Contemporary chiral resolutions

INTRODUCTION
As most molecules in biology are chiral, the handedness of chiral drugs is often very important. Where one enantiomer can be a potent drug with little side-effects, the other enantiomer can be toxic. Therefore, the separation of enantiomers from a racemic mixture remains a topic of interest. Already in 1848, the French scientist Louis Pasteur performed the first resolution via crystal picking of a conglomerate forming phase of a tartaric acid salt. A few years later he performed the first resolution via diastereomeric salt formation, later coined as a classical resolution (1).
Since Pasteur’s discovery, the development of resolution approaches has not ground to a halt but inspired a large influx of ideas; from Pope-Peachey (2) to Dutch Resolution (3) and from preferential crystallization (4) to Viedma Ripening (5).
In this paper some practical examples are shown together with a less-known enantiomer self-disproportionation technique based on density differences (6).

CRYSTALLIZATION INDUCED DIASTEREOMERIC TRANSFORMATION
Enantiomers have the same physical properties in an achiral environment. Formation of diastereomeric salts from the racemate with an enantiomerically pure resolving agent gives a solubility difference between the diastereomeric pair. This so-called classical resolution is the most used technique for the separation of enantiomers on scale. Without racemization, the yield is limited to 50%, although only in rare occasions is the isolated yield greater than 40%. However, if the substrate can be racemized, preferably in solution during the resolution, the isolated yield of the desired enantiomer can reach the 100% limit. Such a dynamic resolution is also called a Crystallization Induced Diastereomeric Transformation (CIDT).