Cyclodextrin/derivatives

The hydroxyl groups at the primary (C-6) and the two secondary positions (C-2, C-3) are prone to displacement reactions at the O- or C-atoms leading to CD derivatives [26], There are several motivations for the derivatization of CDs  

Derivatizations can be performed in well-defined regioselective ways, in which 1,2, 2n, or 3n (n = 6, 7, or 8 for a-CD, (3-CD, or y-CD, respectively) substituents were attached at certain positions of the CD scaffold [26], In addition, CDs have also been derivatized statistically at various positions. Statistical derivatizations require much less effort for synthesis and purification and give rise to higher yields than regioselective ones, but the products are difficult to reproduce and to characterize because of their heterogeneity. All synthetic methods will be briefly summarized subsequently. Those derivatives used most often are listed in Table 2. 

The main entry for CD derivatives, mono-substituted at the C-6 position, are the tosylates for a-CD and (I-CD and 2,4,6-triisopropylbenzene sulfonate for y-CD [43-45]. The 6-O-sulfonates of CDs can be converted to functional CD derivatives, 

Abbreviation Ring size, n Substituents Positions Degree of substitution per CD Aqueous solubility at 25 °C, % Aqueous solubility at 60°C, % 

In addition to the regioselectively derivatized CDs, a number of statistically substituted CDs are in use. Highly water-soluble statistic derivatives are obtained by reaction of CDs with methyl halides [68], with epoxides (e.g., ethylene oxide, propylene oxide [69,70], or allyl glycidylether [71]), and with cyclic sulfates (e.g., butane sultone [72]). Statistical allyl ethers were converted to sulfonates by addition of sulfite [71], Monochlorotriazinyl-P-CD is another available reactive CD. Since these synthetic procedures are rather simple compared to the regioselective ones, many of these statistical compounds are available at the technical scale. 

---

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]. 

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... 

It has been demonstrated [32,44] that the various p-cyclodextrin derivatives shown in Table 10.1 can be applied to the surface of appropriate fibres by dyeing methods traditionally used... 

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 ... 

Albers E, Muller BW (1995) Cyclodextrin derivatives in pharmaceutics. Crit Rev Ther Drug Carrier Syst 12(4) 311—337... 

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... 

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. 

Liu Y, Zhao YL, Chen Y, Liang P, Li L (2005) A water-soluble beta cyclodextrin derivative possessing a fullerene tether as an efficient photodriven DNA-cleavage reagent. Tetrahedron Lett 46 2507-2511. 

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. 

Table 1. Enantiomer Separation of Oxygenated Monoterpenes on Chiral Stationary Phases of Cyclodextrin Derivatives by High Resolution Gas Chromatography...

Schurig V, Nowotny HP, Gas chromatographic separation of enantiomers on cyclodextrin derivatives, Angew Chem 29, 939—957, 1990. 

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

Bicchi C, ArtufFo G, D Amato A, Manzin V, Galli A, Galli M, Cyclodextrin derivatives for the GC separation of racemic mixtures of volatile compotmds, Part VI The influence of the diluting phase on the enantioselectivity of 2,6-di-O-methyl-3-O-pentyl-fi-cyclodextrin, /Resolut Chromatogr 16 209—214, 1993. 

B Chankvetadze, G Endresz, G Blaschke. Charged cyclodextrin derivatives as chiral selectors in capillary electrophoresis. Chem Soc Rev 25 141-146,... 

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

---