Elucidation of the chiral recognition mechanism of cinchona alkaloid carbamate-type receptors for 3,5-dinitrobenzoyl amino acids.
A cinchona alkaloid having extraordinary chiral discriminatory powers (alpha = 32.6 for dinitrobenzoyl leucine) is developed as a chiral stationary phase (CSP) for chromatography. An explanation of how chiral discrimination takes place is presented. Using a soluble analogue of the CSP, we found that NMR spectrometry indicates that 1:1 complexes exist for both optical isomers interacting with the CSP, that the free base form of the CSP exists in an open/closed ratio of 35/65 but that the protonated, bound-state form is exclusively in the anti-open conformation, and that significant intermolecular NOEs exist for the more stable diastereomeric complex but not for the less stable complex. Stochastic molecular dynamics simulations were carried out in solvents of low and high dielectric. The chromatographic retention orders and free energy differences of analyte binding to CSP were reproduced computationally as were the observed intra- and intermolecular NOEs. Data from the simulation were used to evaluate the intermolecular forces responsible for analyte binding as well as to discern fragments of the CSP doing most of the work of holding the complexes together. The enantiodifferentiating forces and the parts of the CSP most responsible for chiral discrimination are described. Moments of distributions of key dihedral angles and distances between centroids were used to assess the relative rigidity of the competing diastereomeric complexes. Simultaneous multiple-contact ion-pairing, hydrogen bonding, and pi-stacking are possible for the longer retained enantiomer only. An X-ray crystallographic study of the more stable complex confirms the conclusions derived from chromatography, NMR spectroscopy, and molecular modeling.
Maier
Norbert M
NM
Institute of Analytical Chemistry, University of Vienna, Austria.
Schefzick
Sabine
S
Lombardo
G M
GM
Feliz
Miguel
M
Rissanen
Kari
K
Lindner
Wolfgang
W
Lipkowitz
Kenny B
KB
D002219:Carbamates / Q000737:chemistry*; D002930:Cinchona Alkaloids / Q000737:chemistry*; D004136:Dinitrobenzenes / Q000737:chemistry; D007930:Leucine / Q000031:analogs & derivatives* / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular; D017459:Receptors, Amino Acid / Q000737:chemistry*; D013237:Stereoisomerism; D013379:Substrate Specificity; D013816:Thermodynamics
D002219:Carbamates; D002930:Cinchona Alkaloids; D004136:Dinitrobenzenes; D017459:Receptors, Amino Acid; C465293:dinitrobenzoyl leucine; D007930:Leucine