Quantitative structure-enantioselectivity

Booth, T.D. and Wainer, I.W. (1996a). Investigation of the Enantioselective Separations of alpha-alkylarylcarboxylic Acids on an Amylose tris(3,5-dimethylphenylcarbamate) Chiral Stationary Phase Using Quantitative Structure-Enantioselective Retention Relationships. Identification of a Conformationally Driven Chiral Recognition Mechanism. J.Chromat., 737A, 157-169. 

Kaliszan, R., Noctor, T.A. and Wainer, I.W. (1992b). Quantitative Structure-Enantioselective Retention Relationships for the Chromatography of 1,4 Benzodiazepines on a Human Serum Albumin Based HPLC Chiral Stationary Phase An Approach to the Computational Prediction of Retention and Enantioselectivity. Chromatographia, 33,546-550. 

Kaliszan, R Noctor, TA. and Wainer, I.W. (1992) Quantitative structure-enantioselective retention relationships for the chromatography of 1,4-benzodiazepines on a human serum albumin based HPLC chiral stationary phase an approach to the computational prediction of retention and enantioselectivity. Chromatographia, 33, 546-550. 

Suzuki, T, Timofei, S., luoras, B.E., Uray, G., Verdino, P. and Fabian, W.M.F. (2001a) Quantitative structure-enantioselective retention relationships for chromatographic separation of arylalkylcarbinols on Pirkle type chiral stationary phases./. Chromat., 922, 13-23. 

Type V CSPs are protein phases. Because of the well established chemo- and stereospecificity of enzymes, a large number of experimentalists have adapted proteins in one form or another as stationary phases for chiral separations. The intermolecular forces responsible for analyte binding to these biopolymers are the same as for most other CSPs but the size and complexity of proteins makes them difficult to study computationally. One would think that with approximately 400 entries in the Brookhaven Protein Databank to select from, separation scientists would have used one of these proteins as a chiral selector and then use those atomic coordinates to carry out molecular modeling studies. Only one example has appeared in the literature where information from the PDB has been used to serve as a beginning point for molecular modeling of a protein CSP. In all other examples the CSP is viewed as having an unknown structure and Quantitative Structure-Enantioselective Retention Relationships (QSERRs) have been carried out. 

U. Norinder and J. Hermansson, Chiral separation of N-aminoalkylsuccinamides on an al-acid glycoprotein column A quantitative structure-enantioselectivity relationship study. Chirality, 3(1991) 422. 

The quantitative structure enantioselectivity approach will consider that the overall A(AG) energy for the interactions of the enantiomeric pair with the CSP in a particular mobile phase is the sum of four independent A(AG)j contributions coming from the four different substituents attached to the asymmetric carbon ... 

Aires-de-Sousa and Gasteiger used four regression techniques [multiple linear regression, perceptron (a MLF ANN with no hidden layer), MLF ANN, and v-SVM regression] to obtain a quantitative structure-enantioselectivity relationship (QSER). The QSER models the enantiomeric excess in the addition of diethyl zinc to benzaldehyde in the presence of a racemic catalyst and an enan-tiopure chiral additive. A total of 65 reactions constituted the dataset. Using 11 chiral codes as model input and a three-fold cross-validation procedure, a neural network with two hidden neurons gave the best predictions ANN 2 hidden neurons, R pred = 0.923 ANN 1 hidden neurons, R pred = 0.906 perceptron, R pred = 0.845 MLR, R p .d = 0.776 and v-SVM regression with RBF kernel, R pred = 0.748. 

Funar-Timofei, S., Suzuki, T, Paier, J.A., Steinreiber, A., Faber, K. and Fabian, W.M.F. (2003) Quantitative structure-activity relationships for the enantioselectivity of oxirane ring-opening catalyzed by epoxide hydrolases. J. Chem. Inf. Comput. Sci., 43, 934-940. 

A series of mono- and dialkylated, chiral 1,2-amino-phosphinamide ligands (752) have been successfully applied in the chiral phosphinamide-Zn(ii) catalysed asymmetric Henry reaction between benzaldehyde and nitromethane (Scheme 210). The effects of the N-substituent sizes of chiral ligands (752) on the enantioselectivities in this reaction have been correlated using a predictive quantitative structure-activity relationship (QSAR) mathematical model. A quantitative correlation model has been also established based on subtractive Sterimol parameters. Ligand optimisation based on the QSAR model led to chiral 1,2-amino-phosphinamide ligand (752a), which produced (R)-p-nitroalcohol (753) in excellent yield (99%) and enantioselectivity (92% ee). ... 

In chemoinformatics, chirality is taken into account by many structural representation schemes, in order that a specific enantiomer can be imambiguously specified. A challenging task is the automatic detection of chirality in a molecular structure, which was solved for the case of chiral atoms, but not for chirality arising from other stereogenic units. Beyond labeling, quantitative descriptors of molecular chirahty are required for the prediction of chiral properties such as biological activity or enantioselectivity in chemical reactions) from the molecular structure. These descriptors, and how chemoinformatics can be used to automatically detect, specify, and represent molecular chirality, are described in more detail in Chapter 8. 

The enantioselective catalytic 1,3-dipolar cycloaddition of linear or cyclic nitrones to enals was accomplished using the half-sandwich rhodium(III) complex S, Rc)-[(ri -C5Me5)Rh (/ )-Prophos (H20)](SbF6)2 as catalyst precursor [33, 34]. At —25°C, quantitative conversions to the cycloadducts, with up to 95% ee, were achieved (Scheme 10). The intermediate with the dipolarophile coordinated to the rhodium has been isolated and completely characterized, including the X-ray determination of its molecular structure [33, 34]. 

Ruthenium amido complexes (137) effected asymmetric Michael addition of /S-keto esters (134) to cyclopent-2-en-l-one (135) to give quantitatively the corresponding Michael adducts (136) with excellent enantioselectivity (<97% ee), although with a 1 1 diastereoisomer ratio (Scheme 8). The stereochemical outcome of the reaction was significantly influenced by the structure of the catalysts (137) and /S-keto esters.170... 

Chiral separations can be considered as a special subset of HPLC. The FDA suggests that for drugs developed as a single enantiomer, the stereoisomeric composition should be evaluated in terms of identity and purity [6]. The undesired enantiomer should be treated as a structurally related impurity, and its level should be assessed by an enantioselective means. The interpretation is that methods should be in place that resolve the drug substance from its enantiomer and should have the ability to quantitate the enantiomer at the 0.1% level. Chiral separations can be performed in reversed phase, normal phase, and polar organic phase modes. Chiral stationary phases (CSP) range from small bonded synthetic selectors to large biopolymers. The classes of CSP that are most commonly utilized in the pharmaceutical industry include Pirkle type, crown ether, protein, polysaccharide, and antibiotic phases [7]. 

---