Unusual hydrogen-bonding differences in stereoisomeric 6-C-alkylated cyclodextrins

The Grignard reaction of perbenzylated β-cyclodextrin derivatives containing one 6-aldehydo group, or two 6-aldehydo groups in the A and D rings, was investigated. The reaction gave the stereoisomeric secondary alcohols expected for 1,2-addition in diastereomeric ratios of about 1 ∶ 3 ratio for the 6R- and 6S-isomers. Surprisingly the 6R-isomers were consistently found to be much less polar in terms of chromatographic retention times than the 6S-isomers. The polarity difference, which disappeared upon acetylation or oxidation, was interpreted as being caused by the presence or absence of intramolecular hydrogen bonding. This was supported by their IR spectra. The configurations of the diastereomers were determined by hydrolysis of the cyclodextrin and comparison of the modified glucose residues with reference compounds. Modelling studies suggest that 6-C-alkylation restricts the conformation around the C5–C6 bond such that the 6S-isomer will adopt a gg conformation, which has the hydroxy group pointing outwards, while the 6R-isomer will adopt a gt conformation, which has the OH group pointing towards the inner face of the cyclodextrin.