Enantiomeric Pairs Research Articles

VCD Analysis of Axial Chirality in Synthetic Stereoisomeric Biaryl-Type bis-Isochroman Heterodimers with Isolated Blocks of Central and Axial Chirality.

Optically active heterodimeric 5,5'-linked bis-isochromans, containing a stereogenic ortho-trisubstituted biaryl axis and up to four chirality centers, were synthesized stereoselectively by using a Suzuki-Miyaura biaryl coupling reaction of optically active isochroman and 1-arylpropan-2-ol derivatives, providing the first access to synthetic biaryl-type isochroman dimers. Enantiomeric pairs and stereoisomers up to seven derivatives were prepared with four different substitution patterns, which enabled us to test how OR, ECD, and VCD measurements and DFT calculations can be used to determine parallel central and axial chirality elements in three isolated blocks of chirality. In contrast to natural penicisteckins A-D and related biaryls, the ECD spectra and OR data of (aS) and (aR) atropodiastereomers did not reflect the opposite axial chirality, but they were characteristic of the central chirality. The atropodiastereomers showed consistently near-mirror-image VCD curves, allowing the determination of axial chirality with the aid of DFT calculation or by comparison of characteristic VCD transitions.

Single-Molecule White Circularly Polarized Photoluminescence and Electroluminescence from Dual-Emission Enantiomers.

The strategy of integrating conformational isomerization donors and chiral acceptors in a single molecule was proposed to construct white circularly polarized luminescence (WCPL) materials in this work. Consequently, a pair of dual-emission enantiomers, namely (R/S)-DO-PTZ, were designed and synthesized, which displayed white emission with blue and yellow dual-emission bands in solution and solid films with Commission Internationale de l'Eclairage (CIE) coordinates of (0.30, 0.33) and (0.33, 0.35), respectively. Meanwhile, (R/S)-DO-PTZ exhibited a high PLQY of up to 67 % in doped films and clear mirror-image WCPL signals with a |glum| value of 3.0×10-3. Moreover, white circularly polarized electroluminescence (WCPEL) based on organic light-emitting diodes (OLEDs) with (R/S)-DO-PTZ as emitters were also achieved with CIE coordinates of (0.32, 0.37) and EQEmax of 4.7 %, representing the state-of-the-art level of white OLEDs based on single-molecule purely organic emitters. By optimizing the device structure, warm WCPEL devices were further obtained with a |gEL| value of 2.8×10-3, CIE coordinates of (0.37, 0.48) and EQEmax of up to 15.6 %. To our knowledge, this is the first report of CP-WOLEDs based on single-molecule purely organic emitters.

Molecular Docking of Chiral Drug Enantiomers With Different Bioactivities.

Chirality has an important role in the drug design because enantiomers may exhibit different bioactivity when interacting with macromolecules of a living organism. In our previous work, based on the analysis of a set of 100 chiral drugs, a relationship was established between the sign of chirality of enantiomers and their bioactivity. To understand the reasons for the observed patterns of chiral specificity of drug enantiomers, the interaction of 10 enantiomeric pairs of chiral drugs with the corresponding target proteins has been considered using molecular docking and further postprocessing by quantum chemistry methods. The data obtained confirm that the energetic aspect of the interaction between opposite enantiomers and target protein affects the enantiomer biological activity. In addition, the results show that molecular docking is able to distinguish between bioactive and inactive/less active enantiomers, although many docking programs are not accurate enough to distinguish a weak inhibitor from a strong one.

Acetylcholinesterase inhibitory phloroglucinols from tropic Rhodomyrtus tomentosa

Four previously undescribed phloroglucinols, including three pairs of enantiomers, (±)-rhodotomentodimer F, (±)-rhodotomentodimer G, and (±)-rhodotomentomonomer E, and one phloroglucinol-sesquiterpene meroterpenoid, rhodotomentodione E, together with one previously reported congener, (±)-rhodomyrtosone A, were obtained from the leaves of Rhodomyrtus tomentosa. The structures including absolute configurations of previously undescribed isolates were elucidated by extensive spectroscopic analysis (HRESIMS and NMR), ECD calculations, and single-crystal X-ray diffraction. (±)-Rhodotomentodimer F is a rare phloroglucinol derivative conjugated by a β-triketone moiety and an unprecedented resorcinol unit via the formation of a rare bis-furan ring system, whereas (±)-rhodotomentomonomer E shares a rearranged pentacyclic scaffold. Pharmacologically, (±)-rhodotomentomonomer E showed the strongest human acetylcholinesterase (hAChE) inhibitory effect with an IC50 value of 1.04 ± 0.05 μM. Molecular formula studies revealed that hydrogen bonds formed between hAChE residues Glu202, Ser203, Ala204, Gly121, Gly122, Tyr337, and His447 and (±)-rhodotomentomonomer E played crucial roles in its observed activity. These findings indicated that the leaves of Rhodomyrtus tomentosa can supply a rich source of hAChE inhibitors. These inhibitors might potentially be utilized in the therapeutic strategy for Alzheimer's disease, offering promising candidates for further research and development.

(Invited) Purification of Enantiomeric Pairs of DNA-Wrapped Carbon Nanotubes and Their Use in Bilateral Chiral Sensing

This presentation will focus on our recent progress in purifying enantiomeric pairs of DNA-wrapped carbon nanotubes (DNA-CNTs) via the aqueous two-phase extraction method. We will also discuss a potential application of enantiomeric pairs of DNA-CNTs in bilateral chiral sensing.

Binaphthalene-Assisted Axial Chirality in Porphyrins: Toward Solid-State Circularly Polarized Luminescence from Self-Assembled Nanostructures.

Circularly polarized luminescence (CPL) is emerging as an effective tool to study the excited-state optical activity in molecules and their self-assembled nanostructures. Chiral porphyrins are a class of optically active molecules wherein the ground-state chirality has been extensively studied in recent times using circular dichroism (CD) spectroscopy. However, obtaining CPL from porphyrin nanostructures, which would have vast implications in biological applications, has remained an uphill task. In this work, we design and synthesize a pair of chiral porphyrin enantiomers functionalized by axially chiral binaphthalene units at the four meso-positions. The molecule undergoes self-assembly following an isodesmic polymerization model, leading to the formation of a spherical nanostructure possessing opposite chirality. Favorable thermodynamic parameters achieved through the controlled experimental conditions helped drive the self-assembly in the forward direction. The limitations imposed by a large nonradiative decay constant arising due to the aggregation-induced quenching could be overcome by fabricating self-standing polymeric films of the nanostructures. The films exhibited relatively high radiative decay and, more interestingly, good CPL activity with clear mirror image spectra for the nanostructures with opposite chirality. The work on CPL-active solid-state materials opens avenue for the design and synthesis of a variety of porphyrin-based chromophoric systems and their nanoaggregates that can find potential application in the field of chiral biosensing and bioimaging, security tags, and display devices.

(±)-Mucroniferal D: a Pair of New Phenolic Enantiomers from Corydalis mucronifera

(±)-Mucroniferal D: a Pair of New Phenolic Enantiomers from Corydalis mucronifera

Simultaneous and in situ syntheses of an enantiomeric pair of homochiral polymers as their perfect stereocomplex in a crystal

Circumventing the issues of conventional stereocomplexation of preformed polymers, herein, we synthesize two enantiopure polymers of opposite chirality simultaneously and in situ as their 1:1 stereocomplex via topochemical polymerization. We design and synthesize an inositol-based achiral monomer for topochemical ene-azide cycloaddition (TEAC) polymerization. In the crystal, the monomer exhibits conformational enantiomerism, and its conformational enantiomers are self-sorted in an arrangement for TEAC polymerization to yield two enantiopure polymers of opposite chirality. Upon heating the monomer crystals, each self-sorted set of conformational enantiomers undergoes regio- and stereospecific polymerization in a single-crystal-to-single-crystal fashion, generating two 1, 4-triazolinyl-linked polymers of opposite chirality simultaneously. The new chiral carbons in all the triazoline rings of a particular polymer chain have the same absolute configuration. These homochiral polymer strands align parallelly, forming a layer, and such enantiopure layers of opposite chirality stack alternately, forming a perfect 1:1 stereocomplex, which we confirmed using single-crystal XRD analysis.

Enantiomer Differentiation by Interaction-Specific Prediction of Residual Dipolar Couplings in Spherical-like Molecules.

Residual Dipolar Couplings (RDCs) are averaged dipolar couplings between nuclear spins of atoms in a molecule that can be measured by nuclear magnetic resonance (NMR) spectroscopy upon partial alignment by a chiral alignment medium. The estimation of differences in alignment of enantiomers may, in principle, enable the determination of absolute configuration. Here, we use molecular dynamics (MD) simulations to mimic the alignment of chiral molecules (i.e., isopinocampheol, quinuclidin-3-ol, borneol, and camphor) to the chiral poly-γ-benzyl-L-glutamate (PBLG) polymer to predict RDCs in silico and compare calculated and experimentally measured residual dipolar couplings for the four enantiomeric pairs. The aim is to validate the computational scheme for the prediction of RDCs in chiral molecules and understand the interaction leading to the alignment in more detail. We determine the indispensable importance of hydrogen bonds between a chiral molecule and the alignment medium on the overall quality of the simulated alignment and interaction poses toward high agreement with experiments. A good correlation with experimental data is found for camphor and isopinocampheol, while the correlation for quinuclidin-3-ol and borneol is lower. We attribute this observation to the high difficulty of the RDC prediction for rather almost spherical molecules. The study reveals that the prediction of alignment with small enantiomeric differences is possible with an MD-based approach; however, extended simulation times (e.g., 50-100 μs) are required to sufficiently reduce the statistical uncertainty. This may be further used for the determination of the relative, as well as absolute, configuration of chiral molecules.

Toxicokinetics and bioavailability of indoxacarb enantiomers and their new metabolites in rats

Indoxacarb is a chiral insecticide that consists of two enantiomers, S-(+)-indoxacarb and R-(−)-indoxacarb, of which only S-(+)-indoxacarb has insecticidal activity. Previous enantioselective toxicology studies of indoxacarb focused mostly on simple environmental model organisms. The lack of a toxicology evaluation of indoxacarb conducted in a mammalian system could mean that the extent of the potential health risk posed by the insecticide to humans is not adequately known. In this study, we reported on a new pair of enantiomers, S-IN-RM294 and R-IN-RM294, derived from the metabolic breakdown of S-(+)-indoxacarb and R-(−)-indoxacarb, respectively, in rats. The toxicokinetics of S-(+)-indoxacarb, R-(−)-indoxacarb, S-IN-RM294, and R-IN-RM294 in rats were evaluated to provide a more comprehensive risk assessment of these molecules. The bioavailability and excretion rates of both S-(+)-indoxacarb and R-(−)-indoxacarb were relatively low, which may be due to their faster metabolism and accumulation in the tissues. In addition, there were significant differences in the metabolism and distribution between the two indoxacarb enantiomers and their metabolites in vivo. S-(+)-Indoxacarb was found to be more easily metabolized in the blood compared with R-(−)-indoxacarb, as shown by the differences in pharmacokinetic parameters between oral and intravenous administration. Analysis of their tissue distribution showed that S-(+)-indoxacarb was less likely to accumulate in most tissues. The results obtained for the two metabolites were consistent with those of the two parent compounds. S-IN-RM294 was more readily cleared from the blood and less likely to accumulate in the tissues compared with R-IN-RM294. Therefore, whether from the perspective of insecticidal activity or from the perspective of mammalian and environmental friendliness, the application of optically pure S-(+)-indoxacarb in agriculture may be a more efficient and safer strategy.

A Homochiral Hexagadolinium Phosphonate Cluster: Structure, Chiral Electrochemical Recognition and a Large Magnetocaloric Effect

AbstractChiral lanthanide clusters have promising applications in chiral recognition, magneto‐optical memories, and spintronic devices. Nonetheless, the precise prediction and controlled development of homochiral polynuclear Ln‐complexes is still a challenge. Herein, through multidentate chelate synthetic strategy, a new homochiral hexagadolinium phosphonate cluster designated as R/S‐[Gd6(pmhpH)8(NO3)2(H2O)8]⋅19H2O (R/S‐1) was successfully obtained by reacting chiral phosphonomethylhomoproline(pmhpH3) with Gd(III) salt. The cluster, shaped like a lantern, is constructed from {GdO8} polyhedra and {PO3C} tetrahedra surrounded by eight pmhpH2− ligands. Within the structure, two types of gadolinium ions with different coordination modes are observed. Each Gd(III) ion is bound to two carboxylate oxygens and six phosphonate oxygens from the coordinated pmhpH2− ligands. Circular dichroism spectra comfirmed that R/S‐1 exists as a pair of enantiomers. Moreover, the cluster exhibits high thermal stability, decomposing at temperatures exceeding 335 °C. Notably, the chiral cluster materials can be used for enantiomeric recognition for tryptophan (Trp) with the differential pulse voltammetry (DPV) peak current ratio (ID/IL) 2.74. Besides, the magnetic measurements revealed that compound R‐1 exhibits a good magnetocaloric effect (MCE) with a maximum entropy change of −ΔSmmax=36.84 Jkg−1 K−1 at T=2 K and ΔH=7 T.

Diastereoselective Synthesis of Sulfoxide-Functionalized N-Heterocyclic Carbene Ruthenium Complexes: An Experimental and Computational Study.

The synthesis of sulfoxide-functionalized NHC ligand precursors were carried out by direct and mild oxidation from corresponding thioether precursors with high selectivity. Using these salts, a series of cationic [Ru(II)(η6-p-cymene)(NHC-SO)Cl]+ complexes were obtained in excellent yields by the classical Ag2O transmetallation route. NMR analyses suggested a chelate structure for the metal complexes, and X-ray diffractometry studies of complexes 4 b, 4 c, 4dBArF and 4 e unambiguously confirmed the preference for the bidentate (κ2-C,S) coordination mode of the NHC-SO ligands. Interestingly, only one diastereomer, in the form of an enantiomeric pair, was observed both in 1H NMR and in the solid state for the complexes. DFT calculations showed a possible intrinsic energy difference between the two pairs of diastereomer. The calculated energy barriers suggested that inversion of the sulfoxide is only plausible from the higher energy diastereomer together with bulky substituents. Inverting the configuration at the Ru center instead shows a lower and accessible activation barrier to provide the most stable diastereomer through thermodynamic control, consistent with the observation of a single species by 1H NMR as a pair of enantiomers. All these complexes catalyse the β-alkylation of secondary alcohols. Complex 4dPF6 bearing an NHC-functionalised S-Ad group has been further studied with different primary and secondary alcohols as substrates, showing high reactivity and high to moderate β-ol-selectivities.

New Ethylated Derivatives of Sulfur- and Nitrogen-Containing Artifacts from Tenodera sinensis Egg Pod and Their Anti-Renal Fibrosis.

Three pairs of enantiomers and one achiral molecule that are new ethylated derivatives of sulfur and nitrogen-containing compounds named mantidisamides E-H (1-4), along with twenty known ones (5-24), were derived from the ethanol extract of Tenodera sinensis Saussure. The structures of these new compounds and their absolute configurations were assigned on the basis of spectroscopic analyses and computational methods. The assessment of activities in NRK-52e cells induced by TGF-β1 demonstrated that the previously undescribed compounds 1 and 2 exhibited a significant capacity to inhibit the expression of proteins (fibronectin, collagen I, and α-SMA). Moreover, the biological activity of these compounds was found to increase with rising concentrations. Notably, compounds 1-4 should be artifacts; however, undescribed compounds 1 and 2, which possessed obvious biological activity, might be attractive for chemists and biologists due to the potential for more detailed exploration of their properties. It is worth mentioning that compounds 1 and 2 remain novel structures even in the absence of the ethoxy group.

Chiral Star-Shaped [CoIII3LnIII] Clusters with Enantiopure Schiff Bases: Synthesis, Structure, and Magnetism.

Two enantiomeric pairs of new 3d-4f heterometallic clusters have been synthesized from two enantiomer Schiff base derivatives: (R/S)-2-[(2-hydroxy-1-phenylethylimino)methyl] phenol (R-/S-H2L). The formulae of the series clusters are Co3Ln(R-L)6 (Ln = Dy (1R), Gd (2R)), Co3Ln (S-L)6 (Ln = Dy (1S), Gd (2S)), whose crystal structures and magnetic properties have been characterized. Structural analysis indicated that the above clusters crystallize in the chiral P213 group space. The central lanthanide ion has a coordination geometry of D3 surrounded by three [CoIII(L)2]- anions using six aliphatic oxygen atoms of L2- featuring a star-shaped [CoIII3LnIII] configuration. Magnetic measurements showed the presence of slow magnetic relaxation with an effective energy barrier of 22.33 K in the DyIII derivatives under a zero-dc field. Furthermore, the circular dichroism (CD) spectra of 1R and 1S confirmed their enantiomeric nature.

Phenolic Constituents with Glucose Uptake and GLUT4 Translocation Bioactivities from the Fruits of Cordia dichotoma.

From the fruits of Cordia dichotoma, 11 new phenolic compounds, dichotomins A-K, were isolated, together with 19 known compounds. Through the analysis of detailed NMR data and HRESIMS data, the planar structures of all compounds were confirmed. Using NMR calculations, the absolute configuration of dichotomins A-K was elucidated by comparing their observed and computed electronic circular dichroism (ECD) spectra. Dichotomin H (8) and dichotomin I (9) were determined as two pairs of enantiomers. The enantiomers of compounds 8 and 9 were separated using chiral-phase high-performance liquid chromatography (HPLC), and the stereostructure of each enantiomer was determined by similarly calculating the ECD. Compounds 3, 5, 7, 17, 18, 23-25, and 27-30 increased glucose uptake by 1.04- to 2.85-folds at concentrations of 30 μg/mL. Further studies revealed that compounds 3 and 5 had a moderate effect on glucose transporter 4 (GLUT4) translocation activity in L6 cells. At 30 μg/mL, compound 3 significantly enhanced AMPK phosphorylation and GLUT4 expression. As a whole, compound 3 has the potential to be a drug candidate for the treatment of type 2 diabetes mellitus (T2DM).

Shortcut model to evaluate the performance of continuous preferential crystallization for conglomerates forming chiral systems

The separation of two enantiomers of a chiral molecule is one of the most difficult tasks for separation technology. Among the available methods, Preferential Crystallization (PC) offers a relatively simple and efficient possibility to separate pairs of enantiomers of conglomerate forming chiral systems. To estimate the potential and to design PC processes, mathematical process models are required. Recently, a short-cut model (SCM) was developed which was found capable to predict the course of batch-wise operated PC until nucleation of the unseeded counter-enantiomer terminates the exploitable production period. In this paper the SCM is reformulated in a dimensionless way and extended to describe also more productive continuous operation of PC. Characteristic dimensionless numbers are demonstrated to be instructive to evaluate effects of system specific kinetic parameters and to identify suitable operating conditions. The sensitivity of the continuous PC process with respect to the most relevant model parameters is investigated based on simulation results. Finally, the role of the SCM in the workflow of designing continuous PC processes is summarized.

Chiral pyrrolidines as multipotent agents in Alzheimer and neurodegenerative diseases

In pharmaceutical science and drug design the versatility of the pyrrolidine scaffold relating to spatial arrangement, synthetic accessibility and pharmacological profile is a largely explored and most likely interesting one. Nonetheless, few evidences suggest the pivotal role of pyrrolidine as scaffold for multipotent agents in neurodegenerative diseases. We then challenged the enrolling in the field of Alzheimer disease of so far not ravelled targets of this chemical cliché with a structure based and computer-aided design strategy focusing on multi-target action, versatile synthesis as well as pharmacological safeness. To achieve these hits, ten enantiomeric pairs of compounds were obtained and tested, and the biological data will be here presented and discussed. Among the novel compounds, coumarin and sesamol scaffolds containing analogues resulted promising perspectives.

Chemical Profiling of Drimys granadensis (Winteraceae) Essential Oil, and Their Antimicrobial, Antioxidant, and Anticholinesterase Properties.

A complete and comprehensive chemical and biological study of Drimys granadensis, a native Ecuadorian aromatic plant, was conducted. By conventional steam distillation from dried leaves, a yellowish, translucent essential oil (EO) with a density of 0.95 and a refractive index of 1.5090 was obtained. The EO was analyzed by gas chromatography coupled to a mass spectrometer (GC/MS) and an FID detector (GC/FID), respectively. Enantiomeric distribution was also carried out by GC/MS using a chiral selective column (diethyl tert-butylsilyl-BETA-cyclodextrin). The microdilution broth method was employed to assess the antibacterial and antifungal activity of the EO against a panel of opportunistic microorganisms. Antioxidant capacity was measured using diphenyl picryl hydrazyl (DPPH) and azino-bis 3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radicals. Finally, the inhibitory potential of the EO against acetylcholinesterase was also valued. Sixty-four chemical compounds, constituting 93.27% of the total composition, were identified, with major components including γ-muurolene (10.63%), spathulenol (10.13%), sabinene (5.52%), and δ-cadinene (4.22%). The characteristic taxonomic marker of the Drimys genus, Drimenol, was detected at very low percentages (<2%). Two pairs of enantiomers ((1S,5R)-(+)-α-pinene/(1S,5S)-(-)-α-pinene; (1S,5R)-(+)-β-pinene/(1S,5S)-(-)-β-pinene) and one pure enantiomer (1R,4S)-(-)-camphene were identified. Regarding antimicrobial potency, the EO exhibited a significant moderate effect on Listeria monocytogenes with a minimal inhibitory concentration (MIC) value of 250 µg/mL, while with the remaining microorganisms, it exerted less potency, ranging from 500 to 2000 µg/mL. The EO displayed moderate effects against the ABTS radical with a half scavenging capacity of 210.48 µg/mL and no effect against the DPPH radical. The most notable effect was noticed for acetylcholinesterase, with a half inhibition concentration (IC50) of 63.88 ± 1.03 µg/mL. These antiradical and anticholinesterase effects hint at potential pharmacological applications in Alzheimer's disease treatment, although the presence of safrole, albeit in low content (ca. 2%), could limit this opportunity. Further in vivo studies are necessary to fully understand their potential applications.

Asymmetric Polarization in a Rough Multilayer: Towards the Discrimination of Enantiomer Pairs.

Chirality plays a significant part in many vital processes, and to further our level of understanding, there is a steadily growing interest in enhancing the yield of enantioselective processes. Here, a multilayer with etched grooves is activated in a Kretschmann geometry and consists of alternating platinum Pt, silica SiO2, and silicon Si, as well as a silver Ag layer. Due to the production process, the groove surface exhibits a micrometric roughness, characterized by a typical vibrational mode at ω = 96 MHz. The mode is attributed to a localized acoustic vibration and has been detected as a transmitted signal. The outcomes of the inquiry include plasmonic amplification of the transmitted signal and its wavevector-less nature; in addition, it is shown that the signal is depolarized in reference to the incident beam because of the rough surface. When the Kretschmann scheme is combined with the depolarization brought on by the roughness, a built-in asymmetry results in a higher optical flux of spectrum photons in the depolarized plane than the co-polarized plane, resulting in distinct, enantioselective, and solely polarization-dependent spectral contrast. In conclusion, enantioselectivity is demonstrated for the D,L-penicillamine.

Single ion mobility monitoring (SIM2) stitching method for high-throughput and high ion mobility resolution chiral analysis

Chiral analysis is of high interest in many fields such as chemistry, pharmaceuticals and metabolomics. Mass spectrometry and ion mobility spectrometry are useful analytical tools, although they cannot be used as stand-alone methods. Here, we propose an efficient strategy for the enantiomer characterization of amino acids (AAs) using non-covalent copper complexes. A single ion mobility monitoring (SIM2) method was applied on a TIMS-ToF mass spectrometer to maximize the detection and mobility separation of isomers. Almost all of the 19 pairs of proteinogenic AA enantiomers could be separated with at least one combination with the chiral references L-Phe and L-Pro. Furthermore, we extended the targeted SIM2 method by stitching several mobility ranges, in order to be able to analyze complex mixtures in a single acquisition while maintaining high mobility resolution. Most of the enantiomeric pairs of AAs separated with the SIM2 method were also detected with this approach. The SIM2 stitching method thus opens the way to a more comprehensive chiral analysis with TIMS-ToF instruments.Graphical