Ligand-exchange chromatography chiral separations

Chiral ligand-exchange chromatography (CLEC) ° separates enantiomers by the formation of diastereomeric metal complexes. In a first instance the technique was mainly used for the separation of amino acids. Impressive results of the first separations gave rise to intensive investigation in the field and numerous publications appeared in the literature, which have been reviewed. 

Chemically modified layers CHIRalplate Enantiomer separation based on ligand exchange chromatography Chiral amino acids, a-hydroxy-carboxyhc acids and other compounds which can form chelate complexes with Cu(II) ions... 

Achiral Columns Together with Chiral Mobile Phases. Ligand-exchange chromatography for chiral separation has been introduced (59), and has been appHed to the resolution of several a-amino acids. Prior derivatization is sometimes necessary. Preparative resolutions are possible, but the method is sensitive to small variations in the mobile phase and sometimes gives poor reproducibiUty. 

TABLE 4 Examples of Chiral Separations in Chiral Ligand-Exchange Chromatography... 

Based on preliminary results from Helfferich130, further developments by Davankov and co-workers5 131 133 turned the principle of chelation into a powerful chiral chromatographic method by the introduction of chiral-complex-forming synlhetie resins. The technique is based on the reversible chelate complex formation of the chiral selector and the selectand (analyte) molecules with transient metal cations. The technical term is chiral ligand exchange chromatography (CLEC) reliable and complete LC separation of enantiomers of free a-amino acids and other classes of chiral compounds was made as early as 1968 131. 

Chiral ligand-exchange chromatography resolves enantiomers on the basis of their ability to complex with transition metal ions, such as copper, zinc, and cadmium, as illustrated by the separation of amino acid racemates using copper102 (Fig. 2.21). The principle of exchange is similar to that... 

Ligand exchange chromatography is a very powerful method for separating enantiomers. However, it is limited to enantiomeric compounds that are able to undergo metal complexes with the chiral stationary phase such as amino acids, amino acid derivatives, and amino alcohols. 

In separation science, ligand-exchange chromatography indeed exploits the rapid and reversible formation of metal complexes to separate compounds, which can donate electrons and coordinate to complexed metal ions immobilised on a solid support [11]. Retention of a given species is directly related to the stability of the mixed ligand complex it forms with the immobilised metal complex. Utilisation of this principle for the separation of chiral molecules, as well as large biological macromolecules such as proteins, has been successfully demonstrated. 

Chiral ligand-exchange chromatography is based on the formation of diastereomeric ternary complexes that involve a transition metal ion (M), usually copper II a single enantiomer of a chiral molecule (L), usually an amino acid and the eitantiomers of the racemic solute R and S). The diastereomeric mixed chelate complexes formed in this system are represented by the formulas L-M-R and L-M-S. When these complexes have different stabilities, the less stable complex is eluted first, and the enantiomeric solutes are separated. 

Chiral separation using ligand-exchange chromatography involves the reversible complexation of metal ions and chiral complexing agents. The central ion, usually or forms a bis complex with bidentates ligands. 

The most important technique for enantiomeric separation in TLC is chiral ligand-exchange chromatography (LEC). LEC is based on the copper(II) complex formation of a chiral selector and the respective optical antipodes. Differences in the retention of the enantiomers are caused by dissimilar stabilities of their diastereomeric metal complexes. The requirement of sufficient stability of the ternary complex involves five-membered ring formation, and compounds such as a-amino and a-hydroxy-acids are the most suitable. 

Chiral separation of racemic drugs is required by the pharmaceutical industry because different optical forms of the drugs often play different roles in their pharmacological action, metabohsm, and toxicity. Chiral ligand exchange chromatography plays an important role in this respect. 

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