Enantioselective chiral stationary phase preparation

Alcaro, S. et al., Enantioselective semi-preparative HPLC of two 2-arylpropionic acids on glycopeptides containing chiral stationary phases, Tetrahedron Asymmetry, 13, 69, 2002. 

The preparative-scale separation of enantiomers on chiral stationary phases (CSPs) by GC cannot match the overwhelming success achieved in the realm of liquid chromatography (LC) (Francotte, 1994, 1996 and 2001). Modern commercial instrumentation for preparative-scale GC is not readily available. In contrast to LC, separation factors a in enantioselective GC are usually small (a = 1.01 - 1.20). This is beneficial for fast analytical separations but detrimental to preparative-scale separations. Only in rare instances are large chiral separation factors (a > 1.5) observed in enantioselective GC. Only in one instance, a separation factor as high as a = 10 was detected in enantioselective GC for a chiral fluorinated diether and a modified 7-cyclodextrin (Schurig and Schmidt, 2003) (vide supra). 

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]. 

Sellergren, B. Molecular imprinting by noncovalent interactions—enantioselectivity and binding-capacity of polymers prepared tmder conditions favoring the formation of template complexes. Makromolek. Chem.—Macromol. Chem. Phys. 1989, 190, 2703-2711. Kempe, M. Mosbach, K. Directed resolution of naproxen on a non-covalently molecularly imprinted chiral stationary phase. J. Chromatogr. 1994, 664, 276-279. 

After successful application of enantioselective GC to the analysis of enantiomeric composition of monoterpenoids in many essential oils (e.g., Werkhoff et al., 1993 Bicchi et al., 1995 and references cited therein), the studies have been extended to the sesquiterpene fraction. Standard mixtures of known enantiomeric composition were prepared by isolation of individual enantiomers from numerous essential oils by preparative GC and by preparative enantioselective GC. A gas chromatographic separation of a series of isolated or prepared sesquiterpene hydrocarbon enantiomers, showing the separation of 12 commonly occurring sesquiterpene hydrocarbons on a 2,6-methyl-3-pentyl-P-cyclodextrin capillary column has been presented by Konig et al. (1995). Further investigations on sesquiterpenes have been published by Konig et al. (1994). However, due to the complexity of the sesquiterpene pattern in many essential oils, it is often impossible to perform directly an enantioselective analysis by coinjection with standard samples on a capillary column with a chiral stationary phase alone. Therefore, in many cases two-dimensional GC had to be performed. 

In the first preparations of 128 and 129, 191 reacted with TMSNCO to give adducts 192, which were transformed to cyclic imines 193 upon dehydratation. Reaction of 193 with lithium cyclopropylacetylenide gave racemic 128 and 129, which were subjected to chiral stationary phase HPLC to isolate 128 and 129 as pure enantiomers [136, 137]. Several improvements were reported for this synthetic scheme. In particular, diastereoselective additions of lithium cyclopropyl acetylenide to the derivatives of 193 containing residues of a-phenylethyl amine or campheic acid were developed [154,155]. Moreover, an enantioselective modification of this method employing amino alcohol 194 as an asymmetric catalyst was discovered [156, 157]. Another enantioselective method involved reaction of the derivatives of 193 and cyclopropyl acetylene itself, catalysed by amino alcohol derivatives (e.g. 195) and Zn(OTf)2 [158]. 

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