Structure-enantioselectivity Relationships Research Articles

High-performance liquid chromatography enantioseparation of chiral 2-(benzylsulfinyl)benzamide derivatives on cellulose tris(3,5-dichlorophenylcarbamate) chiral stationary phase

Recently it has been reported that immobilized chlorinated-type chiral stationary phases based on cellulose tris(3,5-dichlorophenylcarbamate) are able to express an outstanding enantioselectivity towards the structure of 2-(benzylsulfinyl)benzamide. We now introduce two homologue series of chiral sulfoxides based on the same 2-(sulfinyl)benzoyl core as the prototype of new selectands for HPLC, whose enantioselectivity could be modulable through the replacement of the benzyl group with an unbranched alkyl chain varying in length from 1 to 5 carbon atoms. HPLC parameters such as mobile phase composition and column temperature have been carefully evaluated in order to get pertinent structure-enantioselectivity relationships. The enantiomer elution order was unambiguously determined by a combined strategy involving theoretical and experimental procedures. Two cases of temperature-dependent inversion of the elution order of enantiomers in the operative temperature range of chiral chromatographic support were observed.

Quantifying Structural Effects of Amino Acid Ligands in Pd(II)-Catalyzed Enantioselective C–H Functionalization Reactions

Delineating complex ligand effects on enantioselectivity is a longstanding challenge in asymmetric catalysis. With α-amino acid ligands, the essential difficulty lies in accurately describing integrated perturbations induced by simultaneous variation about the α side chain and N protecting group of the ligand, which hampers an intuitive understanding of the structure–enantioselectivity relationships. To deconvolute such complexity in chiral amino acid enabled enantioselective C–H functionalization reactions, a computational organometallic model system was developed. Whereas a model based only on a conventional results in diminished predictive power, the ground state Pd(II)-based models display an excellent ability to describe the observed enantioselectivity. These structures were leveraged using a multivariate modeling approach to successfully describe Pd(II)-catalyzed C–H alkylation, alkenylation, and two C–H arylation reactions, wherein descriptors of torsion angle, percent buried volume, and NBO charge...

3-(Phenyl-4-oxy)-5-phenyl-4,5-dihydro-(1H)-pyrazole: A fascinating molecular framework to study the enantioseparation ability of the amylose (3,5-dimethylphenylcarbamate) chiral stationary phase. Part I. Structure-enantioselectivity relationships

Chiral stationary phases (CSPs) based on amylose (3,5-dimethylphenylcarbamate) (ADMPC) exhibit a wide-range of enantioselectivity in high-performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC). Although this class of CSPs has been extensively used, chiral discriminations at receptorial level, which are useful to develop predictive molecular models, have been rarely reported in the literature.Herein, we describe the results obtained in the enantioselective HPLC of a set of six C5-chiral 4,5-dihydro-(1H)-pyrazole derivatives on the ADMPC-based Chiralpak AD-3 CSP (CSP) under normal-phase and polar organic conditions. Using pure methanol as a mobile phase the exceptional enantioseparation factor value of 50 at 25°C was found for one of the investigated analytes. To the best of our knowledge, the enantiomeric bias represents the most outstanding enantioseparation ever recorded on ADMPC-based CSPs.Systematic variations in chemical groups in specific positions of the 3-(phenyl-4-oxy)-5-phenyl-4,5-dihydro-(1H)-pyrazole molecular framework resulted in peculiar changes in retention and enantioselectivity. A careful analysis of the chromatographic data permitted to advance some hypotheses concerning the role played by the individual chemical groups in determining the exceptional enantioseparation.In particular, under methanol-rich mode, the prenyl moiety of the second eluted enantiomer of the better resolved analyte was recognized as a critical structural element to establish direct and favorable solvophobic interactions with apolar portions of selector.

Machine learning induction of chemically intuitive rules for the prediction of enantioselectivity in the asymmetric syntheses of alcohols

In an asymmetric catalytic reaction involving a specific catalyst, the prediction/determination of the absolute configuration of the major product is one of the essential issues. Some encouraging results of enantioselectivity prediction in asymmetric reactions have been achieved by chemoinformatics methods. However, intuitive empirical rules of enantioselectivity are to be preferred by chemists. This investigation attempted to combine chemoinformatics methods with the empirical rules of experts, i.e., to build chemoinformatics models on the basis of intuitive descriptors to derive interpretable empirical rules. In order to implement this, chiral substituent codes were specially developed, and Fisher linear discriminant analysis was used to construct the relationship between chiral substituent codes and the absolute configurations of the products in asymmetric reactions. The method was successfully applied to two data sets of reactions, namely to the products of the reaction – chiral alcohols. On the basis of the excellent results of structure–enantioselectivity relationships (SER), several empirical rules were extracted from the constructed mathematical models, which highlighted aspects of the mechanism and can almost entirely replace the analytical expressions. This investigation extends the application of chemoinfomatics methods to the area of generation of empirical rules, and the idea has the potential to be generally applied with enantioselective reactions by using different codes and different machine learning methods.

Phosphopeptidomimetic substance libraries from multicomponent reaction: Enantioseparation on quinidine carbamate stationary phase

In the present contribution we report a HPLC enantioseparation method for a library of amido-aminophosphonate structures generated by a novel Ugi-multicomponent reaction. The enantioseparation of these novel potentially bioactive molecules was achieved by means of HPLC on cinchona-carbamate based chiral anion-exchangers under polar organic elution conditions. The compounds were synthesized with the aim of offering a wide degree of heterogeneity in terms of structural elements to evaluate the influence of various structural motifs on enantioselectivity. The resultant compound library allows to derive structure-enantioselectivity relationships useful for understanding the chiral recognition process. As part of the study mobile phase characteristics such as concentration and type of counterion, mobile phase composition, apparent pH and temperature were investigated with regards to their effect on the separation performances. Employing a single mass spectrometry-compatible mobile phase, 23 compounds out of a pool of 42 racemic amido-aminophosphonate structures reached full baseline separation (Rs>1.5) and 5 were almost baseline separated (1<Rs<1.5). This result clearly demonstrates the wide applicability of carbamoylated-cinchona alkaloids as chiral stationary phases for this class of analytes.

Enantioseparations of non-benzenoid and oligo-Tröger’s bases by HPLC on Whelk O1 column

The separation of enantiomers of several ‘bis- and tris-Tröger’s bases’ by HPLC on commercially available chiral stationary phase Whelk O1 is described for the first time. The observed structure–enantioselectivity relationships are in agreement with the previously established molecular recognition model. For all ‘bis- and tris-Tröger’s bases’ studied, satisfactory to excellent enantioselectivities were observed.

Functionalized analogues of Tröger's base: scope and limitations of a general synthetic procedure and facile, predictable method for the separation of enantiomers

A major stumbling block in the applications of enantiomerically pure Tröger's base analogues is their poor availability. We have therefore developed a facile method for the enantioseparation of functionalized Tröger's base analogues possessing various substitution patterns. The systematic separation of a library comprising 36 representatives on the commercially available Whelk O1 chiral stationary phase provided valuable information on structure–enantioselectivity relationships. A mechanistic explanation of observed relationships allows one to predict whether or not enantioseparation of a given, perhaps yet unknown derivative of Tröger's base will be feasible. In addition, we provide a detailed report on the scope and limitations of the general synthetic protocol employing anilines and paraformaldehyde in CF 3COOH, as well as some considerations concerning the mechanism of formation of Tröger's base analogues.

Studies on the Structure—Enantioselectivity Relationships in the Catalytic Asymmetric Intramolecular Cyclopropanation Reaction of α‐Diazo‐β‐keto Sulfones Possessing a Methyl‐Substituted Phenyl Group.

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Studies on the structure–enantioselectivity relationships in the catalytic asymmetric intramolecular cyclopropanation reaction of α-diazo-β-keto sulfones possessing a methyl-substituted phenyl group

This manuscript describes studies on structure–enantioselectivity relationships in the catalytic asymmetric intramolecular cyclopropanation (IMCP) reaction of α-diazo-β-keto sulfones possessing a methyl-substituted phenyl group. Enantioselectivity of the IMCP reaction of the α-diazo-β-keto sulfones was varied by the position of a methyl group on the phenyl group in the substrate, and the 2,3-dimethylphenyl sulfone 11h provided the product 12h in 95% yield with 93% ee. This yield is superior to that of the substrate with a mesityl sulfone 11b, and the product 12h is useful because alkylation of its cyclopropane-opened β-keto sulfone derivative 15h provides the C-alkylated product as a major product.

Structure‐enantioselectivity relationships for the study of chiral recognition in peptide enantiomer separation on cinchona alkaloid‐based chiral stationary phases by HPLC: Influence of the N‐terminal protecting group

AbstractEleven different N‐terminal protecting groups (acetyl, benzoyl, FMOC, etc.) were employed for the HPLC separation of oligoalanine peptide enantiomers containing up to six amino acids. Isocratic HPLC separations were performed using a hydro‐organic buffered mobile phase and 4 mm ID columns containing three different chiral anion exchange stationary phases based on cinchona alkaloid‐derived chiral selectors. For most peptides successful separations could be obtained with all protecting groups, although those comprising aromatic moieties were found to yield higher enantioselectivities than those with aliphatic residues, since they are capable of undergoing favourable π‐π interactions with the selector. Systematic investigations concerning the presence or absence of structural features of related protecting groups showed that the use of protecting groups that are optimally adjusted to the binding pocket of the chiral selector effects a significant gain in enantioselectivity. At the same time these studies provided new insights into the chiral recognition mechanism.

Direct high-performance liquid chromatographic separation of peptide enantiomers: study on chiral recognition by systematic evaluation of the influence of structural features of the chiral selectors on enantioselectivity.

All-R/all-S enantiomers of oligoalanines (Ala(n), n = 1-10) with N-terminal protection group have been separated by HPLC on chiral stationary phases based on various cinchona alkaloid selectors. Structure-enantioselectivity relationships derived by extensive selector structure optimization provided insights into binding mechanisms and chiral recognition. Their interpretation was supported by X-ray crystal structures of amino acid and dipeptide, respectively, in complex with chiral selector. Optimized selectors have bulky elements representing steric barriers and deep binding pockets that afforded very high enantioselectivities; e.g., for the all-R and all-S enantiomers of N-(3,5-dinitrobenzoyl)alanylalanine, an alpha-value of 20.0 (corresponding to deltadeltaG of -7.43 kJ/mol) was obtained with a chiral stationary phase based on 6'-(neopentoxy)-9-O-tert-butylcarbamoylcinchonidine. Further, a chiral stationary phase based on 1,4-bis(9-O-quinidinyl)phthalazine was able to distinguish between the all-R and all-S enantiomers of hepta- to decaalanine peptides with enantioselectivity values between 1.8 and 1.9, corresponding to deltadeltaG of -1.46 and -1.59 kJ/mol, respectively.

Approaches to quantitative structure–enantioselectivity relationship modeling of chiral separations using capillary electrophoresis

Quantitative structure–enantioselectivity relationships (QSERs) have been developed to describe the resolution of a series of chiral arylpropionic acids using capillary electrophoresis. Native β-cyclodextrin and two derivatized forms are used as the chiral resolving agents. The QSER models are developed using the results of molecular mechanics calculations as input to multivariate linear regression and also to neural networks. Single models are developed to predict the optimum cyclodextrin to resolve a given analyte, the migration order, and the magnitude of the separation. Models are also developed to predict only the optimum cyclodextrin.

Quantitative structure-enantioselectivity relationships using neural networks. Bioconversion of carbonyl compounds using baker's yeast

Quantitative structure-enantioselectivity relationships using neural networks. Bioconversion of carbonyl compounds using baker's yeast

Structure-enantioselectivity relationships using neural networks for the reduction of carbonyl compounds with baker's yeast

Structure-enantioselectivity relationships were established for the reduction of a set of 41 carbonyl compounds with baker's yeast. The obtained neural network model, allows the classification of the 41 alcohols (obtained by baker's yeast reduction) as R or S with 85% of success. The implicit rules detected by the neural network were given.

Chromatographic separation of the enantiomers of 1,3-dithiolane-1-oxides

The enantiomers of 2,2-disubstituted 1,3-dithiolane- 1 -oxides (type 1 and 2) are separable by direct high-performance liquid chromatography on commercially available chiral stationary phases derived from the N-3,5-dinitrobenzoyl derivatives of α-amino acids. The chromatographic data for a series of dithiolane oxides is presented. Two chiral recognition models are advanced to account for the structure—enantio-selectivity relationships observed for these series. Using these models, absolute configurations of the enantiomers are assigned on the basis of chromatographic elution order. These assignments are consistent with those determined by independent chemical and spectroscopic means. Resolutions of the enantiomers are compared on nine different chiral stationary phases.