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September 2009
conditions. These classes of investigated Cinchona alkaloids covered in this effort included ester, carbamate, ether, amides, sulfonamide and hydrazide derivatives [2]
various types of Cinchona hetero- and homodimers joined by different types of bifunctional linkers [9, 10]
, and . Fromthis large-scale
combinatorial effort,O9-carbamate derivatives of quinine and quinidine emerged as particularly efficient anion exchange-type selectors [11]
. Further structure-based
optimization studies within this class led to the development of tert-butylcarbamoyl quinine and quinidine as chiral stationary phases, providing an excellent compromise between broad applicability and high enantioselectivity [12]
. These particular chiral
stationary phases were found to very efficiently separate different classes of chiral compounds, includingN-aryl,N-acyl andN-carbamoyl
amino acids of the α-, β- andψ-type, structurally related phosphoric, phosphinic and sulfonic acids, a large variety ofN-protected peptides, and a broad assortment of other chiral acidic compounds of pharmaceutical and biological relevance [2]
. A detailed
discussion of these applications is beyond the scope of this account, but is comprehensively covered in [2]
. Chiral stationary phases
incorporating tert-butylcarbamoyl quinine and tert-butylcarbamoyl quinidine have been commercialized under the trade names CHIRALPAKQNAX andCHIRALPAKQDAX [13]
2.1. Chiral RecognitionMechanism
Cinchona carbamate-type selectorswere found to produce exceptionally high levels of chiral recognition forN-acylated amino acids bearing pi-acidic substituents, e.g. aCSP based on tert- butylcarbamoyl quinine gave forN-3,5- dinitrobenzoyl amino acids in buffered hydro-organicmobile phase enantioselectivities
up toα = 15. This exceptionally favorable selector-analyte combinationwas subsequently used as a suitablemodel systemfor the elucidation ofmolecular recognition mechanisms governing enantioselective binding of acidic analytes to cinchona carbamate-type selectors. This task involved a multidisciplinary approach, utilizingmodern solution-phase and solid phase spectroscopic tools (IR [14,15]
,H-NMR [16-18] , UV andCD[19] , VCD
[20]),molecularmodeling approaches (molecular dynamics simulations [16-18] theory calculations [15]
(variable temperature chromatography [21] isothermal titration calorimetry [22]
. The
), thermodynamic studies ,
) and solid
phase structure elucidation techniques, such as X-ray crystal structure analysis [12, 16-18]
combined experimental evidence emerging fromthese studies provided a very detailed picture of the chiral recognitionmechanism. The crucial structural requirements and intermolecular interaction forces governing
and density functional
Figure 2. X-ray crystal structures of selector–selectand ion-pair complexes of (left) O-9-(β-chloro-tert butylcarbamoyl)quinine with N-(3,5-dinitrobenzoyl)-(S)-leucine, and (right) the pseudoenantiomeric complex of O-9-(β-chloro-tert- butylcarbamoyl)quinidine with N-(3,5-dinitrobenzoyl)-(R)-leucine. Note the mirror imiage-like relationship between the solid- phase structures of ion-pair. Adapted from [2] with permission.
these highly efficient enantioselective binding events are clearly evident fromsolid phase structures of themore stable diastereomeric ion-pair complex of appropriatemodel systems. Figure 1 exemplifies these important structural and functional features based upon the X-ray crystal structure of theO9-tert- butylcarbamoyl quininewith (S)-N-3-5- dinitrobenzoyl leucine.
It becomes evident that the Cinchona carbamate selector forms a tight ion pair-type complex with the acidic analyte, with the latter being situated within a stereochemically well- defined “binding pocket” and stabilized by multiple noncovalent intermolecular interactions. Specifically, complex stabilization is achieved by a charge-supported hydrogen bond existing between the protonated quinuclidine nitrogen at the selector and the deprotonated carboxylic group of the acidic analyte; an amide-type hydrogen bond established between the carbamate carbonyl group of the selector and the amide group of
the analyte; face-to-face pi-pi stacking interactions occurring between the aromatic portions of the selector and selectand; and finally, subtle steric interactions between the bulky side chains of the selector and selectand. The solid phase structure also provides compelling evidence for the crucial contributions of theO9-carbamate group of the selector to chiral recognition event, fulfilling a dual function in providing an important stabilizing intermolecular interaction and as an essential structural element to the formation of a spatially well-defined binding site. The high level of enantioselectivity seen with this selector analyte systemis the consequence of a steric exclusion process, with themismatched enantiomer being evidently incapable of being accommodated within the selector binding site and experiencing stabilizing secondary interactions.
An X-ray crystal structure obtained for quinidine tert-butylcarbamate/(R)-N-3,5- dinitrobenzoyl leucinemodel systemwas
Figure 1. X-ray crystal structure of the more stable selector–selectand ion-pair complex of O-9-( -chloro-tert- butylcarbamoyl)quinine with N-(3,5-dinitrobenzoyl)-(S)-leucine. The intermolecular interactions contributing simultaneous and in co-operative fashion to the enantioselective binding process are indicated.
.
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