Inclusion complexes with podophyllotoxin, structural characterization and chiral recognition

Abstract

The biologically active compound podophyllotoxin can form host–guest complexes which contain two types of guests, i.e. water and a smaller organic molecule. Inclusion compounds which contain two podophyllotoxin and two water molecules per organic guest have been prepared with 15 different guests. They were found to crystallize in the orthorhombic space group P2₁2₁2₁ with unit-cell dimensions a 10.3–10.6 Å, b 17.3–17.8 Å and c 25.8–26.1 Å and one small organic molecule per asymmetric unit. The crystal structures have been determined from low-temperature X-ray diffraction data for the three complexes formed with bromobenzene, nitrobenzene, and racemic butan-2-ol, respectively. The crystal structures display a regular pattern of hydrogen bonds which connects the two crystallographically independent podophyllotoxin and water molecules. Water acts as a donor towards the oxo group from one podophyllotoxin and the hydroxy group from another podophyllotoxin molecule related by translational symmetry along the a-axis, and it accepts a hydrogen from the hydroxy group of a podophyllotoxin molecule which is crystallographically inequivalent. The arrangement leads to voids in the structure bound by the more hydrophobic part of six podophyllotoxin molecules (three of each type). These voids accommodate the smaller organic guests. Both the bromobenzene and the butan-2-ol complexes are disordered. Bromobenzene is found in a plane which contains the molecule in two orientations. The more populated (80%) has bromine in a volume, which corresponds to that containing the nitro group in the nitrobenzene complex. Partial resolution of butan-2-ol has been achieved in the inclusion complex. It contains 70% of the R-form and the less populated S-form (30%) is oriented in such a way that it shares the carbon chain with the R-form. The crystallographically independent podophyllotoxin molecules differ only in the relative orientation of their 3,4,5-trimethoxyphenyl groups.