MICHEL S. LEEMAN
Symeres, Groningen, The Netherlands

Abstract

Isolation of enantiomerically pure materials from the corresponding racemates is an ever-challenging endeavour. Many techniques have been developed over the years to increase the efficiency and improve the success rate. The isolated yield is limited to the maximum amount of enantiomer in a racemate, namely 50%. Using (in situ) racemization, the yield can be boosted to a theoretical 100%. This article provides contemporary resolution techniques that facilitate the isolation of the desired enantiomer in the most efficient manner via crystallization.

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 e ...