Chromatography enantioselective

Chiral stationary phases were applied as a preparative tool for many years before their potential as a powerful technique for the analysis of chiral compounds was recognized. 

As early as 1904, Willstatter attempted to separate optical isomers on the optically active natural polymers wool and silk [10]. About 35 years later, the first partial chromatographic resolution of the enantiomers ofp-phenylene-bis-imino-cam-phor on lactose was achieved by Henderson and Rule [11], and a few years later by Lecoq for the enantiomers of ephedrine [12], and by Prelog and Wieland for the enantiomers ofTroeger s base [13]. 

However, the real potential of enantioselective chromatography for the preparative separation of optical isomers was definitely established in 1973 by Hesse and Hagel who introduced fully acetylated cellulose (triacetylcellulose) as a new efficient chiral CSP [14]. They successfully achieved the preparative separation of the enantiomers of various chiral compounds. For many years, triacetylcellulose was practically the only chiral stationary phase available for preparative separations and it has been used for the chromatographic resolution of a broad variety of chiral molecules [1-3, 15, 16]. 

A few years later, Blaschke designed purely synthetic chiral stationary phases obtained by emulsion polymerization of acrylamides prepared from amino acids [17]. These phases had been developed for preparative purposes and proved to be very efficient for the preparative resolution of various chiral drugs for which the enantiomers have been isolated for the first time. These earher applications include the separation of the enantiomers of the sadly well-known drug thalidomide (Fig. 6.2) [18], 

From the early 1980s, a growing number of analytical chiral columns became available and are now routinely used for the determination of the enantiomeric composition of mixtures of optical isomers from enantioselective syntheses, from biological investigations or from pharmacokinetic or toxicology studies. Some of these phases have also become extremely useful for enantioselective preparative separations [1-4, 16]. 

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Yu, Y-R and Wu, W-H., Simultaneous analysis of enantiomeric composition of amino acids and A -acetyl-amino acids by enantioselective chromatography. Chirality, 13, 231, 2001. 

Francotte, E.R. Enantioselective Chromatography for the Preparation of Drug Enantiomers, ISCD-15, Shizuoka, Japan, October 2003. 

An interesting extension of enantioselective chromatography on protein based CSPs in LC has been made15-17 using proteins to show qualitative and quantitative aspects of ligand-biopolymer interactions this includes chiral aspects. 

Colin, H., Ludemann-Hombourger, O. and Denet, F. (2005) Equipment for preparative and large size enantioselective chromatography, in Preparative Enantioselective Chromatography, 1st edn (ed. G. Cox), Wiley-Blackwell, Hoboken N), pp. 224-252. 

Francotte, E. (2001) Enantioselective chromatography as a powerful alternative for the preparation of drug enantiomers. J, Chromatogr. A 906, 379-397. 

Increased temperature usually improves loadability and solubility and decreases the viscosity of the mobile phase. Consequently, the production rate increases, provided that the selectivity of separation or stability of the separated compounds and stationary phases are not compromised. However, resolution in enantioselective chromatography often improves at lower temperatures. 

In recent years, enantioselective chromatography was extended to semipreparative separations and now simulated moving-bed technology (SMB) has become available for the resolution of some synthetic racemates in preparative scale. In the pharmaceutical industry this progress is of considerable interest with respect to enantiopure drug applications. 

Subsequently, Figadere and coworkers30 analyzed natural rir-solamin by enantioselective HPLC, and found it to be a 9 8 mixture of rir-solamin A (36) and cis-solamin B (37). Thus, natural ar-solamin was stereochemi-cally heterogeneous demonstrating that enantioselective chromatography is indeed a powerful technique in... 

At present, the resolution of racemates via dassical diastereomer crystallization as a method of chiral target production is somewhat hampered by a rapid development of other methods, mainly asymmetric synthesis, including biocatalysis [9] and enantioselective chromatography [11], Diastereomer crystallization remains, however, an important technique because of its two fundamental advantages, especially attradive for industry. First, process development (practical know-how and accessibility to wide libraries of the resolving agents) is usually fast and easy. Second, the cost is often low compared to other methods. 

Enantioselective chromatography and related techniques are based principally on the reversible formation of diastereomeric associates between both enantiomers of the chiral analyte (selectand, SA) and the chiral selector (SO) that is usually covalently immobilized or coated on a solid support (Figure 13.9). 

A significant breakthrough in cinchona-based enantioselective chromatography came with the demonstration by Lindner et al. in 1996 that immobilized quinine or quinidine 9-O-carbamates under polar organic or reversed phase condition efficiently resolved a number of acidic racemates, with opposite elution orders compared to unmodified QN or QD CSPs [44, 61]. Cinchona 9-O-carbamates contain a new functionality that can serve as a binding site of double character, that is, an H-bond donor-acceptor and, depending on the N-substituent, it may also provide a steric barrier or possibly a source of %-% interaction (Figure 13.11). 

The successful application of enantioselective chromatography as a valuable approach to the separation of optical isomers on a preparative and even production scale has attracted the attention of most pharmaceutical companies. 

I 6 Isolation and Production of Optically Pure Drugs by Enantioselective Chromatography... 

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