Enantiomers Of Cis Research Articles

Counterintuitive Isomerization of TFSI- and TFSI--Cation Correlated Isomerization: Insights into the Low Melting Points of TFSI--Based Ionic Liquids.

Ionic liquids (ILs), particularly bis(trifluoromethane)sulfonamide (TFSI-)-based ILs, have attracted substantial attention in electrochemical energy storage, ionic gating for superconductivity, and iontronic sensing. However, underestimating TFSI- isomerization and overlooking TFSI--cation correlation make the origin of their most characteristic property, low melting points (Tm), ambiguous. Traditional static electronic structure calculations assume that C2-symmetric trans enantiomers of TFSI- easily isomerize into cis enantiomers through four symmetrically equivalent pathways over a barrier of 7.1 kJ mol-1. Herein, ab initio molecular dynamics (AIMD) simulations combined with metadynamics reveal that the unusual oscillation of the central nitrogen atom promotes TFSI- to undergo complex isomerization. Specifically, asymmetric trans-to-cis diastereomers of TFSI- experience restricted interconversion (20-52 kJ mol-1) through four distinct asymmetric pathways. The adaptive oscillation and hybridization of chiral nitrogen boost nN → σ*S-C negative hyperconjugation for stabilizing conformational structures and enlarging energy barriers. The orientational distortion of oxygen atoms' lone pairs enhances conjugation but breaks the C2-symmetry. The coexistence of both helicity and chiral nitrogen breaks the enantiomeric relationship. Furthermore, Raman characterization and AIMD simulations confirm the positive correlation between the relative stability of cis-TFSI- and its countercation's polarity. TFSI- and countercations make a mutual conformational selection instead of free isomerization. Surprisingly, Tm increases with the cation-dependent conformational rigidity of TFSI-, offering new fundamental insights into the low Tm of ILs. This descriptor encoding the dependence of thermal property on cation-anion correlated isomerization provides material design guidelines and property prediction capability.

Efforts towards a Noyori reduction of a 3-fluorpiperidin-4-one with dynamic kinetic resolution

A Noyori reduction of racemic 1-Boc-3-fluoropiperidin-4-one has been achieved under dynamic kinetic resolution conditions that results in a single cis enantiomer being obtained with both diastereo- and enantioselectivity > 90%. This medicinal chemistry building block can be generated on multi-gram scale using the developed conditions to a single enantiomer in a 60% yield after employing a crystallisation procedure.

Beyond Solvent Exclusion: i-Motif Detecting Capability and an Alternative DNA Light-Switching Mechanism in a Ruthenium(II) Polypyridyl Complex.

Cytosine-rich DNA can fold into secondary structures known as i-motifs. Mounting experimental evidence suggests that these non-canonical nucleic acid structures form in vivo and play biological roles. However, to date, there are no optical probes able to identify i-motif in the presence of other types of DNA. Herein, we report for the first time the interactions between the three isomers of [Ru(bqp)2]2+ with i-motif, G-quadruplex, and double-stranded DNA. Each isomer has vastly different light-switching properties: mer is "on", trans is "off", and cis switches from "off" to "on" in the presence of all types of DNA. Using emission lifetime measurements, we show the potential of cis to light up and identify i-motif, even when other DNA structures are present using a sequence from the promoter region of the death-associated protein (DAP). Moreover, separated cis enantiomers revealed Λ-cis to have a preference for the i-motif, whereas Δ-cis has a preference for double-helical DNA. Finally, we propose a previously unreported light-switching mechanism that originates from steric compression and electronic effects in a tight binding site, as opposed to solvent exclusion. Our work suggests that many published non-emissive Ru complexes could potentially switch on in the presence biological targets with suitable binding sites, opening up a plethora of opportunity in the detection of biological molecules.

Organocatalytic asymmetric synthesis of both cis- and trans-configured pyrano[2,3-b]chromenes via different dehydration pathways

The enamine-catalyzed [3 + 3]-cycloaddition between chroman-2-ols and β,γ-unsaturated α-ketoesters is developed to access both enantiomers of cis- and trans-fused pyrano[2,3-b]chromene derivatives.

Diastereodivergent Catalysis Using Modularly Designed Organocatalysts: Synthesis of both cis- and trans-Fused Pyrano[2,3-b]pyrans.

Both enantiomers of cis- and trans-fused 3,4,4a,8a-tetrahydro-2H,5H-pyrano[2,3-b]pyran-7-carboxylates have been obtained in high diastereoselectivities and enantioselectivities from the same starting materials using a tandem inverse-electron-demand hetero-Diels-Alder/oxa-Michael reaction catalyzed by modularly designed organocatalysts (MDOs). Diastereodivergence was achieved in these reactions through the direct control of the stereochemistry of the bridgehead atoms of the fused ring using new MDOs self-assembled from both enantiomers of proline and cinchona alkaloid thiourea derivatives.

Diastereodivergent Catalysis Using Modularly Designed Organocatalysts: Synthesis of both cis‐ and trans‐Fused Pyrano[2,3‐b]pyrans

AbstractBoth enantiomers of cis‐ and trans‐fused 3,4,4a,8a‐tetrahydro‐2H,5H‐pyrano[2,3‐b]pyran‐7‐carboxylates have been obtained in high diastereoselectivities and enantioselectivities from the same starting materials using a tandem inverse‐electron‐demand hetero‐Diels–Alder/oxa‐Michael reaction catalyzed by modularly designed organocatalysts (MDOs). Diastereodivergence was achieved in these reactions through the direct control of the stereochemistry of the bridgehead atoms of the fused ring using new MDOs self‐assembled from both enantiomers of proline and cinchona alkaloid thiourea derivatives.

Practical Syntheses of Both Enantiomers of the Conformationally Restricted GABA Analogue cis‐(2‐Aminocyclobutyl)acetic Acid

AbstractTwo efficient routes have been established for the preparation of both enantiomers of cis‐(2‐aminocyclobutyl)acetic acid, a conformationally restricted analogue of GABA. Both procedures converged on the racemic N‐tert‐butoxycarbonyl derivative of the target compound, which was resolved through chiral derivatization with an oxazolidinone auxiliary, which also allowed determination of the absolute configuration of the new compounds. The first route involved the homologation of cis‐2‐aminocyclobutanecarboxylic acid, whereas the second route employed an intramolecular photocyclization protocol, which provided an expedient, cis‐selective access to the lactam form of the target structure.

Enzymatic transesterification of pharmacologically interesting β-aminocycloalkanol precursors

Chemoenzymatic syntheses of both enantiomers of cis- and trans-2-aminocyclopentanol as well as cis- and trans-2-aminocyclohexanol, which are valuable building blocks for a plethora of ligands and pharmaceuticals have been efficiently carried out. The strategy involves the stereospecific syntheses of racemic aminocycloalkanol precursors via tagging of a phthalimide as a masking group and subsequent lipase-catalyzed kinetic resolution. Most of the lipases exhibited excellent enantioselectivity (E≫200) in the transesterification reactions of trans-derivatives, with both N-protected (R,R)-amino acetates and (S,S)-amino alcohols being isolated in enantiopure form. With regard to cis-derivatives, lipases were also very selective, even though the biotransformations were significantly slower.

Chemoenzymatic preparation of optically active 3-(1H-imidazol-1-yl)cyclohexanol-based ionic liquids: application in organocatalysis and toxicity studies

A straightforward and robust modular synthetic approach was developed for the asymmetric synthesis of imidazolium salts, in which several engineered molecular vectors were considered to evaluate their toxicological profile. The diastereoselective synthesis of cis-3-(1H-imidazol-1-yl)cyclohexanol was achieved by the Michael addition of imidazole to cyclohex-2-en-1-one under microwave conditions followed by reduction of the ketone. The racemic cis-alcohol obtained was successfully resolved through a lipase-catalysed kinetic resolution, Pseudomonas cepacia lipase proved to be a good biocatalyst for the exclusive acetylation of the (1R,3S)-cis enantiomer. Using the remaining (1S,3R)-cis alcohol enantiomer as a synthetic precursor, the optically active (1R,3R)-trans alcohol enantiomer was also prepared. The corresponding chiral salts and ionic liquids were obtained via quaternisation with alkyl halides, followed by anion exchange with inorganic salts. In this manner, a family of novel imidazolium-based ionic liquids was prepared, and their properties as phase-transfer catalysts in the Michael addition of diethyl malonate to trans-chalcone were analysed. The toxicity of these compounds against E. coli cells was also evaluated to understand their structural implications through the presented systematic synthetic approach.

Role of Zinc in Isoform-Selective Inhibitor Binding to Neuronal Nitric Oxide Synthase,

In previous studies [Delker, S. L., et al. (2010), J. Am. Chem. Soc. 132, 5437-5442], we determined the crystal structures of neuronal nitric oxide synthase (nNOS) in complex with nNOS-selective chiral pyrrolidine inhibitors, designed to have an aminopyridine group bound over the heme where it can electrostatically interact with the conserved active site Glu residue. However, in addition to the expected binding mode with the (S,S)-cis inhibitors, an unexpected "flipped" orientation was observed for the (R,R)-cis enantiomers. In the flipped mode, the aminopyridine extends out of the active site where it interacts with one heme propionate. This prompted us to design and synthesize symmetric "double-headed" inhibitors with an aminopyridine at each end of a bridging ring structure [Xue, F., Delker, S. L., Li, H., Fang, J., Jamal, J., Martásek, P., Roman, L. J., Poulos, T. L., and Silverman, R. B. Symmetric double-headed aminopyridines, a novel strategy for potent and membrane-permeable inhibitors of neuronal nitric oxide synthase. J. Med. Chem. (submitted for publication)]. One aminopyridine should interact with the active site Glu and the other with the heme propionate. Crystal structures of these double-headed aminopyridine inhibitors in complexes with nNOS show unexpected and significant protein and heme conformational changes induced by inhibitor binding that result in removal of the tetrahydrobiopterin (H(4)B) cofactor and creation of a new Zn(2+) site. These changes are due to binding of a second inhibitor molecule that results in the displacement of H(4)B and the placement of the inhibitor pyridine group in position to serve as a Zn(2+) ligand together with Asp, His, and a chloride ion. Binding of the second inhibitor molecule and generation of the Zn(2+) site do not occur in eNOS. Structural requirements for creation of the new Zn(2+) site in nNOS were analyzed in detail. These observations open the way for the potential design of novel inhibitors selective for nNOS.

Integrated Synthetic, Pharmacological, and Computational Investigation of cis‐2‐(3,5‐Dichlorophenylcarbamoyl)cyclohexanecarboxylic Acid Enantiomers As Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 4

2-(3,5-Dichlorophenylcarbamoyl)cyclohexanecarboxylic acid (1) is a potent and selective positive allosteric modulator of metabotropic glutamate receptor subtype 4 (mGluR4). The activity of 1 was reported to reside in the cis diastereomer with equal potency between its enantiomeric forms (Niswender et al., Mol. Pharmacol. 2008, 74, 1345-1358). In the present study, the asymmetric synthesis of each of the cis enantiomers was performed, and their activities were compared with that of the racemic trans. In our assays, the cis enantiomers differ in potency, with one of them (1R,2S) higher and the other (1S,2R) lower than the racemic trans. High-level quantum chemical calculations were carried out to characterize the structures of minimum energy in all-isomer conformational space as well as particular intermediates between conformational transitions. Computational analysis identified structural features of 1 that can play a role in mGluR4 functionality and establish the basis for subsequent work, in which molecular chirality constructed on conformations derived from those found for the active (1R,2S) enantiomer can provide new ideas for drug discovery. Comparison between experimental and theoretical circular dichroism spectra confirmed both the absolute configuration of the (1R,2S) compound and its calculated most stable conformation, thereby supporting experimental and theoretical work.

Synthesis and Resolution of cis-(±)-Methyl (1R,2S/1S,2R)-2-[(4-Hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl)cyclopropanecarboxylate [(±)-PPCC)]: New σ Receptor Ligands with Neuroprotective Effect

The enantiomers of cis-(+/-)-methyl (1R,2S/1S,2R)-2-[(4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl)cyclopropanecarboxylate [1, (+/-)-PPCC], a selective sigma ligand, were synthesized. The (+)- and (-)-enantiomers bind predominantly to sigma(1) receptors and have a reduced sigma(2) affinity. Both individually restore the astroglial oxidative status modified by glutamate, counteracting also transglutaminase-2 overexpression. They exhibited in vivo anti-opioid effects on kappa opioid (KOP) receptor-mediated analgesia. Our findings demonstrate that the enantiomers display mainly sigma(1) agonist activity and that they have neuroprotective effects.

Efficient kinetic bioresolution of 2-nitrocyclohexanol

The kinetic bioresolution of 2-nitrocyclohexanol 1 was investigated by screening a range of hydrolases both for enantioselective transesterification and for enantioselective hydrolysis of the corresponding acetate. By appropriate choice of biocatalyst and conditions, both enantiomers of cis and trans 2-nitrocyclohexanol 1 can be accessed in enantiopure form.

Applying Lipase Catalysis to Access the Enantiomers of Dorzolamide Intermediates

AbstractThe kinetic resolution of three dorzolamide intermediates has been studied in the presence of Burkholderia cepacia lipase in organic solvents. All the stereoisomers of 6‐methyl‐5,6‐dihydro‐4H‐thieno[2,3‐b]thiopyran‐4‐ol were prepared starting from the racemic cis‐dihydrothiopyranol intermediate giving first the 4R,6S and 4S,6R enantiomers. Subsequent epimerization and purification of the trans enantiomers by enzymatic acylation or alcoholysis then gave the cis enantiomers. The cis‐4‐hydroxy‐6‐methyl‐5,6‐dihydro‐4H‐thieno[2,3‐b]thiopyran 7,7‐dioxide enantiomers were also prepared by enzymatic kinetic resolution. The kinetic resolution of ethyl 3‐(2‐thienylthio)butanoate with lipases gave moderate enantioselectivities but the method was not used on a preparative scale with this substrate. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Contributions to chromatographic chiral recognition of permethrinic acid stereoisomers by a quinine carbamate chiral selector: evidence from X-ray diffraction, DFT computations, 1H NMR, and thermodynamic studies

A chiral stationary phase (CSP) based on O-9-(2,6-diisopropylphenylcarbamoyl)quinine (DIPPCQN) as a chiral selector (SO) exhibits remarkable stereoselectivity for the four stereoisomers of permethrinic acid, 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid (DCCA), a precursor and prime metabolite of the pyrethroid-type insecticide permethrin. The four individual isomers of DCCA were crystallized as salts of DIPPCQN for crystal structure analysis to further our understanding of chiral recognition. X-ray diffraction structures revealed that the diastereomeric complexes displayed only minor differences in their geometries with regard to specific binding interactions. The common feature is an ionic hydrogen bond, which holds the SO-selectand (SO–SA) complexes together and fixes the individual ligands in the same single point in the binding pocket of the SO. Stereoselectivity seems to arise from distinct orientations of the cyclopropane ring and/or its substituents, which means that it is most likely the result of a plethora of weak non-covalent interactions (dispersion forces) or different steric environments for the substituents of the distinct guest stereoisomers. Herein, other interactive and discriminative forces are also discussed on the basis of the additivity of SO–SA binding contributions in accordance to a linear-free energy model for chiral distinction. The chiral recognition mechanism as deduced from the diffraction data has been complemented by DFT computations, liquid chromatographic thermodynamic analysis, and 1H NMR spectroscopy measurements. DFT computations (geometry optimization at the Hartree–Fock level and single point energy calculations at the B3LYP level) could correctly reproduce the relative binding strengths for the two enantiomers of cis- and trans-DCCA (ΔΔ H −4.2 and −0.52 kJ mol −1, respectively) and thus the chromatographic elution order of the enantiomers. Liquid chromatographic thermodynamic investigations are in reasonable agreement with the relative trends regarding enantiomer affinity and the difference in enthalpy changes upon complexation. 1H NMR experiments in acetonitrile-D 3 confirmed that the anti- open conformation of the quinine carbamate SO is, like in the solid-state, the preferential binding conformation in solution phase as well. Other interactions than the ionic hydrogen bond could not be derived from 1H NMR measurements and thus, in sharp contrast to X-ray diffraction, the 1H NMR experiments undertaken did not allow to infer stereoselectivity contributions.

Chemoenzymatic resolution of cis- and trans-3,6-dihydroxy-α-ionone. Synthesis of the enantiomeric forms of dehydrovomifoliol and 8,9-dehydrotheaspirone

A straightforward synthesis of both enantiomers of cis- and trans-3-acetoxy-6-hydroxy-α-ionone is described. The title compounds are prepared by resolution of the diastereoisomerically pure racemic 3,6-dihydroxy-α-ionone isomers. The latter process is based on two steps. The first is the enantio- and regioselective lipase-mediated acetylation of diols to afford the corresponding 3-acetoxy-derivatives. The second is the fractional crystallization of the latter compounds that increase their enantiomeric purity. These building blocks were used for the synthesis of both enantiomeric forms of the natural norterpenoids dehydrovomifoliol 3 and 8,9-dehydrotheaspirone 5. The latter compound is a natural flavor and its odor properties were evaluated by professional perfumers.

Mechanistic insights into the inhibition of prostate specific antigen by β‐lactam class compounds

Prostate Specific Antigen (PSA) is a biomarker used in the diagnosis of prostate cancer and to monitor therapeutic response. However, its precise role in prostate carcinogenesis and metastasis remains largely unknown. A number of studies arguing in the favor of an active role of PSA in prostate cancer development and progression have implicated this serine protease in the release and activation of growth factors such as insulin-like growth factor 1 (IGF1) through cleavage of insulin like growth factor binding protein 3 and Transforming Growth Factor beta (TGF-beta) through cleavage of Latent TGF-beta. In contrast, other studies suggest that PSA activity might hinder tumor development and progression. In light of these contradictory findings, efficient inhibitors of PSA are needed for exploring its biological role in tumor development and metastasis. Towards the goal of developing potent inhibitors of PSA, we have explored the molecular mechanism of a series of beta-lactam based compounds on binding to PSA using activity assays, matrix assisted laser desorption ionization with a time-of-flight mass spectrometry, and GOLD docking methodology. The mass spectrometry experiments and the activity assays confirmed the time-dependent and covalent nature of beta-lactam binding. To gain insights on the reaction intermediates at the molecular level, we docked beta-lactam inhibitors to a homology modeled PSA using the GOLD docking program in noncovalent and covalent binding modes. The docking studies elucidated the molecular details of the early noncovalent Michaelis complex, the acyl-enzyme covalent complex, and the nature of conformational reorganization required for the long term stability of the covalent complex. Additionally, the molecular basis for the effect of stereochemistry of the lactam ring on the inhibitory potency was elucidated through docking of beta-lactam enantiomers. As a validation of our docking methodology, two novel enantiomers were synthesized and evaluated for their inhibitory potency using fluorogenic substrate based activity assays. Additionally, cis enantiomers of eight beta-lactam compounds reported in a previous study were docked and their GOLD scores and binding modes were analyzed in order to assess the general applicability of our docking results. The close agreement of our docking results with the experimental data validates the mechanistic insights revealed through the docking studies and paves the way for the design and development of potent and specific inhibitors of PSA.

Enantiomerically Pure Isophorone Diamine [3-(Aminomethyl)-3,5,5-trimethylcyclohexylamine]: A Chiral 1,4-Diamine Building Block Made Available on Large Scale

Isophorone diamine [IPDA, 3-(aminomethyl)-3,5,5-trimethylcyclohexylamine] is a chiral non-C2-symmetric 1,4-diamine which is produced industrially on large scale as the mixture of all four stereoisomers (cis/trans ca. 3:1). Starting from this industrial bulk product, the preparation of the bis-tosyl, bis-Fmoc, bis-Boc and bis-Z derivatives of cis-IPDA, the preparation of the pure cis enantiomers by HPLC on chiral stationary phase, and the assignment of absolute configurations to the isolated enantiomers are described. We furthermore report an efficient method for the optical resolution of IPDA by salt formation with dibenzoyl tartaric acid. The latter method conveniently affords enantiomerically pure cis-IPDA in 100 g quantities. A number of salen ligands have been prepared from this enantiomerically pure 1,4-diamine and fully characterized. The nickel complex of one of the salen ligands was prepared and analyzed by X-ray crystallography. The crystal structure of the Ni4L4 complex illustrates the pronounced preference of cis-IPDA for adopting the chair conformation in which both the amino- and the aminomethyl substituents occupy equatorial positions. As a consequence, the two salicylidene imine moieties of one ligand molecule do not converge on one metal ion, but act as bridging ligands between two nickel ions.

Enantioseparation of Chiral Organochlorines on Permethylated - and -Cyclodextrin, as well as 1:1 Mixtures of Them

Gas chromatography columns coated with 10% permethylated beta- and gamma-cyclodextrin in 85% dimethyl-15% diphenyl polysiloxane (beta- and gamma-PMCD, respectively) and 1:1 mixures are prepared and tested with regard to the enantioseparation of chiral chloropesticides. On the columns with the individual O-methylated cyclodextrins (O-tCDs), the enantiomers of aaeeee-hexachlorocyclohexane (alpha-HCH), e-aeee-1,3,4,5,6-pentachlorocyclohex-1-ene (beta-PCCH), and e-aaee-1,3,4,5,6-pentachlorocyclohex-1-ene (gamma-PCCH), cis- and trans-chlordane, and cis-heptachlor epoxide are separated on both columns, with the exception of the latter being separated only on beta-PMCD. On the column coated with 5% beta- and 5% gamma-PMCD, the resulting separation factor (a) is virtually 1/2 of the arithmetric mean of the elution-dependent separation factors on the individual O-tCDs. In case of reversed elution order on beta- and gamma-PMCD, the enantiomers are not resolved on the mixed columns as is the case with cis-chlordane. Likewise, the lower resolution of the gamma-PCCH enantiomers on the mixed columns prove the reversed elution order on beta- and gamma-PMCD without having enantioenriched standards available. On the column coated with 5% beta- and 5% gamma-PMCD, similar retention times to those observed on both 10% beta-PMCD and 10% gamma-PMCD are obtained. On the column coated with 10% beta- and 10% gamma-PMCD, significantly longer retention times are obtained compared with the columns that contain a total of 10% chiral stationary phase (CSP). This indicates that a relevant part of the interaction of the analytes with the chiral selector is non-enantioselective and, thus, only delays the elution of both enantiomers. Moreover, these non-enantioselective interactions prevent a direct comparison of CSPs with different amounts of the chiral selector. However, this is possible by using mixed phases of two CSPs with similar properties. Using this system, it is demonstrated that for the organochlorine compounds studied, no higher separation factor is observed on the mixed CSPs than on the individual O-tCD with the higher separation factor. Estimations allow a prediction that enantioseparations of organohalogen compounds can be achieved on columns coated with as little as 1% of the CSP.

Lipase-catalyzed kinetic resolution of 2-aminocyclopentane- and 2-aminocyclohexanecarboxamides

Candida antarctica lipase B (CAL-B)-catalyzed N-acylation with 2,2,2-trifluoroethyl butanoate in solvent mixtures of tert-butyl methyl ether and tert-amyl alcohol was used to prepare all the enantiomers of cis- and trans-2-aminocyclopentane- and -cyclohexanecarboxamides. An unexpected change in enantiopreference, accompanied by low enantioselectivity, was observed when Pseudomonas cepacia lipase ( cis-cyclohexane substrate) or C. antarctica lipase A ( cis-cyclopentane and -cyclohexane substrates) replaced CAL-B.