes (SAs pair of enantiomers) which have been converted to a pair of diastereomers using an optically pure chiral derivatizing agent (CDA) which, in this case, serves as a chiral selector (SO). In this context the definition of " optical purity of the CDA is critical (see Section 3.2.1.2.) and has to be evaluated by complementary methods. 

In any case, in order to ensure reliable results of indirect optical purity determinations using CDAs or for synthesizing optically pure compounds via the formation and separation of covalently bound diastereomers followed by specific cleavage reactions (assuming no racemiza-tion during the building and cleavage reactions), it is mandatory to evaluate and validate the optical purity of CDAs by complementary techniques. 

Possibly the simplest and most versatile method for the preparation of covalent bis-adducts of C(,o with high regio- and diastereoselectivity is the macrocyclization between C(,o and bismalonate derivatives in a double Bingel reaction [7,8,26,27], In theory, each macrocyclic regio-isomer could form as a mixture of diastereomers, depending on how the EtOCO residues at the two methano bridge C-atoms are oriented with respect to each other (in-in, in-out,... 

Moreover, it is possible to lead these compounds into the diastereomeric esters or amides using of optically active acid anhydrides. In this case, the diastereomers with a covalent bond need not always necessarily be a crystalline compound because there are still some other methods left to separate these diastereomers, such as thin layer chromatography, high-performance liquid chromatography, etc. 

Things become complex indeed when we consider all possible combinations 6C + 6H featuring covalent bonds four per carbon and one per hydrogen. There are 217 of these, becoming 328 if diastereomers and enantiomers are taken into account, nearly all unknown and likely highly unstable. We list the four valence isomers of benzene (see for example Ref. 85), all of which appear fairly prominently in the literature (note Figure 2) ... 

To be sure that the chiral inductor and the reactant molecules stay together within a single cage we have explored another strategy. In this method the two components are linked via a covalent bond. This forces the chiral inductor and the reactant parts of a single molecule to stay close to each other. Because of the prior presence of a chiral center in the reactant molecule, the reactant is chiral and the products are formed as diastereomers. Elegant examples of diastereoselective photoreactions in solution are discussed in Chap. 5. We show below that chiral auxiliaries that are ineffective in solution function well within zeolites. In every one of the examples discussed in this section the zeolite is essential to obtain a significant de. We wish to emphasize that the examples should be examined from the perspective of the information they offer in the context of supramolecular interactions. 

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