Cyclodextrin chemistry. Selective modification of all primary hydroxyl groups of α‐ and β‐cyclodextrins

Abstract

Abstract Two efficient methods are described for the selective modification of all six primary hydroxyl groups of α‐cyclodextrin (α‐CD, 1 1 ). 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 13 C‐ and 1 H‐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.