Chiral resolution by crystallization of host-guest supramolecular complexes

The crystallization behaviour and the physical characterization of supramolecular complexes formed between permethylated-α-cyclodextrin (TMα-CD) and the enantiomers of phenylethanol (PE) are investigated. According to crystal structure analyses, complexes containing the pure guest enantiomers are almost isomorphous, indicating that the host presents a poor ability to distinguish PE enantiomers at a molecular level. Nevertheless, crystallizations from racemic PE in water induce an efficient chiral discrimination and allow the enantio-separation of the guests despite the existence of a solid solution revealed by XRPD and coupled TG-DSC analyses. The enantiodifferentiation is explained by solubility differences between the two diastereomeric complexes in the studied temperature range. Moreover, it is shown that the diastereomeric complex TMα-CD/(S)-PE crystallizes in two distinct phases: a monohydrate and an anhydrous form, with a transition temperature close to 37°C. The insertion of a water molecule in the crystals grown below 37°C does not involve any other change of the crystal packing nor of the molecular conformation, but leads to different crystal growth mechanisms inducing different morphologies and distinct thermal behaviours. This revised version was published online in July 2006 with corrections to the Cover Date.     

New synthesis of (Z,E)-2,7-bis(4-cyanobenzylidene)cycloheptan-1-one under stereospecific constraints induced by host-guest interactions

A selective, efficient, and fast access to (Z,E)-2,7-bis(4-cyanobenzylidene)cycloheptan-1-one (BCBCH), precursor of the synthetic antagonist of tissue-plasminogen activator (t-PA), is reported using a solid/solid aldolisation-crotonisation reaction on a supramolecular complex under microwave irradiation. The underlying mechanism is investigated from the crystal structure of the intermediate host-guest complex formed between permethylated gamma-cyclodextrin and (Z)-2-(4-cyanobenzylidene)cycloheptan-1-one.     

Chiral discrimination in host-guest supramolecular complexes. Understanding enantioselectivity and solid solution behaviors by using spectroscopic methods and chemical sensors

Diastereomeric host-guest associations formed between permethylated-beta-cyclodextrin (TMbeta-Cd) and the two enantiomers of p-bromophenylethanol (pBrPE) were characterized in aqueous solution by NMR spectroscopy, revealing similar inclusion geometries and weak binding constants, whatever the guest configuration. These features were confirmed by hydrogenation experiments, and do not allow to account for the ability of TMbeta-Cd to resolve racemic pBrPE by successive crystallizations [Grandeury, A.; Petit, S.; Gouhier, G.; Agasse, V.; Coquerel, G. Tetrahedron: Asymmetry 2003, 14, 2143-2152]. The analysis, by means of solid-state NMR, oxidation experiments, and solubility measurements, of the two crystalline phases containing known proportions of guest enantiomers revealed identical inclusion geometries in a given phase, irrespective of the enantiomeric composition. The corresponding solid solutions were further characterized by the determination of an isothermal section (40 degrees C) in the relevant ternary phase diagram. It appears from all these data that chiral resolution mechanisms in this system can only be envisaged in terms of nucleation conditions of each crystal form (with its specific inclusion geometry) and enantiomeric recognition at crystal solution interfaces during the growth of each crystal packing.