Molecular modelling of the inclusion complexes between β-cyclodextrin and (R)/(S)-methylphenobarbitone and its application to HPLC

Molecular modelling of β‐cyclodextrin and optimisation of its potential energy suggests that a favoured conformation is that distorted from a symmetrical torus. The inclusion of water molecules into the torus cavity simulates the increased stability in an aqueous solvent. Complexes of β‐cyclodextrin with (R)‐ and (S)‐enantiomers of methylphenobarbitone have been modelled and energetically optimised by the application of molecular mechanics. The simulations suggests that the guest molecules adopt an orientation in which the phenyl ring is projected into the torus cavity, with in each case the plane of the ring parallel to a longer axis of the distorted torus and slightly displaced from the axis through the torus cavity. It is suggested that the asymmetry in the macrocyclic ring contributes to chiral recognition as a result of additional discriminatory binding to the barbiturate ring residue of each enantiomer, which occupy different 3D geometries. The enantiomers form complexes of different minimum potential energies. The resulting difference in complex stability can be related to the behaviour of β‐cyclodextrin, as a mobile phase additive in reverse‐phase HPLC to effect chiral separation of rac‐medthylphenobarbitone during chromatography. © 1994 Wiley‐Liss, Inc.