Towards the engineering of enantioselective properties of supported platinum catalysts

Understanding the sub-molecular structure of conformationally complex adsorbed molecules is still a difficult task for experimentalists interested in the structure of modified surfaces, therefore first principles calculations can be a fundamental tool for the investigation of structural details otherwise impossible to identify. Density functional theory (DFT) calculations of the adsorption of cinchonidine (CD) and O-phenyl-cinchonidine (OPhCD) have been performed, using large metal clusters to simulate the metal surface and a zero order regular approximation (ZORA) Hamiltonian to account for relativistic effects due to the heavy nuclei involved. The local geometry of chiral surface sites formed by CD was investigated in detail and discussed in relation to the reaction of enantioselective hydrogenation of activated ketones on cinchona modified platinum. Also, the relevant conformations of OPhCD were investigated and the resulting structure of the chiral sites is discussed and compared to those obtained for the parent alkaloid CD. The adsorption behavior on platinum of a series of substituted anisoles was also investigated, in order to evince the effect that phenyl substitution might have on the relative proportion of surface conformers in substituted OPhCD ethers, that have been shown to possess interesting enantioswitching properties when used as surface modifiers in the enantioselective hydrogenation of activated ketones on cinchona alkaloid modified platinum. A correlation between conformational distribution of the modifiers and the selectivity of the catalyst is proposed.     

Natural alkaloids and synthetic relatives as chiral templates of the Orito's reaction

The enantioselective hydrogenation of methyl or ethyl pyruvate over cinchona‐platinum catalyst system (Orito's reaction) is one of the most intensively studied heterogeneous catalytic asymmetric hydrogenation reactions. Studies aiming at systematic changes of the chiral template have played a crucial role in creating hypotheses for the mechanism of Orito's reaction. It is very important to clarify which structural unit of the alkaloid takes part in the enantiodifferentiation, and learn about the role of the different structural units of chiral templates. In this article, we made an attempt to describe the behavior of natural alkaloids, their synthetic derivatives, and analogues as chiral templates in the heterogeneous catalytic asymmetric hydrogenation of activated ketones. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Spectroscopic,Structural, and Computational Characterization of Three Bispidinone Derivatives,as Ligands for Enantioselective Metal Catalyzed Reactions

Three chiral derivatives of the alkaloid sparteine (bispidines), characterized by the 3,7‐diazabicyclo[3.3.1]nonane moiety, were designed as efficient ligands in a number of enantioselective reactions due to their metal coordination properties. A full evaluation of the 3D properties of the compounds was carried out, as the geometrical features of the bicyclic framework are strictly related to the efficiency of the ligands in the asymmetric catalysis. The selected molecules have different molecular complexity for investigating the effects of different chiral groups on the bicycle conformation. We report here a thorough analysis of their molecular arrangement, by NMR spectroscopy, single crystal X‐ray crystallography, and computational techniques, which put in evidence their conformational preferences and the parameters needed for the design of more efficient ligands in asymmetric synthetic routes. The results confirmed the high molecular flexibility of the compounds, and indicated how to achieve a control of the chair–chair/boat–chair conformational ratio, by adjusting the relative size of the substituents on the piperidine nitrogens. Chirality 28:332–339, 2016. © 2016 Wiley Periodicals, Inc.     

植物与手性化合物的对映体选择性相互作用

植物与手性化合物存在着非常密切的联系.一方面,植物分泌、合成的一些手性化合物,如糖甙、酶、萜类化合物、有机酸及植物激素等,在植物的生理生化过程中起着重要的作用;另一方面,人工合成的手性化合物尤其是农药等环境污染物与植物具有对映体选择性相互作用,它们或是选择性地抑制植物的生长和生理过程,或是被植物选择性地吸收和代谢.因此,在开发、生产和使用手性化合物时需要考虑植物与对映体之间的选择性因素;同时,合理利用植物对手性污染物进行环境修复也具有重要意义.本文对植物与手性化合物相互作用中的对映体选择性进行了综述,并对手性污染物的植物修复进行了展望.     

Monomeric and Dimeric 9‐O Anthraquinone and Phenanthryl Derivatives of Cinchona Alkaloids as Chiral Solvating Agents for the NMR Enantiodiscrimination of Chiral Hemiesters

Mono‐ and bis‐alkaloid chiral auxiliaries with anthraquinone or phenanthryl cores were probed as chiral solvating agents (CSAs) for the enantiodiscrimination of chiral cyclic hemiesters. The dimeric anthraquinone derivative and the monomeric phenanthryl one showed remarkable efficiency in the nuclear magnetic resonance (NMR) differentiation of enantiomeric mixtures of hemiesters. An anthraquinone analogous with a single alkaloid unit was remarkably less effective. The conformational prevalence of the chiral auxiliaries were ascertained by NMR. Chirality 27:693–699, 2015. © 2015 Wiley Periodicals, Inc.     

Synthesis of optically active diols using an efficient polymer bound cinchona alkaloid derivative

A new insoluble polymer containing a Cinchona alkaloid derivative has been synthesized and used as chiral ligand in the heterogeneous enantioselective dihydroxylation of olefins. It is shown that the enantioselectivity of the optically active diols obtained from both aliphatic and aromatic substrates is always comparable to that observed in the homogeneous phase under the same reaction conditions. A method for evaluating the enantiomeric excesses of the optically active products is also described. © 1995 Wiley-Liss, Inc.     

Enantioselective Henry (nitroaldol) reaction catalyzed by axially chiral guanidines

The enantioselective activation of nitroalkanes was attempted on the basis of the complexation between chiral guanidinium and nitronate through two hydrogen bonds. The proposed enantioselective activation was applied to the diastereo- and enantioselective Henry (nitroaldol) reaction of nitroalkanes with aldehydes using axially chiral guanidine bases as the catalyst. Optically active nitroaldol products were obtained in acceptable yields with fairly good enantio- and diastereoselectivities at low temperature.     

Disposition kinetics of ML-1035 sulfoxide enantiomers and the prochiral sulfide in rats

ML-1035, 4-amino-5-chloro-2-[2-(methylsulfinyl)ethoxy]-N-[2-(diethylamino)ethyl]benzamide, is a sulfoxide compound and a racemic gastroprokinetic agent with a chiral center at the sulfur atom. We have investigated the disposition kinetics of (R)-ML-1035 sulfoxide (R) and (S)-ML-1035 sulfoxide (S) after the single enantiomers and the racemic mixture were administered to rats in separate experiments. There was no noticeable chiral inversion after either enantiomer dose. Both enantiomers were rapidly absorbed. After dosing with enantiomers or with the racemate, the resulting plasma concentration-time curve of R was closely parallel to that of S in both intravenous and oral experiments, suggesting that the two enantiomers have approximately the same disposition kinetics. After intravenous enantiomer doses, only S underwent conversion to sulfide, suggesting that sulfidation in the liver is enantioselective. However, the enantioselective sulfidation after intravenous dosing did not introduce a difference in the global plasma disposition profiles between R and S, since the reduction reaction is a minor metabolic process. Other metabolic reactions such as sulfonation and mono-N-desethylations were not enantioselective. After oral administration, conversion to sulfide was observed for both enantioners, implicating the existence of a nonhepatic pathway in sulfidation. Administration of a prochiral sulfide dose was associated with an enantioselective sulfoxidation, in which the R/S concentration ratios increased as a function of time. In addition, enantiomeric interaction causing changes in pharmacokinetic parameters was observed after the oral racemate dose, while the interaction is negligible after an intravenous racemate dose, indicating a route dependency in enantiomeric interaction. © 1993 Wiley-Liss, Inc.     

Computational study of enantioselective interaction between C<Subscript>60</Subscript> fullerene and its derivatives with L-histidine

The mechanism of the enantioselective binding of L-histidine with C₆₀ fullerene and its derivatives, (1,2-methanofullerene C₆₀)-61-carboxylic acid, diethyl (1,2-methanofullerene C₆₀)-61-61-dicarboxylate and tert-butyl (1,2-methanofullerene C₆₀)-61-carboxylate based chiral selectors was studied by quantum chemical calculations. All the molecules were fully optimized at RHF/6-31G* basis set. Relative energies between the different complexes were subsequently estimated with single-point electronic energies computed using Møller-Plesset perturbation theory (MP2). Stability and feasibility of all the generated structures were supported by their respective energy minima and fundamental frequencies. It was observed that interaction of fullerene derivatives with L-histidine is due to the existence of hydrogen bonding forces during the complex formation. The intermolecular forces, flow of atomic charges, binding energy, hardness, dipole moment and localization of electrostatic potential are in agreement with enantioselective interaction of L-histidine with C₆₀ fullerene and its derivatives. It is found that theoretical evaluation to be consistent with the experimental data.     

Design and synthesis of a stereodynamic catalyst with reversal of selectivity by enantioselective self‐inhibition

Chirality plays a pivotal role in an uncountable number of biological processes, and nature has developed intriguing mechanisms to maintain this state of enantiopurity. The strive for a deeper understanding of the different elements that constitute such self‐sustaining systems on a molecular level has sparked great interest in the studies of autoinductive and amplifying enantioselective reactions. The design of these reactions remains highly challenging; however, the development of generally applicable principles promises to have a considerable impact on research of catalyst design and other adjacent fields in the future. Here, we report the realization of an autoinductive, enantioselective self‐inhibiting hydrogenation reaction. Development of a stereodynamic catalyst with chiral sensing abilities allowed for a chiral reaction product to interact with the catalyst and change its selectivity in order to suppress its formation, which caused a reversal of selectivity over time.     

Cinchona alkaloid derivatives catalyzed asymmetric aza‐Friedel–crafts reaction of α‐naphthols with aryl aldimines

Cinchona alkaloid derivatives as organocatalysts were applied in the asymmetric aza‐ Friedel–Crafts reaction of α‐naphthol with aryl aldimines. The desired chiral aminoarylnaphthols were obtained in 85% enantiomeric excess.     

Development of a chiral stationary phase based on cinchonidine. Comparison with a quinine-based chiral column

A chiral anion-exchanger stationary phase based on cinchonidine (CD) was developed. Two columns were packed with and without endcapping (EC) treatment (CD-chiral stationary phase[CD-CSP(EC)] and [CD-CSP], respectively) and studied for their ability to separate N-2,4-dinitrophenyl α-amino acids (DNP-amino acids) enantiomers over a temperature range of 10-40 °C with a hydro-organic buffer mobile phase. The more hydrophobic, endcapped stationary phase showed significantly larger retentive capacity than the non-endcapped one. The apparent thermodynamic transfer parameters of the enantiomers from the mobile to both CSPs were estimated from van't Hoff plots within the cited temperature range. Similar studies with two natural quinine-based columns (QN-CSP and QN-CSP(EC)) were previously reported. In this work, a critical comparison in the chiral recognition ability to DNP-amino acids of these cinchonidine and QN-based chiral columns was drawn. It has been found that QN-based CSPs show greater chiral recognition capability towards these derivatives than CD-CSPs. The influence of the QN methoxy group on the equilibrium constants of the enantioselective interaction between these DNP-amino acids with these two cinchona CSPs could be assessed.     

Transition metal complexes in organic synthesis, part 59.(1) First enantioselective total synthesis of lavanduquinocin, a potent neuronal cell protecting substance from streptomyces viridochromogenes

Using (R)-propene oxide as a chiral building block a convergent enantioselective synthesis of the potent neuronal cell protecting alkaloid lavanduquinocin has been accomplished by the iron-mediated one-pot construction of the carbazole framework.     

Synthesis of 9-N-cinchona alkaloid peptide hybrid derivatives: preparation and conformational study of 9-N-acylamino(9-deoxy)cinchona alkaloids

The synthesis and conformational analyses of several 9-N-acylamino(9-deoxy)cinchona alkaloids is presented. Peptides were connected to cinchona alkaloids via a 9-amino group. The synthesis of the new cinchona alkaloid derivatives was performed straightforwardly from 9-amino(9-deoxy)dihydroquinidine via coupling with carboxylic acid chlorides and several dipeptides. Both alkaloid derivatives with the configuration of the corresponding natural product as well as its unnatural epimer were studied. The conformations of the prepared derivatives in solution were determined by NMR spectroscopy. It is shown that the conformation is strongly influenced by the configuration at the 9-position.     

Exploring enantiospecific ligand-protein interactions using cellular membrane affinity chromatography: chiral recognition as a dynamic process

The chiral recognition mechanisms responsible for the enantioselective binding on the alpha3beta4 nicotinic acetylcholine receptor (alpha3 beta4 nAChR) and human organic cation transporter 1 (hOCT1) have been reviewed. The results indicate that chiral recognition on the alpha3beta4 nAChR is a process involving initial tethering of dextromethorphan and levomethorphan at hydrophobic pockets within the central lumen followed by hydrogen bonding interactions favoring dextromethorphan. The second step is the defining enantioselective step. Studies with the hOCT1 indentified four binding sites within the transporter that participated in chiral recognition. Each of the enantiomers of the compounds used in the study interacted with three of these sites, while (R)-verapamil interacted with all four. Chiral recognition arose from the conformational adjustments required to produce optimum interactions. With respect to the prevailing interaction-based models, the data suggest that chiral recognition is a dynamic process and that the static point-based models should be amended to reflect this.     

Stereoselective binding of 2-(4-biphenylyl)-3-substituted-3-hydroxypropionic acids on an immobilised human serum albumin chiral stationary phase

A series of 2-(4-biphenylyl)-3,3'-hydroxy-substituted phenyl propionic acid, with anti-inflammatory properties, bearing two chiral centres, were studied by HPLC upon HSA-CSP (human serum albumin-based chiral stationary phase). The compounds were analysed in their stereoisomeric erythro and threo forms. The study involved the enantioselective analysis on HSA-CSP, the determination of the racemate lipophilicity (log k'(w)), a QSRR (quantitative structure-retention relationship) analysis and CD study for the assessment of the absolute configuration of the most retained enantiomer. Lipophilicity was found to be an important factor affecting the affinity of the compounds for the HSA stationary phase, but electronic properties seemed to play a role. The position of the substituent of the phenyl group on carbon 3 was found important to modulate stereoselective interaction, the highest value of enantioselectivities being found for the erythro ortho-substituted phenyl derivatives. The previously proposed two steps mechanism of enantiodiscrimination for cyclohexylphenyl substituted derivatives was confirmed for this series of derivatives bearing the biphenylyl moiety.     

New chiral stationary phases for liquid chromatography based on small molecules: Development,enantioresolution evaluation and chiral recognition mechanisms

Recently, we reported the development of new chiral stationary phases (CSPs) for liquid chromatography (LC) based on chiral derivatives of xanthones (CDXs). Based on the most promising CDX selectors, 12 new CSPs were successfully prepared starting from suitable functionalized small molecules including xanthone and benzophenone derivatives. The chiral selectors comprising one, two, three, or four chiral moieties were covalently bonded to a chromatographic support and further packed into LC stainless-steel columns (150 × 2.1 mm I.D.). The enantioselective performance of the new CSPs was evaluated by LC using different classes of chiral compounds. Specificity for enantioseparation of some CDXs was observed in the evaluation of the new CSPs. Besides, assessment of chiral recognition mechanisms was performed by computational studies using molecular docking approach, which are in accordance with the chromatographic parameters. X-Ray analysis was used to establish a chiral selector 3D structure.     

Study of the Enantioselective Interaction of Diclofop and Human Serum Albumin by Spectroscopic and Molecular Modeling Approaches In Vitro

In this contribution, the enantioselective interactions between diclofop (DC) and human serum albumin (HSA) were explored by steady‐state and 3D fluorescence, ultraviolet‐visible spectroscopy (UV‐vis), and molecular modeling. The binding constants between R‐DC and HSA were 0.9213 × 10⁵, 0.9118 × 10⁵, and 0.9009 × 10⁵ L · mol^‐1 at 293, 303, 313 K, respectively. Moreover, the binding constants of S‐DC for HSA were 1.4766 × 10⁵, 1.2899 × 10⁵, and 1.0882 × 10⁵ L · mol^‐1 at 293, 303, and 313 K individually. Such consequences markedly implied the binding between DC enantiomers and HSA were enantioselective with higher affinity for S‐DC. Steady‐state fluorescence study evidenced the formation of DC‐HSA complex and there was a single class of binding site on HSA. The thermodynamic parameters (ΔH, ΔS, ΔG) of the reaction clearly indicated that hydrophobic effects and H‐bonds contribute to the formation of DC‐HSA complex, which was in excellent agreement with molecular simulations. In addition, both site‐competitive replacement and molecular modeling suggested that DC enantiomers were located within the binding pocket of Sudlow's site II. Furthermore, the alterations of HSA secondary structure in the presence of DC enantiomers were verified by UV‐vis absorption and 3D fluorescence spectroscopy. This study can provide important insight into the enantioselective interaction of physiological protein HSA with chiral aryloxyphenoxy propionate herbicides and gives support to the use of HSA for chiral pesticides ecotoxicology and environmental risk assessment. Chirality 25:719–725, 2013. © 2013 Wiley Periodicals, Inc.     

Identification of enantioselective extractants for chiral separation of amines and aminoalcohols

The major obstacle for the introduction of fractional reactive extraction as a chiral separation method in the chemical and pharmaceutical industries is the lack of versatile enantioselective extractants. Therefore, a rational approach is developed to transfer the extensive knowledge of chiral selectors reported in the literature on chiral recognition and other chiral separation techniques to extraction. Based on a similarity in separation mechanisms, it was expected that chiral selectors originating from a technique in which chiral recognition takes place in the liquid phase are most likely to function as enantioselective extractant. Using this approach, a selection of promising extractants was made from the literature and experimentally evaluated for the enantioseparation of aminoalcohols and amines. As a result, four enantioselective extractant systems, namely, dibutyl-L-tartrate with boric acid, N-(2-hydroxydodecyl)-L-hydroxyproline Cu(II) complex, N-dodecyl-L-hydroxyproline Cu(II) complex, and azophenolic crown ether, have been identified. The azophenolic crown ether system performed the best and demonstrated an enantioselectivity between 1.3-5.0 for five out of six test compounds. Identification of the enantioselective extractant systems was highly facilitated by the developed rational transfer approach that, although partially qualitative, appeared capable of reducing more than 50 encountered candidates to only three promising systems for further experimental evaluation. Therefore, it is expected that this approach can be successfully applied to identify enantioselective extractants for other classes of enantiomers as well.     

Spectroscopic investigations of the chiral interactions between lipase and the herbicide dichlorprop

The enantioselective interaction between penicillium expansum alkaline lipase and chiral phenoxypropionic acid herbicide dichlorprop was studied by using UV differential spectrophotometry and fluorescence spectrophotometry in the presence of a pH 8, phosphate buffer solution. Chiral differences in the UV absorption and fluorescence spectra of lipase with dichlorprop were detected. (R)-Dichlorprop interacted the strongest with lipase as measured by both UV absorption and fluorescence spectrophotometry, followed by (Rac)-dichlorprop, while (S)-dichlorprop had the weakest interaction. The hydrophobic interaction seem to play the dominant role in the interactions and the (R)-enantiomer needed the minimum put of energy to drive the endothermic reaction, while the Rac-type and S-type compounds needed more for the reaction to take place. In the meantime, the catalytic hydrolysis of FDA with lipase show that (R)-DCPP could inhibit lipase the most strongly relatively at the same condition, perhaps because (R)-DCPP had a stronger combining effect and high enantiomeric selectivity on lipase than (Rac)-DCPP and (S)-DCPP.