Chiral recognition by enantioselective liquid chromatography: Mechanisms and modern chiral stationary phases

Efficient Separation of Enantiomers Using Stereoregular Chiral Polymers

Chiral separations: a review of current topics and trends.

Chirality is a ubiquitous feature in living systems. Today, it is widely recognized that many biologically interesting compounds, such as drugs, agrochemicals, food additives, and fragrances, are chiral and their physiological properties usually rely on their chirality due to the extremely high chiral discrimination ability of enzymes and receptors.1-6 Particularly, the different pharmacological effects between enantiomers are ultimately an important concern in the pharmaceutical field in which only one enantiomer of a chiral drug often exhibits the desirable therapeutic activity, while the other shows an antagonistic function, side effects, or even toxic effects.7-14 During the late 1950s and early 1960s, a racemate of N-phthalylglutamic acid imide, which is a sedative and hypnotic drug known as thalidomide, was administrated to pregnant women and caused the birth of approximately 10 000 babies with malformations. Later, Blaschke pointed out that this teratogenic effect was attributed to the S-(-)isomer.15 Even though the administration of the pure R-(+)isomer could not halt the disaster because thalidomide is unstable in the body and easily undergoes racemization,16-18 this tragedy undoubtedly brought a profound movement in the drug administration and industries. In 1992, the U.S. Food and Drug Administration issued a specific guideline for the production of new chiral drugs,19 which demanded a systematic investigation of the biological behavior of their individual enantiomers and significantly encouraged the development of single enantiomer drugs.20-22 Today, most of the best-selling drugs around the world are administered as single enantiomers with the desired therapeutic activity,23 and the annual sales of single enantiomer drugs are expected to exceed 200 billion dollars in 2008. Furthermore, the preparation of single enantiomers has also become important in the fields of functional materials, such as ferroelectric liquid crystals and organic nonlinear optical molecules.24-26 Based on this historical background, substantial efforts have been undertaken to develop practical techniques for the preparation of enantiomers with a high enantiomeric excess (ee). In general, two approaches are utilized for this objective, asymmetric synthesis and chiral separation. Asymmetric synthesis using chiral sources, such as chiral pools, chiral auxiliaries, asymmetric catalysts, and enzymes, has significantly progressed over the last few decades.27-41 Although the large-scale preparation of enantiomers can be economically attained using this approach, the products do not always show a high ee, and therefore, a further purification step may be inevitable. Additionally, nature produces only one of the enantiomers as a chiral source in most cases. This means that if both enantiomers of the target compounds are required, at least two kinds of chiral sources are necessary for each enantiomer. However, it is sometimes difficult to obtain both of them. On the other hand, the chiral separation approach can easily provide both enantiomers with a high ee. Since Pasteur first isolated two enantiomers of sodium ammonium tartrate using a magnifying glass and a pair of tweezers in 1848,42,43 the innovation of chiral separation techniques has attracted great interest. Basically, chiral separations44 are carried out by (i) crystallization,45-47 (ii) enzymatic kinetic resolution,48-50 and (iii) chromatographic separation.51-53 Specifically, direct chiral separation using chiral stationary phases (CSPs) for high-performance liquid chromatography (HPLC) has significantly evolved during the past few decades and is recognized as the most popular and reliable tool for both the analysis of enantiomer compositions and the preparation of pure enantiomers.51-64 Chiral separations can * To whom correspondence should be addressed. Mailing address: EcoTopia Science Institute, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 4648603, Japan. Phone: +81-52-789-4600. Fax: +81-52-789-3188. E-mail: okamoto@apchem.nagoya-u.ac.jp. † Nagoya University. ‡ Harbin Engineering University. Chem. Rev. 2009, 109, 6077–6101 6077

Structure control of polysaccharide derivatives for efficient separation of enantiomers by chromatography

Recent applications in chiral high performance liquid chromatography: a review.

Cellulose tris(3,5-dichlorophenylcarbamate) immobilised on silica: a novel chiral stationary phase for resolution of enantiomers.

Protein-based chiral stationary phases, in particular α 1 -acid glycoprotein, are chromatographic materials with a very broad application range. The chiral recognition ability of this selector allows the resolution of more than 90% of the molecules tested. A step-by-step description of the screening approach that we have developed is described in this article with two objectives in mind: obtaining a high success rate with a straightforward methodology that can be generally applied and allowing LC-MS compatibility. Second, the screening strategy is required to take into account the main functional nature of the racemic compound to be resolved (neutral, acidic or basic) for method optimisation step, but should be independent of other structural features, in order to allow the routine application of screening sequences and the application to the largest number of samples.

Takashi Michishita

Papers

Cellulose tris(3,5-dichlorophenylcarbamate) immobilised on silica: a novel chiral stationary phase for resolution of enantiomers.

New approaches of LC‐MS compatible method development on α1‐acid glycoprotein‐based stationary phase for resolution of enantiomers by HPLC