Examples of Chiral Recognition and Discrimination

Chiral Chemistry, Recognition, and Control in living Systems 

Our noses can obviously be very sensitive detectors of chirality, but there are few examples as obvious as the enantiomers of carvone. Perusal of the Leffingwell database illustrates this point as, the terms used to describe the different enantiomeric smells are often very similar. It has been shown that animal species other than humans can demonstrate chiral selectivity better than humans can. This is to be expected because of the greater importance of this sense to these animals. Trained human sniffers are better able to discriminate between subtle differences in smell than most of us are, and it is not surprising that much of the current research in this area is associated with the perfume industry. Some of the impetus for obtaining more information concerning the structure-smell relationships is, of course, driven by economic considerations and market competition among perfume producers. However, there is also increasing awareness and concern for the environ- 

It should not be a surprise to learn that taste can also be sensitive to chirality. A good example is, in fact, MSG. This compound, which may be purchased at the supermarket and 

FIGURE 4.6. Molecular structures of monosodium glutamate (MSG) enantiomers. 

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One may use the stronger term chirality discrimination when a substantial suppression of one intermolecular diastereomer with respect to the other occurs. This requires multiple strong interactions between the two molecular units and therefore more than simple monofunctional alcohols. Some examples where one of the molecules involved is a chiral alkanol are reported in Refs. 112 and 119 121. Pronounced cases of higher-order chirality discrimination have been observed in clusters of hydroxy esters such as methyl lactate tetramers [122] and in protonated serine octamers [15,123,124]. The presence of an alcohol functionality appears to be favorable for accentuated chirality discrimination phenomena even in these complex systems [113,123,125,126]. Because the border between chirality recognition and discrimination is quite undefined, it is suggested that the two may be used synonymously whenever both molecular partners are permanently chiral [127]. 

Related materials can be prepared in which the polysaccharides are linked to a silica support by covalently bound tether groups. For example, silica derivatized by 3-aminopropyl groups can be linked to polysaccharides using diisocyanates. These materials seem to adopt organized structural patterns on the surface, and this factor is believed to contribute to their resolving power. The precise structural basis of the chiral recognition and discrimination of derivatized polysaccharides has not been elucidated, but it appears that in addition to polar interactions, tt-tt stacking is important for aromatic compounds. ... 

Early examples of enantioselective extractions are the resolution of a-aminoalco-hol salts, such as norephedrine, with lipophilic anions (hexafluorophosphate ion) [184-186] by partition between aqueous and lipophilic phases containing esters of tartaric acid [184-188]. Alkyl derivatives of proline and hydroxyproline with cupric ions showed chiral discrimination abilities for the resolution of neutral amino acid enantiomers in n-butanol/water systems [121, 178, 189-192]. On the other hand, chiral crown ethers are classical selectors utilized for enantioseparations, due to their interesting recognition abilities [171, 178]. However, the large number of steps often required for their synthesis [182] and, consequently, their cost as well as their limited loadability makes them not very suitable for preparative purposes. Examples of ligand-exchange [193] or anion-exchange selectors [183] able to discriminate amino acid derivatives have also been described. 

A number of specialised stationary phases have been developed for the separation of chiral compounds. They are known as chiral stationary phases (CSPs) and consist of chiral molecules, usually bonded to microparticulate silica. The mechanism by which such CSPs discriminate between enantiomers (their chiral recognition, or enantioselectivity) is a matter of some debate, but it is known that a number of competing interactions can be involved. Columns packed with CSPs have recently become available commercially. They are some three to five times more expensive than conventional hplc columns, and some types can be used only with a restricted range of mobile phases. Some examples of CSPs are given below ... 

The spherically shaped cryptophanes are of much interest in particular for their ability to bind derivatives of methane, achieving for instance chiral discrimination of CHFClBr they allow the study of recognition between neutral receptors and substrates, namely the effect of molecular shape and volume complementarity on selectivity [4.39]. The efficient protection of included molecules by the carcerands [4.40] makes possible the generation of highly reactive species such as cyclobutadiene [4.41a] or orthoquinones [4.41b] inside the cavity. Numerous container molecules [A.38] capable of including a variety of guests have been described. A few representative examples of these various types of compounds are shown in structures 59 (cyclophane) 60 (cubic azacyclophane [4.34]), 61a, 61b ([4]- and [6]-calixa-renes), 62 (cavitand), 63 (cryptophane), 64 (carcerand). 

The existence of chirality in nature is of particular importance in numerous recognition processes, often illustrated by examples detectable by non-spectroscopic methods such as the different orange and lemon odors of R-(+)- and S-(-)-limonene, respectively (Fig. 3) [8]. As such, chiral discrimination is also of considerable consequence in the medical sciences, as often one enantiomer is pharmaceutically active whereas the other may show adverse side effects. A historic example is the anti-emetic activity of one of the enantiomers of thalidomide, while the other can cause fetal damage [9,10]. These considerations highlight the importance of chiral discrimination in the production of biologically active materials, whereas on the other hand, the design of routes to asymmetric synthesis presents an active challenge to synthetic chemists worldwide. 

We reported the first examples of asymmetric catalysis of intramolecular carbonyl-ene reactions of types (3,4) and (2,4), using the BINOL-derived titanium complex (1) [54,57]. The catalytic 7-(2,4) carbonyl-ene cyclization gives the ox-epane with high ee, and gem-dimethyl groups are not required (Scheme 18). In a similar catalytic 6-(3,4) ene cyclization, the trans-tetrahydropyran is preferentially obtained with high ee (Scheme 19). The sense of asymmetric induction is exactly the same as observed for the glyoxylate-ene reaction the (i )-BINOL-Ti catalyst provides the (i )-cyclic alcohol. Therefore, the chiral BINOL-Ti catalyst works efficiently for both the chiral recognition of the enantioface of the aldehyde and the discrimination of the diastereotopic protons of the ene component in a truly catalytic fashion. 

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