Resolutions of sibutramine with enantiopure tartaric acid derivatives: chiral discrimination mechanism

The resolution of sibutramine 1 was investigated with enantiopure tartaric acid derivatives. Based on the resolving efficiency assay using a 'Dutch resolution', O,O'-di-p-anisoyl-(R,R)-tartaric acid (R,R)-DMTA was identified as an effective resolving agent, which is easily obtained from natural and inexpensive (R,R)-tartaric acid. Compound (R)-1 was obtained with high enantiomeric purity and yield. The chiral discrimination mechanism and resolving effect in the process were explained with X-ray crystallographic studies. The crystal structures of the conglomerate salts revealed that the more soluble diastereomer (S)-1.(R,R)-DMTA formed a parallel ribbon supramolecular structure while the less soluble diastereomer (R)-1.(R,R)-DMTA formed a spiral net packing structure by enantio-differentiation self-assembly. The effect of the side substituent of the resolving agent on the enantioseparation of 1 via a supramolecular chiral host consisting of tartaric acid analogues is discussed. (C) 2015 Elsevier Ltd. All rights reserved.