Amino acids chiral phases

The first chiral phases introduced for gas chromatography were either amino acid esters, dipeptide, diamide or carbonyl-bis(amino acid ester) phases [721,724,756-758]. In general, these phases exhitdted poor thermal stability and are infrequently used today. Real interest and progress in chiral separations resulted from the preparation of diamide phases grafted onto a polysiloxane backbone. These phases were thermally stable and could be used to prepare efficient open tubular columns [734,756,758-762]. These phases are prepared from commercially available poly(cyano-propylmethyldimethylsiloxanes) or poly (cyanopropylmethylphenyl-... 

Such cases can be encountered in the case of thin-layer chromatographic separation of amino acids, using copper complexes of long chain amino acids as chiral additives via a ligand exchange approach. The copper complexes of alkyl amino acid chiral additives are so strongly adsorbed on the RP stationary phase that they act as a chiral stationary phase [154-156]. 

Maruoka K, Ooi T. Enantioselective amino acid synthesis by chiral phase-transfer catalysts. Chem. Rev. 2003 103 3013-3028. O Donnell MJ. The enantioselective synthesis of a-amino acids by phase-transfer catalysis with achiral Schiff base esters. Acc. Chem. Res. 2004 37 506-517. 

Blacklock,T. J. Shuman, R. F. Butcher, J. W Shearin,W. E.,Jr. Budavari, J. Grenda,V., Synthesis of Semisynthetic Dipeptides Using N-Carboxyanhydrides and Chiral Induction on Raney Nickel. A Method Practical for Large Scale. J. Org. Chem. 1987, 53, 836 Pradhan, A. A. Vera, J. H., Effect of acids and bases on the solubility of amino acids. Fluid Phase Equilibria 1998, 152, 121. 

The model chiral phases, iV-(tert-butylaminocarbonyl)-(5 )-valylaminobutane (Phase 1) and (J )-l-(a-naphthyl)ethylaminocarbonyl-glycylaminobutane (Phase 2) are shown in Figure 8.1. Phase 1 was used for the enantioseparation of N-acetylamino acid methylesters and [R]- and (5)-4-nitrobenzoyl amino acids, but Phase 2 could not separate these enantiomers. The enantiomer selectivities of N-(5 )-l-(a-naphthyl)ethylaminocarbonyl-(5)-valylaminobutane (Phase 3), N-(5 )-l-(a-naphthyl)ethylaminocarbonyl-(P)-valylaminobutane (Phase 4), N-[R]-1-(oc-naphthyl)ethylaminocarbonyl-(R)-valylaminobutane (Phase 5), and N-[R)-l- a-naphthyl)ethylaminocarbonyl-(5 )-valylaminobutane (Phase 6), which all have two chiral centers, were examined by computational chemical analysis. The structures of model Phases 3-6 are also shown in Figure 8.1. 

As mentioned above, SAMs are organic assemblies formed by the adsorption of molecules from solution or the gas phase onto the surface of solids. If the adsorbed molecules are chiral, the self assembled monolayer is also rendered chiral. The chirality of the molecule can be distributed within the monolayer interior or located at the terminus of the molecule. However, the chirality is only expressed when the chiral constituent is exposed at the monolayer surface. Chiral SAMs are used in chiral systems. The SAMs can be used to specifically interact with chiral species, such as proteins or amino acids. Chiral SAMs have been used in enantioselective crystallization. In this case, a racemic solution of a chiral molecule is crystallized on a chiral SAM. The chiral SAM serves as a nucleating surface for one of the enantiomers, thereby increasing its crystallization on the SAM. Thus, enantioselective crystallization is achieved. 

Ilisz I, Berkecz R, Forro E, Fulop F, Armstrong DW, Peter A (2009) The Role of tt-acidic and 7t-basic chiral stationary phases in the high-performance liquid chromatographic enantioseparation of unusual P-amino acids. Chirality 21 339-348... 

Mixing of an appropriate chiral selector with adsorbent, for example, silica gel during chromatographic plate impregnation, results in the formation of two diastereomers L-amino acid-chiral selector and D-amino acid-chiral selector molecules. It is known that two enantiomers have the same physicochemical properties in achiral environment but not diastereomers. Two diastereomers of given amino acids have different properties (solubility, diastereomeric complex stability, etc.), so can be separated on achiral, conventional phases. 

Chiral stationary phases in tic have been primarily limited to phases based on normal or microcrystalline cellulose (44,45), triacetylceUulose sorbents or siHca-based sorbents that have been chemically modified (46) or physically coated to incorporate chiral selectors such as amino acids (47,48) or macrocyclic antibiotics (49) into the stationary phase. 

Proteias, amino acids bonded through peptide linkages to form macromolecular biopolymers, used as chiral stationary phases for hplc iaclude bovine and human semm albumin, a -acid glycoproteia, ovomucoid, avidin, and ceUobiohydrolase. The bovine semm albumin column is marketed under the name Resolvosil and can be obtained from Phenomenex. The human semm albumin column can be obtained from Alltech Associates, Advanced Separation Technologies, Inc., and J. T. Baker. The a -acid glycoproteia and ceUobiohydrolase can be obtained from Advanced Separation Technologies, Inc. or J. T. Baker, Inc. 

Diamide Chiral Separations. The first chiral stationary phase for gas chromatography was reported by GH-Av and co-workers in 1966 (113) and was based on A/-trifluoroacetyl (A/-TFA) L-isoleucine lauryl ester coated on an inert packing material. It was used to resolve the tritiuoroacetylated derivatives of amino acids. Related chiral selectors used by other workers included -dodecanoyl-L-valine-/-butylamide and... 

Among various types of chiral stationary phases, the host-guest type of chiral crown ether is able to separate most amino acids completely (58). 

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. 

Licjuid Crystals. Ferroelectric Hquid crystals have been appHed to LCD (Uquid crystal display) because of their quick response (239). Ferroelectric Hquid crystals have chiral components in their molecules, some of which are derived from amino acids (240). Concentrated solutions (10—30%) of a-helix poly(amino acid)s show a lyotropic cholesteric Hquid crystalline phase, and poly(glutamic acid ester) films display a thermotropic phase (241). Their practical appHcations have not been deterrnined. 

The first partial chiral resolution reported in CCC dates from 1982 [120]. The separation of the two enantiomers of norephedrine was partially achieved, in almost 4 days, using (/ ,/ )-di-5-nonyltartrate as a chiral selector in the organic stationary phase. In 1984, the complete resolution of d,l-isoleucine was described, with N-dodecyl-L-proline as a selector in a two-phase buffered n-butanol/water system containing a copper (II) salt, in approximately 2 days [121]. A few partial resolutions of amino acids and dmg enantiomers with proteic selectors were also published [122, 123]. 

Early examples of enantioselective extractions are the resolution of a-aminoalco-hol salts, such as norephedrine, with lipophilic anions (hexafluorophosphate ion) [184-186] by partition between aqueous and lipophilic phases containing esters of tartaric acid [184-188]. Alkyl derivatives of proline and hydroxyproline with cupric ions showed chiral discrimination abilities for the resolution of neutral amino acid enantiomers in n-butanol/water systems [121, 178, 189-192]. On the other hand, chiral crown ethers are classical selectors utilized for enantioseparations, due to their interesting recognition abilities [171, 178]. However, the large number of steps often required for their synthesis [182] and, consequently, their cost as well as their limited loadability makes them not very suitable for preparative purposes. Examples of ligand-exchange [193] or anion-exchange selectors [183] able to discriminate amino acid derivatives have also been described. 

Small chiral molecules. These CSPs were introduced by Pirkle about two decades ago [31, 32]. The original brush -phases included selectors that contained a chiral amino acid moiety carrying aromatic 7t-electron acceptor or tt-electron donor functionality attached to porous silica beads. In addition to the amino acids, a large variety of other chiral scaffolds such as 1,2-disubstituted cyclohexanes [33] and cinchona alkaloids [34] have also been used for the preparation of various brush CSPs. 

The mixture of deprotected amino acid derivatives in solution was then immobilized onto a polymeric solid support, typically activated 5-)xm macroporous poly(hydroxyethyl methacrylate-co-ethylene dimethacrylate) beads, to afford the chiral stationary phases with a multiplicity of selectors. Although the use of columns... 

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