Page 79 - Chiral Separation Techniques

Chiral Separation Techniques: A Practical Approach, Second, completely revised and updated edition
Edited by G. Subramanian
Copyright © 2001 Wiley-VCH Verlag GmbH
ISBNs: 3-527-29875-4 (Hardcover); 3-527-60036-1 (Electronic)
3 Combinatorial Approaches to Recognition

of Chirality:

Preparation and Use of Materials for the
Separation of Enantiomers

˘
˘
Frantisek Svec, Dirk Wulff and Jean M. J. Fréchet

3.1 Introduction

The continuing trend to replace racemic drugs, agrochemicals, flavors, fragrances,
food additives, pheromones, and some other products with their single enantiomers
is driven by their increased efficiency, economic incentive to avoid the waste of the
inactive enantiomer, and regulatory action resulting from the awareness that indi-
vidual enantiomers have different interactions with biological systems. There are
several methods to obtain enantiomerically pure compounds. The most important
are: (i) syntheses based on chiral starting materials from natural sources such as
amino acids; (ii) enantioselective reactions; and (iii) separations of mixtures of enan-
tiomers using methods such as crystallization via diastereoisomers, enzymatic or
chemical kinetic resolution, and chromatographic separation [1–3].
Although very efficient, the broad application of the direct preparation is
restricted due to the limited number of pure starting enantiomers. The design of a
multistep process that includes asymmetric synthesis is cumbersome and the devel-
opment costs may be quite high. This approach is likely best suited for the multi-ton
scale production of “commodity” enantiomers such as the drugs ibuprofen,
naproxen, atenolol, and albuterol. However, even the best asymmetric syntheses do
not lead to products in an enantiomerically pure state (100 % enantiomeric excess).
Typically, the product is enriched to a certain degree with one enantiomer. Therefore,
an additional purification step may be needed to achieve the required enantiopurity.
The chromatographic methods that include gas and liquid chromatography, as
well as electrophoresis fit into the third group of methods designed for the separa-
tion of individual enantiomers from their mixtures. These techniques, characterized
by the use of chiral stationary phases (CSP) and chiral additives, respectively,
emerged more than three decades ago as valuable methods for analytical assays in
academic laboratories and clinical testing. Since chromatography can be used in vir-
tually any scale, it has also been used for preparative- and production-scale separa-
tions due to its high efficiency and ease of operation. For example, preparative liq-
uid chromatography implemented in the simulated moving bed (SMB) format
enables the isolation of sufficient quantities of pure chiral compounds to carry out
early pharmacological and toxicological studies providing both enantiomers for