Intrinsic Enantioselectivity Research Articles

Effect of Methyl-substitution of the Quinoline Ring of Cinchona Alkaloids on the Performance as a Modifier for the Enantioselective Hydrogenation of (E)-2,3-di(4-methoxyphenyl)propenoic Acid Over Pd/C: Kinetic Analysis

The asymmetric hydrogenation of (E)-2,3-di(4-methoxyphenyl)propenoic acid was conducted over Pd/C chirally modified with cinchona alkaloids methyl-substituted at 2′-position of the quinoline ring. It is revealed that the adsorption strength of the modifiers and the intrinsic enantioselectivity at the modified sites are decreased by the methyl-substitution. The intrinsic enantioselectivity of the modifier is correlated to kinetic parameters.

Kinetic analysis of the asymmetric hydrogenation of (E)-2,3-diphenylpropenoic acid over cinchonidine derivative-modified Pd/C: quinoline ring modification

The substitutions at the 2′- and/or 6′-positions of the quinoline ring of cinchonidine reduce both the intrinsic enantioselectivity and adsorption strength for the enantioselective hydrogenation of α-phenylcinnamic acid over Pd/C.

Kinetic Analysis of Enantioselective Hydrogenation of 2,3-(E)-Diarylpropenoic Acids over a Chiral Cinchona Alkaloid-Modified Pd/C Catalyst

Abstract Enantioselective hydrogenations of α,β-unsaturated carboxylic acids over cinchona alkaloid-modified Pd metal heterogeneous catalysts have received considerable attention because of scientific importance in molecular recognition catalysis as well as feasibility of industrial applications. In the present study, comprehensive kinetic analysis of the hydrogenation was conducted to disclose the crucial kinetic parameters controlling enantiodifferentiation and reaction rate with the combinations of four kinds of modifier and three kinds of substrate. Despite simplicity of the kinetic model, the present novel kinetic formulation allows us to describe the enantioselectivity as a function of modifier concentration, to estimate intrinsic enantioselectivity at the modified sites, to estimate respective reaction rates at the modified and unmodified sites, and to establish a correlation between the magnitude of ligand acceleration and kinetic parameters. The enantioselectivity is successfully correlated to the reaction rate. The adsorption strength of the modifier on Pd is suggested to decrease in the order, cinchonidine > cinchonine > quinine > quinidine. The roles played by benzylammine and the observed decrease in the selectivity at a high modifier concentration are also discussed. The kinetic model and formulation can be applied to analyze the catalytic behaviors and performance of Pt counterparts.

Study on extraction kinetics of α -cyclopentylmandelic acid enantiomers with hydroxyethyl- β -cyclodextrin as chiral selector

Abstract In this work, the kinetic study on reactive extraction of α -cyclopentylmandelic acid ( α -CPMA) enantiomers was performed in a Lewis cell using hydroxyethyl- β -cyclodextrin (HE- β -CD) as chiral selector. The enantioselective complexation equilibrium between HE- β -CD and α -CPMA enantiomers was studied by phase solubility method. The important process parameters affecting the initial extraction rate were separately studied and the reaction rate equations were deduced. The optimal conditions for kinetic study were as follows: stirring speed of 75 r·min − 1 , interfacial area of 12.56 cm 2 , pH of 2.5, initial HE- β -CD concentration of 0.05 mol ·L − 1 , initial α -CPMA concentration of 5 mmol·L − 1 , and temperature of 278 K. The reaction has been found to be first order in α -CPMA and second order in HE- β -CD with the forward rate constants of 2.056 × 10 − 3 m 6 ·mol − 2 ·s − 1 and 1.459 × 10 − 3 m 6 ·mol − 2 ·s − 1 for ( S )- α -CPMA and ( R )- α -CPMA, respectively. The complexation equilibrium constants were evaluated as 61 L·mol − 1 and 117 L·mol − 1 for ( S )- α -CPMA and ( R )- α -CPMA, and the intrinsic enantioselectivity is estimated as 1.92.

Mass Spectrometric Back Reaction Screening of Quasi‐Enantiomeric Products as a Mechanistic Tool

In this account, we discuss a mass spectrometric method that enables unambiguous identification of intermediates involved in the enantioselective step of a catalytic cycle. This method, which we originally developed for rapid evaluation of chiral catalysts, is based on monitoring the back reaction of mass-labeled quasi-enantiomeric products by ESI-MS. In this way, the intrinsic enantioselectivity of a chiral catalyst can be determined directly by quantification of catalytically relevant intermediates. By comparing the results from the forward and back reaction, direct evidence for the involvement of a catalytic intermediate in the enantioselective step can be obtained. In addition, insights about the energy profile of the catalytic cycle may be gained. The potential of back reaction screening as a mechanistic tool is demonstrated for organocatalytic aldol reactions, 1,4-additions of aldehydes to nitroolefins, Diels-Alder reactions, Michael additions, and Morita-Baylis-Hillman reactions.

Intrinsic enantioselectivity of natural polynucleotides modulated by copper ions.

Natural polynucleotides including Micrococcus lysodeikticus and calf thymus DNA exhibit enantioselective recognition to S-ofloxacin regulated by Cu(2+). This is the first report that ofloxacin and Cu(2+) have cooperative effects on the local distortions of polynucleotides. At the [Cu(2+)]/[base] ratio of 0.1, S-ofloxacin is more liable to induce the locally distorted structures of polynucleotides, of which the association constant of S-ofloxacin toward DNA-Cu(II) is three times higher than that of the R-enantiomer. The apparent increase of adsorption capability and cooperativity, as well as the change of adsorption mechanism were detected in the adsorption of ofloxacin enantiomers on polynucleotides upon Cu(II)-coordination. This study not only discloses the effect of the chiral drug on the structural transition of long double-stranded DNA, but provides fundamental data to develop a novel enantioseparation method based on natural polynucleotides.

Asymmetric Ion‐Pairing Catalysis of the Reversible Cyclization of 2′‐Hydroxychalcone to Flavanone: Asymmetric Catalysis of an Equilibrating Reaction

AbstractThe asymmetric catalytic cyclization of the simple 2′‐hydroxychalcone (1) to flavanone (2), a model for the chalcone isomerase reaction, has been realized as a catalytic asymmetric ion‐pairing process with chiral quaternary ammonium salts (e.g., 9‐anthracenylmethlycinchoninium chloride; 9‐Am‐CN‐Cl) and NaH as small‐molecule co‐catalyst. In toluene/CHCl3 solution, the process reaches an intrinsic enantioselectivity of up to S = 14.4 (er = 93.5:6.5). The reversible reaction proceeds in two steps: A fast initial reaction approaches a quasi‐equilibrium with KR/S = 4.5, followed by a second, slow racemization phase approaching Krac = 9. A simple mechanistic model featuring a living ion‐pairing catalysis with full reversibility is proposed. Deuterium transfer from co‐solvent CDCl3 to product 2 and isolation of a Michael conjugate formed from 2 and 1 demonstrate the intermediacy of flavanone enolate ion pairs. A kinetic model shows good agreement with the experimentally observed, peculiar, time‐dependent evolution of the species concentrations and the enantiomeric excess of 2. The reaction is a chemical model of the chalcone isomerase enzymatic reaction. Furthermore, it is an ideal model for studying the characteristic behavior of reversible asymmetric catalyses close to their equilibria.

Efficient, scalable asymmetric synthesis of an epoxy quinol via Noyori desymmetrization of a meso diketone

Epoxy quinol 1a was prepared on a multi-gram scale by Noyori transfer hydrogenative desymmetrization of the readily available meso-epoxy diketone 4. Although the intrinsic enantioselectivity for the desymmetrization was modest (82:18 er at 4% conversion), a highly enantiopure product (99.6:0.4 er) could be obtained in one operation in 44% yield via kinetic resolution of the minor enantiomer with long reaction times (48 h), or in 73% yield by combination with an enzymatic resolution of a 93:7 er mixture.

A computational study of enantioselective adsorption in a homochiral metal–organic framework

The potential application of a homochiral metal–organic framework (MOF) made from cadmium corners and BINOL-type linkers for enantioselective separations of chiral hydrocarbons was investigated using grand canonical Monte Carlo simulations. Adsorption of racemic mixtures of (R,S)-1,3-dimethyl-1,2-propadiene, (R,S)-1,2-dimethylcyclobutane and (R,S)-1,2-dimethylcyclopropane was simulated. The results show that an enantiomeric excess (ee) of over 50% can be achieved for 1,3-dimethyl-1,2-propadiene, while more moderate ee values were observed for the cyclic compounds. The adsorption sites, diastereomeric complexes and adsorption energies were analysed to understand the enantioselective adsorption. It is shown that the small zigzag pores of the homochiral MOF account primarily for the enantioselective adsorption, whereas the larger helical pores show almost no enantioselectivity. The results also demonstrate that both intrinsic enantioselectivity and accessibility of the adsorption sites are important for the overall enantioselective separation.

Mass spectrometric screening of chiral catalysts and catalyst mixtures

The use of quasi-enantiomeric substrates and ESI-MS as an analytical tool has made it possible to determine the intrinsic enantioselectivity of chiral catalysts by monitoring catalytic intermediates. In this way, potential problems of methods based on product analysis, which may be caused by catalytically active impurities, partial dissociation of a chiral ligand-metal complex, or a non-catalytic background reaction can be avoided. ESI-MS-based screening is fast, reliable, and operationally simple, as it does not require work-up or purification steps. Moreover, mixtures of catalysts with different molecular masses can be screened simultaneously, which is not possible with methods relying on product analysis. In this way catalyst libraries prepared in one batch by combinatorial methods can be screened without the need to synthesize and purify the catalysts individually. This screening method was successfully applied to Pd-catalyzed allylic substitutions and metal-catalyzed and organocatalytic Diels-Alder reactions.

Chiral effects of alkyl-substituted derivatives of N,O-bismethacryloyl ethanolamine on the performance of one monomer molecularly imprinted polymers (OMNiMIPs)

New monomers were synthesized and evaluated for their molecular imprinting performance by a recently discovered methodology referred to as one monomer molecularly imprinted polymers (OMNiMIPs). The structural design of the new monomers was based on a lead compound methacrylamidoethyl methacrylate (1) used for the synthesis of OMNiMIP1, and introduced alkyl groups of various sizes at the alpha-amino position of the lead compound. Enantioselectivity, determined by liquid chromatography, was used to compare the performance of the imprinted polymers. Methyl substitution provided crosslinker 5 (2-methacrylamidopropyl methacrylate), which upon imprint polymerization afforded OMNiMIP5 with approximately the same enantioselectivity (alpha = 3.8) as OMNiMP1 (alpha = 3.7) made with the lead compound (1). The other two monomers (6 and 7) with larger alkyl substitutions (isopropyl and sec-butyl respectively) resulted in OMNiMIPs with low selectivity values (alpha = 1.0 and 1.2 respectively). Last, a strong influence of diastereomeric complexes on OMNiMIP5 selectivity was determined, with L: /L: and D: /D: monomer/template pairs giving alpha values of 3.6-3.8, while L: /D: and D: /L: monomer/template pairs had alpha values of 2.3-2.4. There is no intrinsic enantioselectivity seen for the OMNiMIP5 control polymer made without template at all, giving an alpha value of 1.03.

Separation of Racemic Mixture by Ultrafiltration of Enantioselective Micelles. 2. (De)complexation Kinetics

The application of enantioselective micelles in ultrafiltration systems can be an alternative route to meet the increasing demand for enantiopure products. We have studied the separation of D,L-phenylalanine (Phe) by cholesteryl-L-glutamate:CuII (CLG:CuII) anchored in nonionic micelles (intrinsic enantioselectivity D/L,int = 1.9). A cascaded system is needed to complete the separation, as a single stage is insufficient to obtain >99␘ptically pure products. It is shown that the complexation and decomplexation processes are not instantaneous; hence, elucidation of the complexation kinetics is essential to the design of a multistage system. Linear driving force (LDF) models describe both the complexation and decomplexation rates of enantiomers. It can be concluded that the complexation rates of D- and L-Phe, (32 ± 11) x 10-5 s-1 and (28 ± 14) x 10-5 s-1, respectively, are not limited by enantiomer diffusion in the hydrophilic shell of the micelles. Consequently, the formation and rearrangement of the chelate complexes must be rate-limiting. In addition, decomplexation of both enantiomers is even slower, on the order of 10-6 s-1. Fortunately, ultrafiltration experiments indicate that a rapid exchange rate of bound L-Phe by unbound D-Phe improves the decomplexation of L-Phe to (360 ± 250) x 10-5 mM-1 s-1. This exchange process can be described by a second-order LDF model.

Evaluation of enantioselective nonaqueous ion-pair capillary electrophoresis as screening assay in the development of new ion exchange type chiral stationary phases

This study evaluates how enantioselectivity values for the separation of chiral N-derivatized amino acids achieved in non-aqueous ion-pair CE with cinchona alkaloid derived chiral counter-ions are related quantitatively to those obtained in enantioselective anion-exchange chromatography with the same selectors immobilized on silica supports. Three different setups of CE experiments, viz. a conventional total filling technique (TFT), a countercurrent technique (CCT), and a partial filling technique (PFT), were investigated and were tested in terms of the goodness of fit of correlations between apparent electrophoretic and chromatographic a values. Both selectands and selectors have been varied. Correlation coefficients higher than 0.95 are commonly obtained with all three CE techniques, yet even better fits are found for TFT-CE and CCT-CE. The common premise for the good correlations is the equal molecular recognition mechanism in ion-pair and ion-exchange modes, both involving ionic interactions as driving force for selectand-selector association, and the fact that separation selectivity in both techniques is primarily determined by the difference of the binding constants of (R) and (S) enantiomers with the chiral selector, i.e. the intrinsic or thermodynamic enantioselectivity. Factors related to the separation technique, which also influence apparent enantioselectivity and possibly contribute to a deterioration of the fit, are discussed. The good correlations prove that enantioselective ion-pair CE may be used as screening method in the development and optimization of ion-exchange type chiral stationary phases.

Asymmetric Baeyer-Villiger oxidations of 4-mono- and 4,4-disubstituted cyclohexanones by whole cells of engineered Escherichia coli.

Whole cells of an Escherichia coli strain that overexpresses Acinetobacter sp. NCIB 9871 cyclohexanone monooxygenase have been used for the Baeyer-Villiger oxidations of a variety of 4-mono- and 4,4-disubstituted cyclohexanones. In cases where comparisons were possible, this new biocatalytic reagent provided lactones with chemical yields and optical purities that were comparable to those obtained from the purified enzyme or a strain of bakers' yeast that expresses the same enzyme. The efficient production of cyclohexanone monooxygenase in the E. coli expression system (ca. 30% of total soluble protein) allowed these oxidations to reach completion in approximately half the time required for the engineered bakers' yeast strain. Surprisingly, 4,4-disubstituted cyclohexanones were also accepted by the enzyme, and the enantioselectivities of these oxidations could be rationalized by considering the conformational energies of bound substrates along with the enzyme's intrinsic enantioselectivity. The enzyme expressed in E. coli cells also oxidized several 4-substituted cyclohexanones bearing polar substituents, often with high enantioselectivities. In the case of 4-iodocyclohexanone, the lactone was obtained in > 98% ee and its absolute configuration was assigned by X-ray crystallography. The crystal belongs to the monoclinic P2(1) space group with a = 5.7400(10), b = 6.1650(10), c = 11.377(2) A, b = 99.98(2) degrees, and Z = 2. Taken together, these results demonstrate the utility of an engineered bacterial strain in delivering useful chiral building blocks in an experimentally simple manner.

DNA Binding Thermodynamics and Sequence Specificity of Chiral Piperazinecarbonyloxyalkyl Derivatives of Anthracene and Pyrene

In this paper we report the DNA binding proper ties of piperazinecarbonyloxy-2-propyl derivatives of anthracene (2), pyrene (3), and phenylanthracene (4). An intercalative binding mode is found for 2 and 3, while the phenyl group of 4 prevents intercalation and leads to external binding. Preferential binding of the (S)-enantiomers is found for both anthracene 2 and pyrene 3. However, the enantiomeric preference is small, with K-(R)/K-(S) being around 0.5 for both the anthracene and the pyrene compounds. This is interpreted in terms of orientation polarity in the binding, by which any intrinsic enantioselectivity is canceled by averaging of opposite binding orientations. The affinities for poly(dA-dT)(2) (AT) are 10(4) M-1 for anthracene derivative 2, and 5 x 10(5) M-1 for pyrene derivative 2. The affinities for poly(dG-dC)(2) (GC) are I order of magnitude lower than those for AT. This is explained by steric interference of the piperazinium tail with the exocyclic amino groups of guanine in the minor groove of GC, leading to a more shallow intercalation in GC than in AT, as also indicated by significantly less negative reduced linear dichroism of the intercalator absorption bands in the GC complexes. This behavior is consistent with that observed for the previously studied achiral analogues.(1) Binding thermodynamics support the difference in binding mode between AT and GC. The binding enthalpy of the AT complexes is significantly more negative than that of the corresponding GC complexes. This indicates a larger overlap of intercalating moiety and nucleobases in the AT complexes, consistent with the linear dichroism results.

The enantiomeric ratio: origin, determination and prediction

The enantiomeric ratio E =(kcatR/KmR)/(kcatS/KmS) offers a concise representation of the enantioselective properties of an enzyme in reactions that involve chiral compounds. Both as a measure of the intrinsic selectivity of the catalyst, and as a parameter to model the performance of enzymatic processes for the production of enantiopure fine-chemicals, its merits have been well-recognized.Several methods for the determination of E exist. The scope and limitations of these methods are evaluated in terms of accuracy and feasibility. There appears to be no single method that is both reliable and readily applicable in all cases. Complementary methods, however, are available.The outstanding characteristics of the enantiomeric ratio as a quantitative measure of the effects of physical and chemical conditions on the intrinsic enantioselectivity of enzymes are presented in terms of the difference in Gibbs energies of the diastereomeric enzyme-substrate transition states. The prospects of molecular modeling strategies for the prediction of E are discussed.

Asymmetric Synthesis of Naproxen by Supported Aqueous-Phase Catalysis

A supported aqueous-phase, asymmetric, hydrogenation catalyst, SAP-Ru-BINAP-4SO3Na, is synthesized. Impregnation of water from an organic phase, ethyl acetate, is used to hydrate the SAP catalyst. Both the activity and enantioselectivity for the asymmetric hydrogenation of 2-(6′-methoxy-2′-naphthyl)acrylic acid to naproxen are found to be dependent on the water content. Maximum activity and e.e. are observed when water-saturated ethyl acetate is used to hydrate the SAP catalyst, an initial turnover frequency of 18.2 hr−1 and a 70.0% e.e. at room temperature under ≅ 1350 psig of hydrogen pressure. At similar conditions, initial turnover frequencies of 131 and 0.34 hr−1 are observed from Ru-BINAP-4SO3Na in homogeneous (methanol as solvent) and two-phase (water-ethyl acetate) reaction systems, respectively. Although an excellent 96.1 % e. e. (at 4°C and 1230 psig of H2) is found in neat methanol (homogeneous), the enantioselectivity of the SAP catalyst (up to 70% e.e.) is bounded by the intrinsic enantioselectivity limit of the ruthenium complex in water. Recycling of the SAP catalyst is easily achieved without any leaching of ruthenium into the organic phase.