Page 27 - Chiral Separation Techniques

2 1 Techniques in preparative chiral separations

ever, not all preparative techniques are useful at the same scale; some are more eas-
ily adapted to the manipulation of large amounts of material, while others may only
be applicable to the isolation of few milligrams, or even less, though this may be
enough for given purposes.
In this chapter a number of the preparative techniques used in the resolution of
enantiomers is presented. Some of these techniques will be developed more fully in
following chapters.

1.2 Crystallization Techniques

Although crystallization is used routinely to separate solid compounds from impuri-
ties and by-products coming from secondary reactions in their synthesis, it may also
be applied in the isolation of individual enantiomers from a racemic or an enan-
tiomerically enriched sample [1–3]. Indeed, until the development of chiral chro-
matographic techniques, crystallization was one of the few existing ways to resolve
enantiomers. Although crystallization is a very powerful technique for preparative
purposes, few industrial applications have been reported [3] for reasons of confi-
dentiality. Moreover, the technique is far from being generally applicable, and thus
only those compounds which behave as conglomerates (different crystals for both
enantiomers) can be resolved from their equimolecular enantiomeric mixtures, either
by seeding their solutions with crystals of one enantiomer (preferential crystalliza-
tion) [4–6], or by using a chiral environment to carry out the crystallization. The lim-
itation of the preferential crystallization is, therefore, the availability of crystals of
the pure enantiomer.
A chiral environment can be produced by using a chiral solvent in the crystalliza-
tion, but most of these are organic and therefore not useful for highly polar com-
pounds. Therefore, a chiral co-solute is often used [7–9]. Applying this methodol-
ogy, d,l-threonine was resolved into its enantiomers using small amounts of L-serine
or 4-(R)-hydroxy-L-proline [7]. Moreover, an inhibitory effect on the crystallization
of D-glutamic acid from its racemic mixture of some D-amino acids, such as lysine,
histidine or arginine has been described, while their L-counterparts inhibit crystal-
lization of the L-enantiomer [8].
Unfortunately, the occurrence of conglomerates in nature is not common. On
occasion, the probability of obtaining a conglomerate can be increased by trans-
forming the considered compound into a salt, when possible. Racemic compounds
(both enantiomers in the same lattice) are more frequently encountered in nature.
Therefore, it is useful to know which is the behavior of the considered product, tak-
ing into account that it can change depending on the temperature of crystallization.
Several methods exist to determine such a point easily [3]. Racemic compounds may
be enriched by crystallization of a nonracemic mixture, in which case the success
and yield of the enrichment depends (among others) on the composition of the orig-
inal mixture.