Wiley InterScience Backfile Collection 1832-2000
Chemistry and Pharmacology
Two efficient methods are described for the selective modification of all six primary hydroxyl groups of α-cyclodextrin (α-CD, 11). One, using an indirect strategy, involves protection of all 18 hydroxyl functions as benzoate esters, followed by selective deprotection of the six primary alcohol groups. The other, using a direct strategy, involves selective activation of the primary hydroxyl groups via a bulky triphenylphosphonium salt, which is then substituted by azide anion as the reaction proceeds. A number of modified α-cyclodextrin derivatives have been prepared and fully characterized, among which are: the useful intermediate α-cyclodextrin-dodeca (2, 3) benzoate (3); hexakis (6-amino-6-deoxy)-α-cyclodextrin hexahydrochloride (7); hexakis (6-amino-6-deoxy)-dodeca (2, 3)-O-methyl-α-cyclodextrin hexahydrochloride (9), hexa (6)-O-methyl-α-cyclodextrin (13). The direct substitution is shown to be even more efficient for β-cyclodextrin (16), giving the heptakis (6-azido-6-deoxy)-β-CD-tetradeca (2, 3)acetate (17), while the indirect strategy fails. The compounds are characterized by extensive use of 13C- and 1H-NMR. spectroscopy. The steric and statistical problems of selective polysubstitution reactions for the cyclodextrins are discussed, and possible reasons for the observed differences in reactivity between α- and β-cyclodextrins are examined.The dodecabenzoate 3 presents a very marked solvent effect on physical properties (IR. and NMR. spectra, optical rotation); the effects observed may be ascribed to an unusually strong intramolecular network of hydrogen bonds which severely distorts the α-cyclodextrin ring and lowers the symmetry from six-fold to three-fold.
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