Computational Modeling of Inclusion Complexes of β-Cyclodextrin with enantiomers of Salsolinol, N-Methyl-Salsolinol, and 1-Benzyl-Tetrahydroisoquinoline.

Capillary electrophoresis with β-CD as a chiral selector has successfully separated the two enantiomers of salsolinol, N-methyl-salsolinol, and 1-benzyl-tetrahydroisoquinoline. The migration times of each enantiomer in capillary electrophoresis reflect the stability of their β-CD inclusion complexes. This paper reports a computational modeling study of the inclusion complexes of β-cyclodextrin (β-CD) with salsolinol, N-methyl-salsolinol, and 1-benzyl-tetrahydroisoquinoline by using PM3 (Parametric Method 3) semi-empirical molecular orbital calculations and the ONIOM hybrid method. Two types of the inclusion complexes, cis- and trans-orientations, are considered for each enantiomer of the guest molecules, salsolinol, N-methyl-salsolinol, and 1-benzyl-tetrahydroisoquinoline. In the cis-orientation, the nitrogen in the salsolinol, N-methyl-salsolinol, and 1-benzyl-tetrahydroisoquinoline points toward the secondary hydroxyls of the β-CD, while in the trans-orientation, the nitrogen in salsolinol, N-methyl-salsolinol, and 1-benzyl-tetrahydroisoquinoline points toward the primary hydroxyls of the β-CD. We found that the stabilization energies of these inclusion complexes from these PM3 and ONIOM different methods correlate very well with the migration order deduced from the study of capillary electrophoretic separation.