Methylated CyDs

Widespread use of natural CyDs as hosts for drugs is restricted by their low aqueous solubility, particularly that of (3-CyD. Methylation or hydroxyalkylation of the hydroxyl groups of (3-CyD has been nsed to obviate this problem. For example, hydroxyalkylated CyDs are amorphous mixtures of chemically related components with different degrees of snbstitntion. This mnlticomponent character prevents crystallization, and thus the hydroxyalkylated CyDs have higher solubility (>50%) in both water and ethanol. The solubility of natural 3-CyD in water increases with increase in tempera-tnre. On the other hand, 2,6-dimethyl-(3-CyD (DM-(3-CyD) shows exothermic dissolntion in water, so that the solubility decreases with increase in temperature, because of... 

Figure 12 Gradient separation of bases, nucleosides and nucleoside mono- and polyphosphates. Column 0.6 x 45 cm. Aminex A-14 (20 3 p) in the chloride form. Eluent 0.1 M 2-methyl-2-amino-l-propanol delivered in a gradient from pH 9.9-100 mM NaCl to pH 10.0-400 mM NaCl. Flow rate 100 ml/hr. Temperature 55°C. Detection UV at 254 nm. Abbreviations (Cyt) cytosine, (Cyd) cytidine, (Ado) adenosine, (Urd) uridine, (Thyd) thymidine, (Ura) uracil, (CMP) cytidine monophosphate, (Gua) guanine, (Guo) guanosine, (Xan) xanthine, (Hyp) hypoxanthine, (Ino) inosine, (Ade) adenosine, (UMP) uridine monophosphate, (CDP) cytidine diphosphate, (AMP) adenosine monophosphate, (GMP) guanosine monophosphate, (IMP) inosine monophosphate, (CTP) cytidine triphosphate, (ADP) adenosine diphosphate, (UDP) uridine monophosphate, (GDP) guanosine diphosphate, (UTP) uridine triphosphate, (ATP) adenosine triphosphate, (GTP), guanosine triphosphate. (Reproduced with permission of Elsevier Science from Floridi, A., Palmerini, C. A., and Fini, C., /. Chromatogr., 138, 203, 1977.)...

Ill principle, many intramolecular aldol reactions can lead to a mixturei products, depending on which enolate ion is formed. For example, 2,5-1 dione might yield either the five-membered-ring product 3-methyl-2-cyd( tenone or the three-membered-ring product (2-methylcyclopropenyltethanoo (Figure 23.4). In practice, though, only the cyclopentenone is formed. 

With the intent to selectively derivatize CyD oligosaccharides,80 Abelt enlisted nitrogenous carbene precursors as labile guests.81 The involvement of supramolecular carbenes could be inferred based on intramolecular products stemming from 1,2-H shifts. Of course, 3//-diazirines that possess a-C-H bonds, like 3-methyl-3-phenyl-3//-diazirine (6) (Scheme 2), are susceptible to rearrangements in the excited state (RIES) that mimic the results of carbene 1,2-H shifts,82 e.g., 6 —>10 (Scheme 2). 

It was hypothesized that the tight fit of a CyD clathrate might lessen the preference of the methyl group in 26 to reside in an equatorial position (Scheme 6). If diazirine 26 were forced to adopt an axial conformation then the hydrogen at C2 would assume an equatorial position. This misalignment of the filled MO of the... 

The vinyl monomer of CyD is synthesized by the ester exchange reaction of m-nitrophenyl acrylate with (3-CyD or a-CyD in water. The imprinted polymers are prepared in water by a conventional radical co-polymerization of the vinyl monomer of CyD with N,N,-methyl-enebisacrylamide (MBAA) as crosslinker in the presence of various templates acryloyl CyD (300 pmol) and template (150 pmol) are dissolved in 15 mL of Tris buffer solution ([Tris] = 5 mM, pH 8.0). After stirring for a few minutes, the polymerization is started by adding MBAA (3.0 mmol) and potassium persulfate (35 mg) under nitrogen at 50 °C. The system becomes opaque as the polymerization proceeds. After stirring for 2 h, the obtained white precipitate is collected and... 

Hydrophilic derivatives Methylated p-CyD Soluble in cold water and in organic solvents, surface active, haemolytic Oral, dermal, mucosal ... 

Abbreviations DM, 2,6-di-O-methyl TM, 2,3,6-tri-O-methyl DMA, acetylated DM-P-CyD 2-HE, 2-hydroxyethyl 2-HP, 2-hydroxy propyl 3-HP, 3-hydroxypropyl 2,3-DHP, 2,3-dihydroxypropyl Gi, glycosyl G2, maltosyl GUG, Glucuronyl-glucosyl DE, 2,6-di-0-ethyl TE, 2,3,6-tri-O-ethyl CME, O-carboxymethy 1-0-ethyl TAcyl, 2,3,6-tri-O-acyl (C2 Cig) TValeryl, 2,3,6-tri-O-valeryl SEE, sulfobutyl ether. 

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. 

Treating the hepta-iodo-) -CyD derivative with NaNs in DMF gave, in 96% yield, the hepta-azide, which was methylated using a large excess of Mel and NaH to afford the permethylated derivative quantitatively. Treatment with PhsP followed by aqueous NH3 furnished the hepta-amino-/ -CyD. The disaccharide[Pg.36]

A )8-CyD derivative modified with p-xylylenediamine at the 3-position, mono-3-[4-(aminomethyl)benzylamino]-yS-CyD, was prepared by the reaction of ) -CyD-2,3-manno-epoxide with p-xylylenediamine [97]. The three isomeric mono-2-, 3-, or 6-hydroxy permethylated yS-CyDs are good precursors for a wide variety of monofunctionalized permethyl yS-CyDs. As protecting groups, the benzyloxy group was used for C2, and the t-butyldimethylsilyl group for C6. Mono-C3 hydroxy CyD was obtained by partial methylation of 2,6-dimethyl CyD [98]. 

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