ABSTRACT
Cinchona Alkaloid-Based Chiral Stationary Phases . . . . . . . . . . . . . . . . . . . . . . 4 1.3 Retention Mechanisms and Method Development . . . . . . . . . . . . . . . . . . . . . . . . 7
1.3.1 Retention Mechanism for Chiral Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 1.3.1.1 Enantioselective Anion Exchange. . . . . . . . . . . . . . . . . . . . . . . 7 1.3.1.2 Anion-Exchange Mechanism in PO and NP Modes . . . . 11 1.3.1.3 Hydroorganic Elution Mode: Superimposition of RP
or HILIC Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 1.3.2 Retention Mechanisms for Neutral/Basic Compounds . . . . . . . . . . . 15
1.4 Structural Modifications of Cinchonan-Type Selectors . . . . . . . . . . . . . . . . . . . 17 1.4.1 Effect of Carbamoylation and Pendant Carbamate Residue . . . . . . 18 1.4.2 Effect of C8/C9 Stereochemistry. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 1.4.3 Effect of 6′-Quinoline Substitution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 1.4.4 Other Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
1.5 Linker/Surface Bonding Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 1.6 Effects of Supports. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
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1.7 Chiral Recognition Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 1.7.1 Binding Strengths and Binding Thermodynamics . . . . . . . . . . . . . . . . 33
1.7.1.1 Binding Constants by Microcalorimetric and Spectroscopic Measurements . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
1.7.1.2 Measurement of Binding Constants by CE . . . . . . . . . . . . . 39 1.7.1.3 Binding Energetics by Chromatography . . . . . . . . . . . . . . . . 41 1.7.1.4 Estimation of Binding Strengths by Transfer NOE
Measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 1.7.2 Structure of SO-SA Complexes by Spectroscopic, X-Ray
Diffraction, and Molecular Modeling Investigations . . . . . . . . . . . . . 48 1.7.2.1 NMR Spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 1.7.2.2 FT-IR Spectroscopic Investigations . . . . . . . . . . . . . . . . . . . . . 53 1.7.2.3 Single-Crystal X-Ray Diffraction Analysis . . . . . . . . . . . . . 57 1.7.2.4 Computational Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
1.8 Chromatographic Applicability Spectrum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 1.8.1 Analysis of Amino Acids and Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . 66 1.8.2 Amino Sulfonic, Phosphonic, Phosphinic Acids . . . . . . . . . . . . . . . . . . 76 1.8.3 Peptide Stereoisomer Separations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 1.8.4 Enantiomer Separations of Miscellaneous Acids . . . . . . . . . . . . . . . . . 81
1.9 Implementation of Cinchona Alkaloid Selectors in Other Separation Methodologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 1.9.1 Supercritical Fluid Chromatography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 1.9.2 Capillary Electrophoresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 1.9.3 Capillary Electrochromatography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 1.9.4 Liquid-Solid Batch Extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 1.9.5 Liquid-Liquid Extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 1.9.6 Supported Liquid Membrane Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 1.9.7 Centrifugal Partition Chromatography . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
1.10 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Alphabetical List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Cinchona alkaloids that comprise the group of various natural basic chiral compounds including mainly quinine, quinidine, cinchonidine (CD), and cinchonine (CN) as well as their corresponding C9-epimers (Figure 1.1) have become important “ex chiral pool” materials for chiroscience and chiral technologies. They were first isolated in 1820 by the two scientists, Pelletier and Caventou, as antimalarial agents from the bark of Cinchona sp. Although a first stereoselective total synthesis of quinine was achieved recently for the first time by Stork et al. [1] and shortly thereafter also the first catalytic, stereoselective syntheses of quinine and quinidine [2] have been reported, they are still more cheaply obtained from the bark of various Cinchona sp., in particular, from that of Cinchona succirubra. Since a long time, organic chemists
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make use of these natural chiral compounds for fractionated crystallization of chiral acids via their diastereomeric salts [3], as chiral shift reagents in NMR spectroscopy [4-7], and not least as chiral catalysts in stereoselective synthesis concepts [8,9].
