Native CyDs

Rg. 1.2. Schematic view of the glucopyranoside ring with the atom numbering and native CyD sizes and the average orientation of the most important atoms and OH groups. 

The very fast internal movement of native CyDs and of most of their derivatives, leading to the observation of averaged structures by most experimental techniques, is frequently overlooked. In addition to the temperature-dependent process of selfinclusion of substituent(s) [104-107], we were able to find only two studies of substituted CyDs in which movement of the macrocydes was at least partly frozen [104, 108]. Some other experimental results proving CyD flexibility using NMR... 

On the basis of X-ray analysis, methylated or acetylated CyDs are sometimes considered to be more flexible than the native ones (see Chapter 7). Such a conclusion seems unfounded since X-ray diffraction can yield straightforwardly only the structure of the macrocyclic ring averaged over time and space, not its mobility. As a matter of fact, native CyDs are more flexible, and thus more difficult to freeze, than permethylated ones. This fact is frequently overlooked since the above mentioned averaging is not taken into account. As shown above, NMR spectra in solution and in the solid state are much more sensitive to CyD flexibUity and clearly prove their nonrigidity. 

The classic chemistry of native CyDs is now a kind of completed area, described in a book [1] and several reviews that summarize state-of-the-art syntheses of these macrocycles [2-4], while syntheses of several novel CyD structures or their analogues are given in the literature [5-8). Studies of CyDs as enzyme models, involving syntheses of numerous selectively substituted derivatives, have been reviewed [9-11]. Numerous journals and proceedings can also be mentioned here [12, 13). 

Amphiphilic heptakis(6-alkylthio)- 8-CyD derivatives were synthesized and their monolayer behavior on a water surface was studied on the basis of surface-molecular area [n-K) isotherms [61]. j8-CyD functionalized at the 6-position with trifluoromethylthio groups have been obtained from the native j8-CyD [62]. Heptakis(2,3-dihexanoyl)-yS-CyD, heptakis(6-hexanamido)-j8-CyD, and heptalds(6-myristamido)-j8-CyD have been synthesized and nanocapsules prepared by nanoprecipitation [63]. Heptakis(6-0-amphiphilic)-jS-CyDs with substituents of varying chain lengths (C and C14) and bond types (ester or amide) have been studied [64]. 

Heptakis-6-amino-6-deoxy-j8-CyD 25 is protonated at neutral pH [146). The binding constant of 25 for phosphate 26 was three times larger than that of the native f -CyD, whereas the binding constant of 25 for phenol 27 was only 2% of that of the native S-CyD. 

The 2-naphthylamine-appended jS-CyD-calix[4]arene couple 49 showed sensitivity for analytes such as steroids and terpenes with different selectivity from the native CyD. On the other hand, the dansyl-appended j8-CyD-calix[4]arene couple 50 did not show any change in fluorescence intensity upon the addition of guests because of the strong inclusion of the dansyl group into the CyD cavity [166]. 

Crown ether-capped jS-CyD 71 showed a binding afEnity for 8-anilino-l-naphthalenesulfonate (AN S) 88 times higher than the native j8-CyD, but the affinity for Acridine Red and Rhodamine B was lower than that of the native 8-CyD... 

A yS-CyD-calrx[4]arene dyad 72 and a calrxarene-bridged bis(j8-CyD) 73 showed enhanced binding ability with some fluorescence dyes compared to the native p-CyD... 

First-order dendrimers based on a fi-CyD core containing fourteen Val, Phe, and Val-Phe were synthesized 83-86 [186]. This tetradecapeptidyl CyD could form a 2 1 host/guest inclusion complex with adamantanecarboxylic acid, although the native fi-CyD makes a 1 1 host/guest complex with this guest. 

A wide variety of native and derivatized CyDs are available for use as mobile phase additives in HPLC. In liquid chromatography to study the interaction of CyDs with guest molecules, the information about cydodextrin adsorption on the stationary phase is very substantial. It should be noted that the separation ability of bonded CyDs and CyDs added to the mobile phase in HPLC is not always the same (see below). To assess the adsorption of CyDs on the stationary phase, the chromatographic properties of native and permethylated CyDs applied in RP18 and porous graphitic carbon (PGC) column have been studied [25-29]. On the RP18 column the adsorption of yS-CyD is much stronger than that of a- or y-CyDs. On the PGC, the order of elution is a- < < y-CyD, in accordance with the increase of... 

As discussed in Chapter 1 in Section 1.4, contrary to Harata s opinion [32, 33], methylated CyDs are in general not better selectors than the native ones [34, 35]. 

The chromatographic behavior of mandelic acid and its esters was studied in reversed-phase HPLC (RP-HPLC) with a-, p-, y-, and permethylated-) -CyD as additive to the mobile phase. It was found that native CyDs do not recognize enantiomers of esters although they form relatively stable 1 1 complexes with them. Estimated stability constants for these guests are presented in Table 5.1 [43]. 

CyDs can be used alone as chiral selectors in CE or in combination with other achiral and chiral buffer additives. Native CyDs and their neutral and charged derivatives are currently available as chiral selectors for CE. Derivatized CyDs can be randomly substituted multicomponent mixtures or a sdectivdy derivatized singlecomponent CyD. Randomly substituted mixtures offer the advantages of being readily available and less expensive but are less suitable for mechanistic studies and method validation. Single-component mixtures are more expensive but better suited to mechanistic studies and method validation. 

Table 6.1. Enantiomer affinity pattern of selected chiral analytes towards native CyDs having different cavity size (Reproduced with permission from Ref. 56).

The structural reasons for the above-mentioned opposite affinity of the enantiomers of ACT towards native f- and y-CyD are reported in Ref. [59]. The nuclear Overhauser effect (NOE) data shown in Fig. 6.6 allow us to deduce the structure of... 

One of the interesting questions of CyD chemistry is whether inclusion complex-ation represents a prerequisite for chiral recognition and, if not, which part of the CyD, external or internal, provides a more favorable environment for enantioselec-tive recognition The synthesis of highly crowded heptakis-(2-0-methyl-3,6-di-0-sulfo)-j8-CyD (HMdiSu-jg-CyD) with 14 bulky sulfate substituents on both primary and secondary CyD rims can provide insights to this problem [62] since the bulky substituents on both sides of the cavity entrance may hinder inclusion complex formation between chiral analytes and HMdiSu-yS-CyD. In one study, 27 cationic chiral analytes were resolved in CE using native f-CyD and HMdiSu-yS-CyD [63]. For 12 of 16 chiral analytes resolved with both chiral selectors the enantiomer migration order was opposite. Analysis of the structures of analyte-CyD complexes in solution indicated that in contrast to mainly inclusion-type complexation between chiral analytes and j8-CyD, external complexes are formed between the chiral analytes and HMdiSu-j8-CyD [63]. 

Figure 7.1 shows the structure of CyDs consisting of 6-9 glucose units. Some average parameters describing the macrocyclic conformation of native CyDs are summarized in Table 7.1. The pyranose ring of each glucose unit in native CyDs is relatively rigid and assumes the Ci chair conformation. Some structural characteristics of CyDs are illustrated in Fig. 7.2. Primary hydroxyl groups have rotational...

Certainly, DSC is a perfectly applicable technique for the detailed characterization of pharmacological formulations obtained by such traditional methods as cogrinding, as exemplified by Cirri et al. [47], who obtained and stabilized glyburide in the activated form as a complex with native and modified CyDs via the cogrinding technique. 

CyDs are intrinsically chiral macrocydic hosts and this explains the recent trend of ITC application to eluddate the thermodynamics of chiral discrimination of enantiomeric and diastereomeric guest pairs by native and modified CyDs. It is... 

Further development of the above-mentioned ideas [82] has been reported [83, 84]. Mono- and diaminated j8-CyDs were employed as chiral discriminators for a variety of chiral guest molecules [83, 84]. Thus, chiral centers less-symmetrically distributed inside the cavities of mono- and diaminated j8-CyDs, compared to native j8-CyD, do indeed lead to better chiral discrimination by the amino-modified hosts. The major findings [83, 84] may be summarized as follows (1) the direct correlation between the mode of penetration and chiral recognition established above for j8-CyD [82] holds for aminated j8-CyD, and may now be considered a general rule for CyD complexation reactions. We may further conclude that the origi-... 

Recently, experimental confirmation of the Grunwald theory was achieved by comparison of the quality of differential enthalpy-entropy compensation plots for the exchange equilibrium between (R)- and (S)-enantiomers of chiral guests in ff CyD cavities (Eq. (9)) [82], and the exchange equilibrium between native fi-CyXi and 6-ammonio-6-deoxy-jg-CyD (am- 8-CyD) for chiral and achiral guests (Eq. (10)) [119] ... 

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