Cyclodextrins and Cyclodextrin Derivatives

The first electrically driven enantioseparations involved the addition of a chiral selector to the mobile phase in CE. This selector is usually a complexing agent and acts as a pseudo-stationary phase. The separation is accomplished by the difference in the distibution equilibria between the pseudo-stationary phase and the enantiomers [134], The most common additives incorporated into these CE experiments were cyclodextrins and cyclodextrin derivatives [135-138], However, these experiments required the replacement of the chiral selector after each electrophoretic run. 

Since a very large number of rotaxanes and poly rotaxanes that contain cyclodextrins and cyclodextrin derivatives are known, discussion of only a representative selection of such compounds is presented in this section. 

Mayer, S. Schurig, V. Enantiomer separation by electrochromatography in open tubular columns coated with chirasil-dex. J. Liquid Chromatogr. 1993,16, 915. Sezemam, J. Ganzler, K. Use of cyclodextrins and cyclodextrin derivatives in high-performance liquid chromatography and capillary electrophoresis. J. Chromatogr. A, 1994, 668, 509. 

The type of CSPs used have to fulfil the same requirements (resistance, loadabil-ity) as do classical chiral HPLC separations at preparative level [99], although different particle size silica supports are sometimes needed [10]. Again, to date the polysaccharide-derived CSPs have been the most studied in SMB systems, and a large number of racemic compounds have been successfully resolved in this way [95-98, 100-108]. Nevertheless, some applications can also be found with CSPs derived from polyacrylamides [11], Pirkle-type chiral selectors [10] and cyclodextrin derivatives [109]. A system to evaporate the collected fractions and to recover and recycle solvent is sometimes coupled to the SMB. In this context the application of the technique to gas can be advantageous in some cases because this part of the process can be omitted [109]. 

Gas chromatography (GC) has also been used for preparative purposes, but is restricted to relatively volatile racemates such as anesthetics, pheromones or monoterpenes and, therefore, very few applications are reported. Nevertheless, in the cases to which GC may be applied, it could be considered as an economical alternative to HPLC. Most of the resolutions of enantiomers were performed on cyclodextrin-derived CSPs [109, 144-153], and only on very few occasions were other chiral selectors used [153]. 

The condensation reactions described above are unique in yet another sense. The conversion of an amine, a basic residue, to a neutral imide occurs with the simultaneous creation of a carboxylic acid nearby. In one synthetic event, an amine acts as the template and is converted into a structure that is the complement of an amine in size, shape and functionality. In this manner the triacid 15 shows high selectivity toward the parent triamine in binding experiments. Complementarity in binding is self-evident. Cyclodextrins for example, provide a hydrophobic inner surface complementary to structures such as benzenes, adamantanes and ferrocenes having appropriate shapes and sizes 12) (cf. 1). Complementary functionality has been harder to arrange in macrocycles the lone pairs of the oxygens of crown ethers and the 7t-surfaces of the cyclo-phanes are relatively inert13). Catalytically useful functionality such as carboxylic acids and their derivatives are available for the first time within these new molecular clefts. 

Trotta F, Martina K, Robaldo B, Barge A, Cravotto G (2007) Recent advances in the synthesis of cyclodextrin derivatives under microwaves and power ultrasound. J Incl Phenom Macro Chem 57 3-7... 

The mechanisms by which certain P-cyclodextrin derivatives can become successfully attached to respective fibres are analogous to those operating between dyes and fibres. The monochlorotriazine derivative can be applied to cellulosic fibres either ... 

In conclusion, it is noteworthy that cyclodextrins, liposomes and chitin derivatives are all readily available from renewable biochemical sources and offer advantages of biodegradability and safety in use. However, it needs to be borne in mind that this fact alone does not necessarily mean that they are entirely environmentally innocuous in the long run. Demands on resources for the husbanding and processing of bioforms that may be necessary in order to sustain demand for commercially viable qualities and quantities can exert deleterious effects, not least because they may give by-products that present problems of utilisation or disposal [70]. 

A chiral GC column is able to separate enantiomers of epoxy pheromones in the Type II class, but the applications are very limited as follows a custom-made column packed with a p-cyclodextrin derivative as a liquid phase for the stereochemical identification of natural 3,4- and 6,7-epoxydienes [73, 74] and a commercialized column of an a-cyclodextrin type (Chiraldex A-PH) for the 3,4-epoxydiene [71] (See Table 3). The resolution abilities of chiral HPLC columns have been examined in detail, as shown in Table 7 and Fig. 14 [75,76, 179]. The Chiralpak AD column operated under a normal-phase condition separates well two enantiomers of 9,10-epoxydienes, 6,7-epoxymonoenes and 9,10-epoxymonoenes. Another normal-phase column, the Chiralpak AS column, is suitable for the resolution of the 3,4-epoxydienes. The Chiralcel OJ-R column operated under a reversed-phase condition sufficiently accomplishes enantiomeric separation of the 6,7-epoxydienes and 6,7-epoxymonoenes. 

Piel et al. [109] studied the pharmacokinetics of miconazole after intravenous administration to six sheep (4 mg/kg) of three aqueous solutions - a marketed micellar solution containing polyoxyl-35 castor oil was compared with two solutions both containing 50 pM lactic acid and a cyclodextrin derivative (100 pM hydro-xylpropyl-/l-cyclodextrin or 50 pM sulfobutyl ether (SBE7)-/i-cyclodextrin. This work demonstrated that these cyclodextrin derivatives have no effect on the pharmacokinetics of miconazole by comparison with the micellar solution. The plasma concentration-time curves have shown that there is no significant difference between the three solutions. 

Isoxazolines 38 and 39 were obtained in different ratios by direct cycloaddition of 4-t-butylbenzonitrile oxide with acids 35 (R = H, path B) and by the intermediate formation of cyclodextrin derivatives 36 and 37 followed by basic hydrolysis and acidification (path A). The reversed regioselectivity as well as an increased rate of the cycloaddition step could be explained through the temporary association of the nitrile oxide with the cyclodextrin to give the inclusion complex 40 <06CEJ8571>. 

Addition of an aqueous solution of PEG to a saturated aqueous solution of a-CD at room temperature did not lead to complex formation unless the average molecular weight of PEG exceeded 200 [46]. Moreover, carbohydrate polymers such as dextran and pullulan failed to precipitate complexes with PEG, and the same was true for amylose, glucose, methyl glucose, maltose, maltotriose, cyclodextrin derivatives, such as glucosyl-a-CD and maltosyl-a-CD, and water-soluble polymers of a-CD crosslinked by epichlorohydrin. These facts suggested to Harada et al. the direction for further research. 

Cylodextrins (CDs) are a class of chiral cyclic oligosaccharides that have molecule-sized cavities. They commonly comprise between six and eight D-glucopyranoside units that are linked via a-l,4-glycosidic links. Their bowl-shaped form is generally represented as a cylindrical funnel by analogy to the calixarenes family. There is a large number of cyclodextrin derivatives in the... 

Figure 11. Amphiphilic cyclodextrins (Host molecules) and naphthalene derivatives (Guests).

See for example the pioneering work of Breslow Bres-low, R. Dong, S. D. Biomimetic Reactions Catalyzed by Cyclodextrins and their Derivatives Chem. Rev. 1998, 98,1997-2011 and Breslow, R. Biomimetic Chemistiy and Artificial Enzymes - Catalysis by Design Acc Chem. Res. 1995,28,146-153. 

Only the silica-based stationary phases with covalently bonded alkyl chain, cyano and propylamino ligands have found practical applications in HPLC. Besides these common ligands, the experimental use of naphthalene, pyrene and nitroaromatic as ligands has also been reported. Silica-based stationary phases with covalently bonded cyclodextrins or cyclodextrin derivatives have been frequently employed in the separation and quantitative determination of isomer pairs. 

With capillary electrophoresis (CE), another modern primarily analytically oriented separation methodology has recently found its way into routine and research laboratories of the pharmaceutical industries. As the most beneficial characteristics over HPLC separations the extremely high efficiency leading to enhanced peak capacities and often better detectability of minor impurities, complementary selectivity profiles to HPLC due to a different separation mechanism as well as the capability to perform separations faster than by HPLC are frequently encountered as the most prominent advantages. On the negative side, there have to be mentioned detection sensitivity limitations due to the short path length of on-capillary UV detection, less robust methods, and occasionally problems with run-to-run repeatability. Nevertheless, CE assays have now been adopted by industrial labs as well and this holds in particular for enantiomer separations of chiral pharmaceuticals. While native cyclodextrins and their derivatives, respectively, are commonly employed as chiral additives to the BGEs to create mobility differences for the distinct enantiomers in the electric field, it could be demonstrated that cinchona alkaloids [128-130] and in particular their derivatives are applicable selectors for CE enantiomer separation of chiral acids [19,66,119,131-136]. 

Tesafova, E. and Bosikova, Z., Comparison of enantioseparation of selected benzodiazepine and phenothiazine derivatives on chiral stationary phases based on P-cyclodextrin and macrocyclic antibiotics, J. Sep. ScL, 26, 661, 2003. 

Schulte, G., Heitmeier, S., Ghankvetadze, B., and Blaschke, G. (1998). Ghiral capillary electrophoresis-electrospray mass spectrometry coupling with charged cyclodextrin derivatives as chiral selectors. /. Chromatogr. A 800, 77—82. 

Preparation of cyclodextrin derivatives substitution at a secondary hydroxyl group of the cyclodextrin annulus. Murakami and cowor-kers described a new and convenient method for the regioselective tosylation of the 2-hydroxyl groups of alpha, beta, and gamma cyclodextrin by means of a cyclic tin intermediate. The method is based on the reaction of dibutyltin oxide with 1,2-diols to form five-membered dibutyl-stannylidene derivatives. Useful yields of the 2-6>-tosyl derivatives of the cyclodextrins were obtained. 

In the previous section we observed that intramolecular a-(1- -4.) glycosylative cyclization leading to alpha cyclodextrin was 2.J times more efficient in terms of the yield obtained than that leading to gamma cyclodextrin. We have examined how regioselective this type of cyclization is when the A,6-diol derivative 30 is used to give 31 and 32. Product 32 may be regarded as an iso-alpha cyclodextrin derivative. 

A lot of published data on the separation of enantiomers of flavors and fragrances by GC is reviewed by Chirbase/Flavor database. Table 1. summarizes the enantiomer separation of oxygenated monoterpenes on chiral stationary phases of cyclodextrin derivatives by high resolution gas chromatography. 

Bicchi C, Manzin V, D Amato A, Rubiolo P, Cyclodextrin derivatives in GC separation of enantiomers of essential oil, aroma and flavour compounds, Flavour... 

G Dollo, P Le Corre, F Chevanne, R Le Verge. Inclusion complexation of amide-typed local anaestetics with /3-cyclodextrin and its derivatives. II. Evaluation of affinity constants and in vitro transfer rate constants. Int J Pharm... 

H Jakubetz, M Juza, V Schurig. Electrokinetic chromatography employing an anionic and a cationic /3-cyclodextrin derivative. Electrophoresis 18 897-904,... 

Y Tanaka, M Yanagawa, S Terabe. Separation of neutral and basic enantiomers by cyclodextrin electrokinetic chromatography using anionic cyclodextrin derivatives as chiral pseudo-stationary phases. J High Res Chromatogr 19 421-433, 1996. 

H Yamamura, A Akasaki, Y Yamada, K Kano, T Katsuhara, S Araki, M Kawai, T Tsuda. Capillary zone electrophoretic chiral discrimination using cationic cyclodextrin derivative determination of velocity and association... 

---