G‐quadruplex DNA‐based asymmetric catalysis of michael addition: Effects of sonication,ligands, and co‐solvents

There is an escalating interest of using double stranded DNA molecules as a chiral scaffold to construct metal‐biomacromolecule hybrid catalysts for asymmetric synthesis. Several recent studies also evaluated the use of G‐quadruplex DNA‐based catalysts for asymmetric Diels‐Alder and Friedel‐Crafts reactions. However, there is still a lack of understanding of how different oligonucleotides, salts (such as NaCl and KCl), metal ligands and co‐solvents affect the catalytic performance of quadruplex DNA‐based hybrid catalysts. In this study, we aim to systematically evaluate these key factors in asymmetric Michael addition reactions, and to examine the conformational and molecular changes of DNA by circular dichroism (CD) spectroscopy and gel electrophoresis. We achieved up to 95% yield and 50% enantiomeric excess (ee) when the reaction of 2‐acylimidazole 1a and dimethylmalonate was catalyzed by 5′‐G₃(TTAG₃)₃?3′ (G4DNA1) in 20 mM MOPS (pH 6.5) containing 50 mM KCl and 40 µM [Cu(dmbipy)(NO₃)₂], and G4DNA1 was pre‐sonicated in ice bath for 10 min prior to the reaction. G‐quadruplex‐based hybrid catalysts provide a new tool for asymmetric catalysis, but future mechanistic studies should be sought to further improve the catalytic efficiency. The current work presents a systematic study of asymmetric Michael addition catalyzed by G‐quadruplex catalysts constructed via non‐covalent complexing, and an intriguing finding of the effect of pre‐sonication on catalytic efficiency. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:891–898, 2016     

Stereochemical Properties of Multidentate Nitrogen Donor Ligands and Their Copper Complexes by Electronic CD and DFT

UV–Vis and electronic circular dichroism (ECD) spectroscopy, complemented with Density Functional Theory (DFT) calculations, were used to elucidate the structural diversities of three multidentate nitrogen donor ligands and two associated copper complexes in solution directly. The three chiral salen ligands all consist of trans‐cyclohexane‐1,2‐diamine as a chiral scaffold and also of pyridine rings as chromophores, differing only in the linking groups between the two functional groups mentioned above. Very different ECD intensities and somewhat different ECD patterns were observed for these ligands and satisfactorily interpreted theoretically. For the geometry optimization and spectral simulation of the open‐shell metal complexes, the LANL2DZ basis set with effective core potential for the Cu and Cl atoms and pure cc‐pVTZ for the rest of the atoms was utilized. The performance of the same calculations with the polarization functions (f,g) from the cc‐pVTZ basis added to the LANL2DZ basis was compared. While the three ligands exhibit different conformational flexibility, the associated copper complexes show great rigidity imposed by the metal–ligand coordination, taking on a single structure in each case. In addition, dispersion interactions were shown to change the conformational stability ordering of the ligands noticeably and to exert considerable influence on the simulated UV–Vis and ECD spectra. Chirality 28:545–555, 2016. © 2016 Wiley Periodicals, Inc.     

Enantioselective Addition of Diethylzinc to Aldehydes Catalyzed by Chiral O,N,O‐tridentate Phenol Ligands Derived From Camphor

Chiral O,N,O‐tridentate phenol ligands bearing a camphor backbone were found to be effective chiral catalysts for the enantioselective addition of diethylzinc to aromatic aldehydes, resulting in high enantioselectivities (80–95% ee) at room temperature. Chirality 28:65–71, 2016. © 2015 Wiley Periodicals, Inc.     

Zwitterionic Phosphorylated Quinines as Chiral Solvating Agents for NMR Spectroscopy

Because of their unique 3D arrangement, naturally occurring Cinchona alkaloids and their synthetic derivatives have found wide‐ranging applications in chiral recognition. Recently, we determined the enantioselective properties of C‐9‐phosphate mixed triesters of quinine as versatile chiral solvating agents in nuclear magnetic resonance (NMR) spectroscopy. In the current study, we introduce new zwitterionic members of this class of molecules containing a negatively charged phosphate moiety (i.e., ethyl, n‐butyl and phenyl hydrogen quininyl phosphate). An efficient approach for synthesizing these compounds is elaborated, and full characterization, including conformational and autoaggregation phenomena studies, was performed. Therefore, their ability to induce NMR anisochrony of selected enantiomeric substrates (i.e., primarily N‐DNB‐protected amino acids and their methyl esters) was analyzed compared to uncharged diphenyl quininyl phosphate and its positively charged quaternary ammonium hydrochloride salt. In addition, ¹H and ¹³C NMR experiments revealed their enantiodiscrimination potential toward novel analytes, such as secondary amines and nonprotected amino acids. Chirality 27:752–760, 2015. © 2015 Wiley Periodicals, Inc.     

A Helical Polyphenylacetylene Having Amino Alcohol Moieties Without Chiral Side Groups as a Chiral Ligand for the Asymmetric Addition of Diethylzinc to Benzaldehyde

One‐handed helical polyphenylacetylenes having achiral amino alcohol moieties, but no chiral side groups, were synthesized by the helix‐sense‐selective copolymerization of an achiral phenylacetylene having an amino alcohol side group with a phenylacetylene having two hydroxyl groups. Since the resulting helical copolymers were successfully utilized as chiral ligands for the enantioselective alkylation of benzaldehyde with diethylzinc, we can conclude that the main‐chain chirality based on the one‐handed helical conformation is useful for the chiral catalysis of an asymmetric reaction for the first time. The enantioselectivities of the reaction were controlled by the optical purities of the helical polymer ligands. In addition, the polymer ligands could be easily recovered by precipitation after the reaction. Chirality 27:454–458, 2015. © 2015 Wiley Periodicals, Inc.     

β‐Hydroxyamide‐Based Ligands and Their Use in the Enantioselective Borane Reduction of Prochiral Ketones

Hydroxyamide‐based ligands have occupied a considerable place in asymmetric synthesis. Here we report the synthesis of seven β‐hydroxyamide‐based ligands from the reaction of 2‐hydroxynicotinic acid with chiral amino alcohols and test their effect on the enantioselective reduction of aromatic prochiral ketones with borane in tetrahydofuran (THF). They produce the corresponding secondary alcohols with up to 76% enantiomeric excess (ee) and good to excellent yields (86‐99%). Chirality 26:21–26, 2013. © 2013 Wiley Periodicals, Inc.     

Nanocellulose 3, 5‐Dimethylphenylcarbamate Derivative Coated Chiral Stationary Phase: Preparation and Enantioseparation Performance

Nanocrystalline cellulose (NCC) with high surface area and high ordered crystalline structure was prepared from microcrystalline cellulose (MCC) under the hydrolysis of sodium hypochlorite. NCC was further reacted with 3,5‐dimethylphenyl isocyanate to obtain the nanocellulose derivative, and then coated successfully on the surface of silica gel to a prepared NCC‐coated chiral stationary phase (CSP) as a new kind of chiral separation material. Similarly, MCC derivative‐coated CSP was also prepared as contrast. The chiral separation performance of NCC‐based CSP was evaluated and compared with MCC‐based CSP by high‐performance liquid chromatography. Moreover, the effects of the alcohol modifiers, mobile phase additives, and flow rates on chiral separations were investigated in detail. The results showed that 10 chiral compounds were separated on NCC‐based CSP with better peak shape and higher column efficiency than MCC‐based CSP, which confirmed that NCC‐based CSP was a promising packing material for the resolution of chiral compounds.Chirality 28:376–381, 2016. © 2016 Wiley Periodicals, Inc.     

The Use of Phosphite‐Type Ligands in the Ir‐Catalyzed Asymmetric Hydrogenation of Heterocyclic Compounds

A series of chiral phosphite‐type ligands was tested in asymmetric Ir‐catalyzed hydrogenation of quinolines and 2,4,5,6‐tetrahydro‐1H‐pyrazino(3,2,1‐j,k)carbazole. Hydrogenation of quinaldine hydrochloride provided superior enantioselectivity up to 65% ee compared to quinaldine free base. The ligands were tested for the first time in the asymmetric Ir‐Ircatalyzed hydrogenation of 2,4,5,6‐tetrahydro‐1H‐pyrazino(3,2,1‐j,k)carbazole yielding the antidepressant drug, pirlindole. Chirality 26:56–60, 2013. © 2013 Wiley Periodicals, Inc.     

The Syntheses of new Camphorsulfonylated Ligands Derived from 2-Amino-2'-Hydroxy-1,1'-Binaphthyl and Their Enantioselectivities in the Addition of Dialkylzinc Reagents to Aldehydes

A series of new camphorsulfonylated ligands derived from chiral 2‐amino‐2′‐hydroxy‐1,1′‐binaphthyl (NOBIN) and (+)‐camphorsulfonic acid were synthesized by a short and simple synthetic sequence, and their enantioselective catalytic activities were assessed in the nucleophilic addition reaction of dialkylzinc reagents to aldehydes in the presence of titanium tetraisopropoxide. The most efficient ligand, N‐hydroxycamphorsulfonylated (S)‐NOBIN, gave (S)‐addition products with good yields and up to 87% of ee value. The ¹H nuclear magnetic resonance (NMR) and ¹³C NMR results of the titanium titration experiments on this ligand indicate that the most likely catalytic reactive species involved in this catalytic asymmetric addition is a bimetallic titanium complex. A possible catalytic reaction mechanism is proposed. Chirality 24:825–832, 2012. © 2012 Wiley Periodicals, Inc.     

Enantiomeric 4‐Acylamino‐6‐alkyloxy‐2 Alkylthiopyrimidines As Potential A3 Adenosine Receptor Antagonists: HPLC Chiral Resolution and Absolute Configuration Assignment by a Full Set of Chiroptical Spectroscopy

The chiral separation of enantiomeric couples of three potential A₃ adenosine receptor antagonists: (R/S)‐N‐(6‐(1‐phenylethoxy)‐2‐(propylthio)pyrimidin‐4‐yl)acetamide ( 1 ), (R/S)‐N‐(2‐(1‐phenylethylthio)‐6‐propoxypyrimidin‐4‐yl)acetamide ( 2 ), and (R/S)‐N‐(2‐(benzylthio)‐6‐sec‐butoxypyrimidin‐4‐yl)acetamide ( 3 ) was achieved by high‐performance liquid chromatography (HPLC). Three types of chiroptical spectroscopies, namely, optical rotatory dispersion (ORD), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD), were applied to enantiomeric compounds. Through comparison with Density Functional Theory (DFT) calculations, encompassing extensive conformational analysis, full assignment of the absolute configuration (AC) for the three sets of compounds was obtained. Chirality 28:434–440, 2016. © 2016 Wiley Periodicals, Inc.     

Solution structure by nuclear magnetic resonance of the two lantibiotics 97518 and NAI‐107

Lantibiotics 97518 and NAI‐107, produced by the related genera Planomonospora and Microbispora respectively, are members of a family of nisin‐related compounds. They represent promising compounds to treat infections caused by multiresistant Gram‐positive pathogens. Despite their similar structure and a similar antibacterial spectrum, the two lantibiotics exhibit significant differences in their potency. To gain an insight into the structure–activity relationships, their conformational properties in solution are determined by NMR. After carrying out an NOE analysis of 2D ¹H NMR spectra, high‐resolution 3D structures are determined using molecular dynamics simulations. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.     

A 3D Homochiral MOF [Cd2(d‐cam)3]•2Hdma•4dma for HPLC Chromatographic Enantioseparation

Up to now, some chiral metal‐organic frameworks (MOFs) have been reported for enantioseparation in liquid chromatography. Here we report a homochiral MOF, [Cd2(d‐cam)3]·2Hdma·4dma, used as a new chiral stationary phase for high‐performance liquid chromatographic enantioseparation. Nine racemates of alcohol, naphthol, ketone, and base compounds were used as analytes for evaluating the separation properties of the chiral MOF packed column. Moreover, some effects such as mobile phase composition, column temperature, and analytes mass for separations on this chiral column also were investigated. The relative standard deviations for the resolution values of run‐to‐run and column‐to‐column were less than 2.1% and 3.2%, respectively. The experimental results indicate that the homochiral MOF offered good recognition ability, which promotes the application of chiral MOFs use as stationary phase for enantioseparation. Chirality 28:340–346, 2016. © 2016 Wiley Periodicals, Inc.     

Enantioselective Ethylation of Various Aldehydes Catalyzed by Readily Accessible Chiral Diols

Four chiral C₂‐symmetric diols were synthesized in a straightforward three‐step reaction and demonstrated excellent enantioselectivities and good overall yields. Their catalytic activities were examined via the addition of diethylzinc to various aldehydes. The enantioselective addition of diethylzinc to 2‐methoxybenzaldehyde gave the corresponding chiral secondary alcohol with high yields (up to 95%) and moderate to good enantiomeric excess (up to 88%). All synthesized ligands were evaluated in the addition of diethylzinc to various aldehydes in the presence of an additional metal such as Ti(IV) complexes. Chirality 28:593–598, 2016. © 2016 Wiley Periodicals, Inc.     

Comparative HPLC Enantioseparation of Thirty‐Six Aromatic Compounds on Four Columns of the Lux® Series: Impact of Substituents,Shapes and Electronic Properties

With the aim to define a combined computational/chromatographic empirical approach useful for the high‐performance liquid chromatography (HPLC) method development of new chiral compounds, 36 racemic aromatic compounds with different chemical structures were used as test probes on four polysaccharide‐based chiral stationary phases (CSPs) of the Lux series, namely Lux Cellulose‐1, Lux Cellulose‐2, Lux Cellulose‐4, and Lux Amylose‐2, using classical n‐hexane/2‐propanol mixtures as mobile phase. Electrostatic potential surfaces (EPSs) determined using Density Functional Theory (DFT) calculations were used to derive size, shape, and electronic properties of each analyte. Then a comparative HPLC screening was carried out in order to evaluate the impact of substituents, shapes, and electronic properties of the analytes on the chromatographic behavior as the column changes. The four CSPs showed good complementary recognition ability. The elution sequence was determined in 30 cases out of 36. The success rate to afford baseline separations (R_s ≥ 1.5) was estimated: 29 compounds out of 36 showed baseline enantioseparation on at least one of the four selected CSPs. The combined computational‐chromatographic screening furnished useful collective structure‐chromatographic behavior relationships and a map of the chiral discrimination abilities of the considered CSPs towards the analytes. On this basis, the chromatographic behavior of new analytes on a set of polysaccharide‐based CSPs can be mapped through the qualitative correlation of chromatographic parameters (k, α, R_s) to computed molecular properties of the analytes. Chirality 25:709–718, 2013. © 2013 Wiley Periodicals, Inc.     

The Stereodynamics of 5,5’‐Disubstituted BIPHEPs

We investigated the stereodynamics of 5,5’‐substituted tropos BIPHEP ligands (2,2’‐bis(diphenylphosphino)‐biphenyls) by enantioselective dynamic high‐performance liquid chromatography (DHPLC) to elucidate the influence of the substitution pattern and electronics of the substituents (methyl, methoxy, and hydroxyl groups). By temperature‐dependent dynamic HPLC measurements the activation parameters ΔG^╪, ΔH^╪, and ΔS^╪ could be determined with high precision, revealing that the activation barrier of these 5,5’‐substituted BIPHEP ligands ranges in a narrow band between 87.8 and 93.0 kJ mol^–1, making them highly attractive as deracemizable dynamic chiral ligands in asymmetric catalysis. Interestingly, the activation parameters are highly influenced by a hydroxyl or methoxy group in the 5,5’‐position of the BIPHEP ligands. Chirality 25:126–132, 2013. © 2012 Wiley Periodicals, Inc.     

Alteration of the Enantioselective Toxicity of Diclofop Acid by Nonylphenol: Effect on Ascorbate‐Glutathione Cycle in Microcystis Aeruginosa

The enantioselective effects of chiral compounds have been the subject of extensive studies in recent years due to their important implications for contaminant behavior and risk as well as the design of drug and pesticide formulations. The potential alterations of enantioselectivity, however, still remain elusive from the available data suggesting the effects of numerous environmental factors and the coexisting achiral and chiral compounds. Herein we studied the effect of nonylphenol (NP), a ubiquitous contaminant and ingredient in pesticide formulation, on the enantioselectivity of diclofop acid (DC) through ascorbate‐glutathione (AsA‐GSH) cycle in Microcystis aeruginosa. The enantioselectivity of DC in the AsA and GSH antioxidant defense system of M. aeruginosa was affected significantly by the addition of NP. Specifically, although R‐ DC and S‐DC were added with an equal toxic concentration (at their EC₅₀ values), NP addition to the DC treatments altered the enantiomeric ratios of the activities of monodehydroascorbate reductase (MDHAR) and glutathione reductase (GR), key enzymes in the regeneration of AsA and GSH, respectively. NP also modified the enantiomeric ratios of AsA and GSH levels in both the AsA and GSH antioxidant defense systems of M. aeruginosa. Overall, the oxidative damage induced by R‐DC was further deteriorated, whereas that induced by S‐DC was alleviated after NP addition. These altered enantioselectivities indicate a need to reexamine the risks and biological effects of chiral compounds in the complex environmental matrices containing a multitude of other chemicals, including commercial chiral agricultural chemicals. Chirality 28:475–481, 2016. © 2016 Wiley Periodicals, Inc.     

Green synthesis of enantiopure quinoxaline alcohols using Daucus carota

Green chemistry comprises a new approach in the synthesis of biologically active compounds using biocatalysts, thus diminishing the hazards for human health and environmental pollution. Asymmetric bioreduction is one of the most widely employed strategies in chemoenzymatic synthesis to produce enantiomerically pure chiral alcohols. The present study highlights the use biocatalyst Daucus carota for selective bioreduction of quinoxaline ketones 1a‐6a to their corresponding optically pure alcohols 1b‐6b in high yields (up to 84%) and good enantioselectivity (up to 98%). The absolute configuration of the chiral product (R)‐1‐(3‐methyl 7‐nitroquinoxalin‐2‐yl) ethan‐1‐ol 2b was confirmed by X‐ray crystallography studies. The chiral R‐configuration of the products obtained was confirmed by absolute configuration studies and was assigned following anti‐Prelogs rule. Quinoxaline pharmacophores form a part of well‐known potent drug molecules; hence, the chiral products were studied for determination of their molecular properties using SwissADME property analyser. All the chiral products show no Lipinski rule violations and are expected to have good oral bioavailability. As per the molecular properties prediction studies, the compound 6b (R)‐1‐(6,7‐dichloro‐3‐ methylquinoxalin‐2‐yl) ethanol is observed to show the best physicochemical properties to be a good lead molecule. Thus, the sustainable methodology was developed, and it confirms the synthesis of novel quinoxaline chiral alcohols in a simple, inexpensive, and eco‐friendly condition using D carota.     

Synthesis and Characterization of Conformationally Rigid Chiral Pyridine–N‐Heterocyclic Carbene‐Based Palladacycles with an Unexpected Pd–N Bond Cleavage

The versatility of a previously developed method for the synthesis of chiral carbene‐based palladacycles is demonstrated through the synthesis of two new chiral pyridine‐functionalized N‐heterocyclic carbene palladacycles with different wingtip groups. The efficiency in their resolution with different counter anions and different chiral amino acid salt auxiliaries has been studied. The absolute stereochemistries of all the chiral compounds were confirmed by single crystal X‐ray crystallography. An unexpected Pd–N bond cleavage that resulted in the racemization of the α‐carbon center in these complexes has also been investigated. Chirality 25:149–159, 2013. © 2013 Wiley Periodicals, Inc.     

Conformational and Chiral Properties of Cyclic‐tri(N‐methyl‐meta‐benzamide) Bearing Amidino Groups

Cyclic triamides 4 bearing amidino groups at the meta position of the phenyl rings were synthesized, and their conformational properties in the crystal and in solution were examined. Compound 4a exists as a capsule‐type dimer of the enantiomers with a bowl‐shaped syn conformation in the crystal state. Compound 4 exists mainly in the syn form in solution, and chiral induction was observed upon addition of a chiral acid to a solution of 4a . Chirality 27:487–491, 2015. © 2015 Wiley Periodicals, Inc.     

VCD study of α‐methylbenzyl amine derivatives: Detection of the unchanged chiral motif

Chiral α‐methylbenzyl amine is a well known and often used chiral auxiliary, e.g., in the resolution of racemates or asymmetric catalysis. In this work, α‐methylbenzyl amine and its derivatives N,α‐dimethylbenzyl amine, N,N,α‐trimethylbenzyl amine, and bis[α‐methylbenzyl] amine were investigated by vibrational circular dichroism (VCD) spectroscopy and density functional theory (DFT). For all compounds, stable low energy conformers were obtained by the DFT calculations and based on those, the theoretical vibrational absorption (VA) and VCD spectra were calculated and compared with experimental spectra. Hence, the absolute configurations and conformational preferences were determined. A qualitative comparison of all the experimental VCD spectra of the investigated chiral molecules supported by the calculated ones is given which clearly shows similarities between the spectra of the different chiral amines. These can be assigned to vibrations of the unchanged chiral center. Chirality 2010. © 2010 Wiley‐Liss, Inc.