Molecular modeling of saccharides, 6. Small‐ring cyclodextrins: Their geometries and hydrophobic topographies

A detailed force‐field‐based evaluation of the molecular geometries of small‐ring cyclodextrins 1–3 with three, four, and five α(1→4)‐linked glucose residues and the starch‐derived α‐cyclodextrin ( 4 ) was performed by using molecular mechanics and high‐temperature annealing. The resulting minimum‐energy structures reveal that the progressive strain imposed by diminution of the cyclodextrin macrocycle from six glucose units (α‐CD, 4 ) to five (cycloglucopentaoside 3 ), four (tetraoside 2 ), and three (cyclotrioside 1 ) is reflected in a widening of the intersaccharidic bond angle, in a complex balance of the interrelated glucose tilt angles τ and the glycosidic torsions Φ and Ψ against each other, and most strikingly, in a specific unilateral distortion of the pyranoid rings, i.e. flattening at C‐4 towards the E 1 envelope conformation. This successive levelling at C‐4, induced by a decrease of the two related ring torsion angles, is small in the pentamer 3 , pronounced in 2 , and fully realized in the cyclotrioside 1 . – The respective contact surfaces of the minimum‐energy conformers and their molecular lipophilicity patterns (MLP), in color‐coded form, were also generated, allowing an assessment of their capabilities to form inclusion complexes. Accordingly, only the cyclopentaoside 3 exhibits a hydrophobic central cavity similar to that of α‐CD ( 4 ), the smaller cyclodextrins 2 and 1 are closed, yet contain a hydrophobic indentation for potential binding.