Solvent-induced chirality control in the enantioseparation of 1-phenylethylamine via diastereomeric salt formation.

Solvent-induced chirality control in the enantioseparation of 1-phenylethylamine 1 by N-(p-toluenesulfonyl)-(S)-phenylalanine 2 via diastereomeric salt formation was studied. (S)-1·(S)-2 was preferentially crystallized as a less-soluble salt from aqueous alcohol, while (R)-1·(S)-2 salt was mainly obtained by addition of solvents with a six-membered ring such as dioxane, cyclohexane, tetrahydropyran, and cyclohexene to 2-propanol. Further investigations were carried out from the viewpoints of molecular structures, optical rotation measurement, and X-ray crystallographic analyses. Crystallographic analyses have revealed that incorporation of the six-membered ring solvent molecule in (R)-1·(S)-2 without hydrogen bonds changed the molecular conformation of (S)-2 to stabilize the salt, which changed the selectivity of 1 in the enantioseparation.

New resolution technologies controlled by chiral discrimination mechanisms.

It is well known that optical resolution via crystallization is still a useful and practicalmethod for obtaining enantiomerically pure compounds for both laboratory experiment and industrial production,although it is a classical technique discovered nearly 160 years ago. In particular, diastereomericsalt formation using a resolving agent (diastereomer method) has been well applied in various fieldssuch as the pharmaceutical, agrochemical, and liquid crystal industries. Despite these affluent reportedand patented examples, unfortunately no concrete theory to determine an optimum resolution condition hasbeen devised, and only empirical procedures seem to provide a unique path in process development. Inthis chapter, three novel approaches for optical resolution via diastereomeric salt formation are presented:(1) chiral purity improvement by crystal habit modification with a tailored chiral additive; (2) a newapproach for finding a suitable resolving agent based on the space filler concept; and (3) chiralitycontrol by dielectrically controlled resolution.

Molecular Mechanisms of Dielectrically Controlled Resolution (DCR).

It is widely believed that the chiral discrimination process is solely dependent on the stereochemistryof the relevant molecules. However, through systematic studies on several resolution systems with popularchiral selectors, we have discovered a new fact that triggers modification of this prevailing conceptof chiral resolution. The studies have demonstrated that one enantiomer of a chiral selector can recognizeboth enantiomers of a target molecule in different solvent systems with different dielectric constants.The phenomenon was termed dielectrically controlled resolution (DCR). Since DCR was observed in differentresolution systems and was not too specific to a particular system, DCR was expected to widely occurin various resolution systems. We have investigated the molecular mechanism underlying this interestingphenomenon based on X-ray analysis of the relevant diastereomeric salts. The disclosed mechanism clearlyindicates that a chiral selector can inherently recognize both enantiomers of a target moleculeand only the dielectric property of the solvent employed in the resolution process governs the selectionof the enantiomer.

Epimerization of diastereomeric alpha-amino nitriles to single stereoisomers in the solid state.

[reaction: see text] A diastereomeric mixture of the alpha-amino nitrile prepared by the Strecker reaction of benzaldehyde, (1S,2R)-1-aminoindan-2-ol, and cyanotrimethylsilane thermally epimerizes in the solid state to give a single diastereomer with an (S)-configuration at the alpha position to the nitrile moiety. This shows a sharp contrast to the reaction conducted in DMSO at room temperature, which gives a 1:1 mixture of (S)- and (R)-isomers. Several other alpha-amino nitriles also epimerize in the solid-state toward single diastereomers.

Molecular mechanism of dielectrically controlled optical resolution (DCR).

We have recently found the first example of dielectrically controlled optical resolution (DCR). By adjusting the dielectric constant of the solvent used in the resolution process, each optical isomer of (R,S)-alpha-amino-epsilon-caprolactam can be selectively obtained using N-tosyl-(S)-phenylalanine as a chiral selector. The molecular mechanism of DCR has been investigated by comparing the molecular and crystal structures of the optical selector, its target substrate and their diastereomeric salts. Strong hydrophobic interactions between the phenyl rings of the optical selector govern the molecular aggregation of the selectors and form a hydrophilic layer in which molecular recognition takes place. The recognition site in the hydrophilic layer can inherently identify both of the isomers. The dielectric constant of the solvent used in the discrimination process controls the intermolecular interaction which determines the isomer to be selected. The molecular mechanism of DCR disclosed in this study strongly suggests that DCR is not a specific but a general phenomenon. This method can be applicable to a large variety of optical resolution processes.