Chiral Compounds Research Articles

A novel ratiometric fluorescent nanoprobe based on “antenna effect” for discriminating leucine enantiomers

D-Leucine is a potential biomarker for diagnosing diabetes, therefore detection of D-Leu and discrimination of Leu enantiomers are of great importance. Herein, a new fluorescent nanosensor Eu-DLSiNPs was synthesized at room temperature. Based on the “antenna effect”, a chiral ratiometric fluorescent nanoprobe Eu-DLSiNPs/OTC was obtained by simple mixing with oxytetracycline (OTC). This new sensing system showed two distinctive emission peaks at 480 nm and 616 nm, respectively. The addition of D-Leu can cause the fluorescence intensity decreased at 480 nm and enhanced at 616 nm, while L-Leu has no significant effect on the emission of the nanoprobe, so the ratiometric discrimination of Leu enantiomers can be realized. The mechanism of the enantiomeric fluorescence recognition was systematically studied. This work provides a new strategy for the recognition of leucine enantiomers and will paved a new way for discriminating other important chiral compounds.

Iron-Catalyzed Three-Component Asymmetric Carboazidation of Alkenes with Alkanes and Trimethylsilyl Azide

AbstractThe fusion of transition-metal catalysis with radical chemistry provides a versatile platform for the asymmetric radical carboazidation of alkenes to enable the rapid assembly of highly functionalized chiral azide compounds. Here, we present an iron-catalyzed asymmetric three-component radical carboazidation that processes electron-deficient alkenes by direct activation of aliphatic C–H bonds. This strategy provides access to a range of valuable chiral azides from readily available chemical feedstocks bearing a tetrasubstituted carbon stereocenter, and their synthetic potential is further showcased through straightforward transformations to provide other valuable enantioenriched building blocks.

Chiral Selectivities of Permethylated α-, β-, and γ-Cyclodextrins Containing Gas Chromatographic Stationary Phases towards Ibuprofen and Its Derivatives.

Ibuprofen is a well-known and broadly used, nonsteroidal anti-inflammatory and painkiller medicine. Ibuprofen is a chiral compound, and its two isomers have different biological effects, therefore, their chiral separation is necessary. Ibuprofen and its derivatives were used as model compounds to establish transportable structure chiral selectivity relationships. Chiral selectors were permethylated α-, β-, and γ-cyclodextrins containing gas chromatographic stationary phases. The chiral selectivity of ibuprofen as a free acid and its various alkyl esters (methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and isoamyl esters) derivatives were tested at different temperatures. Every tested stationary phase was capable of the chiral separations of ibuprofen in its free acid form. The less strong included S optical isomers eluted before R optical isomers in every separate case. The results offer to draw transportable guidelines for the chiral selectivity vs. analyte structures. It was recognized that the S isomers of free ibuprofen acid showed an overloading phenomenon, but the R isomer did not. The results were supported by molecular modeling studies.

Chromium Catalyzed Asymmetric Reformatsky Reaction.

This study describes an unprecedented chromium-catalyzed asymmetric Reformatsky reaction, enabling the synthesis of chiral β-hydroxy carbonyl compounds from α-chlorinated or α-brominated esters and amides. By employing a chiral chromium/diarylamine bis(oxazoline) catalyst, we achieved relatively broad functional group tolerance. Distinct from known reports, the protocol operates under both classical and photoredox conditions, facilitated by the in situ formation of a nucleophilic chiral chromium intermediate through a radical-polar crossover mechanism. Preliminary mechanistic insights, supported by DFT calculations, identify the nucleophilic aldehyde addition as the key stereo-determining step. This approach not only overcomes the limitations of existing Reformatsky reactions but also provides a versatile strategy for accessing complex chiral molecules.

A new leaf essential oil from the Andean species Gynoxys szyszylowiczii Hieron. of southern Ecuador: chemical and enantioselective analyses

The essential oil obtained from the dry leaves of Gynoxys szyszylowiczii Hieron. was described in this study for the first time. The chemical analysis, conducted on two stationary phases of different polarity, permitted to identify sixty-four compounds, that were quantified with at least one column. The main components, on a non-polar and polar stationary phase respectively, were germacrene D (21.6–19.2%), α-pinene (4.4–4.9%), n-tricosane (4.3% on both columns), (E)-β-caryophyllene (3.3–4.3%), 1-docosene (3.2–2.8%), α-cadinol (2.8–3.1%), and cis-β-guaiene (2.6–3.0%). This investigation was complemented by the enantioselective analysis of some major chiral compounds, carried out on two chiral selectors based on β-cyclodextrines. As a result, (S)-( +)-α-phellandrene, (S)-( +)-β-phellandrene, and (1S,2R,6R,7R,8R)-( +)-α-copaene appeared enantiomerically pure, whereas α-pinene, β-pinene, terpinen-4-ol, and germacrene D were detected as scalemic mixtures. Finally, linalool was practically racemic. The distillation yield, analytically calculated by weight of dry plant material, was 0.03%.

Regio- and Stereoselective Transfer Hydrogenation of Aryloxy Group-Substituted Unsymmetrical 1,2-Diketones: Synthetic Applications and Mechanistic Studies.

Developing a general method that leads to the formation of different classes of chiral bioactive compounds and their stereoisomers is an attractive but challenging research topic in organic synthesis. Furthermore, despite the great value of asymmetric transfer hydrogenation (ATH) in both organic synthesis and the pharmaceutical industry, the monohydrogenation of unsymmetrical 1,2-diketones remains underdeveloped. Here, we report the aryloxy group-assisted highly regio-, diastereo-, and enantioselective ATH of racemic 1,2-diketones. The work produces a myriad of enantioenriched dihydroxy ketones, and further transformations furnish all eight stereoisomers of diaryl triols, polyphenol, emblirol, and glycerol-type natural products. Mechanistic studies and calculations reveal two working modes of the aryloxy group in switching the regioselectivity from a more reactive carbonyl to a less reactive one, and the potential of ATH on 1,2-diketones in solving challenging synthetic issues has been clearly demonstrated.

Highly Efficient Asymmetric [3+2] Cycloaddition Promoted by Chiral Aziridine-Functionalized Organophosphorus Compounds.

The asymmetric [3+2] cycloaddition of azomethine ylides generated from the corresponding imino ester-to-trans-β-nitrostyrene catalysis by chiral aziridine-containing phosphines and phosphine oxides is described. Of the sixteen stereoisomers that could be formed as a result of the title reaction, three were formed, two of which were obtained in an enantiomerically enriched or pure form, and one in a racemic form. One of the products underwent epimerization under basic reaction conditions.

Chirality Determination of Nanocrystals by Electron Crystallography.

Chirality is a common phenomenon in nature and plays an important role in the properties of matter. The rational synthesis of chiral compounds and exploration of their applications in various fields require an unambiguous determination of their handedness. However, in many cases, determinations of the chiral crystal structure and chiral morphology have been a challenging task due to the lack of proper characterization methods, especially for nanosized crystals. Therefore, it is crucial to develop novel and efficient characterization methods. Owing to the strong interactions between matter and electrons, electron crystallography has become a powerful tool for structural analysis of nanomaterials. In recent years, methods based on electron crystallography, such as high-resolution electron microscopy imaging and electron diffraction, have been developed to unravel the chirality of nanomaterials. This brings new opportunities to the design, synthesis, and applications of versatile chiral nanomaterials. In this perspective, we summarize the recent methodology developments and ongoing research of electron crystallography for chiral structure and morphology determination of nanocrystals, including inorganic and organic materials, as well as highlight the potential and further improvement of these methods in the future.

Intelligent Recommendation Systems Powered by Consensus Neural Networks: The Ultimate Solution for Finding Suitable Chiral Chromatographic Systems?

The selection of suitable combinations of chiral stationary phases (CSPs) and mobile phases (MPs) for the enantioresolution of chiral compounds is a complex issue that often requires considerable experimental effort and can lead to significant waste. Linking the structure of a chiral compound to a CSP/MP system suitable for its enantioseparation can be an effective solution to this problem. In this study, we evaluate algorithmic tools for this purpose. Our proposed consensus model, which uses multiple optimized artificial neural networks (ANNs), shows potential as an intelligent recommendation system (IRS) for ranking chromatographic systems suitable for the enantioresolution of chiral compounds with different molecular structures. To evaluate the IRS potential in a proof-of-concept stage, 56 structural descriptors for 56 structurally unrelated chiral compounds across 14 different families are considered. Chromatographic systems under study comprise 7 cellulose and amylose derivative CSPs and acetonitrile or methanol aqueous MPs (14 chromatographic systems in all). The ANNs are optimized using a fit-for-purpose version of the chaotic neural network algorithm with competitive learning (CCLNNA), a novel approach not previously applied in the chemical domain. CCLNNA is adapted to define the inner ANN complexity and perform feature selection of the structural descriptors. A customized target function evaluates the correctness of recommending the appropriate CSP/MP system. The ANN-consensus model exhibits no advisory failures and requires only an experimental attempt to verify the IRS recommendation for complete enantioresolution. This outstanding performance highlights its potential to effectively resolve this problem.

Unconventional Spectral Gaps Induced by Charge Density Waves in the Weyl Semimetal (TaSe4)2I.

Coupling Weyl quasiparticles and charge density waves (CDWs) can lead to fascinating band renormalization and many-body effects beyond band folding and Peierls gaps. For the quasi-one-dimensional chiral compound (TaSe4)2I with an incommensurate CDW transition at TC = 263 K, photoemission mappings thus far are intriguing due to suppressed emission near the Fermi level. Models for this unconventional behavior include axion insulator phases, correlation pseudogaps, polaron subbands, bipolaron bound states, etc. Our photoemission measurements show sharp quasiparticle bands crossing the Fermi level at T > TC, but for T < TC, these bands retain their dispersions with no Peierls or axion gaps at the Weyl points. Instead, occupied band edges recede from the Fermi level, opening a spectral gap. Our results confirm localization of quasiparticles (holes created by photoemission) is the key physics, which suppresses spectral weights over an energy window governed by incommensurate modulation and inherent phase defects of CDW.

NMR-Based Chiral Discrimination of Bulky Amines with a 19F-Tagged NNO Pincer Complex.

Within pharmaceutical research, ensuring the enantiomeric purity of chiral compounds is critical. Specifically, chiral amines are a crucial category of compounds, due to their extensive therapeutic uses. However, the enantiomeric analysis of these compounds, particularly those with significant steric hindrance, remains a challenge. To address this issue, our research introduces a novel chiral 19F-tagged NNO palladium pincer probe, strategically engineered with an open binding site to accommodate bulky amines. This probe facilitates the enantiodifferentiation of such amines, as evidenced by the distinct 19F NMR signals generated by the enantiomers. Moreover, our findings highlight the probe's applicability in the chiral discrimination of various psychoactive substances, underscoring its potential for the identification of illegal stimulant use and contributing to forensic investigations.

Selectfluor and alcohol-mediated synthesis of bicyclic oxyfluorination compounds by Wagner-Meerwein rearrangement.

Herein, we report the first environmentally friendly systematic fluoroalkoxylation reactions in bicyclic systems. New oxyfluorination products were obtained with excellent yields (up to 98%) via Wagner-Meerwein rearrangement using benzonorbornadiene and the chiral natural compound (+)-camphene as bicyclic alkenes, selectfluor as an electrophilic fluorine source, and water and various alcohols as nucleophile sources. The structure of bicyclic oxy- and alkoxyfluorine compounds was determined by NMR and QTOF-MS analyses.

Ebselen: A Review on its Synthesis, Derivatives, Anticancer Efficacy and Utility in Combating SARS-COV-2.

Ebselen is a selenoorganic chiral compound with antioxidant properties comparable to glutathione peroxidase. It is also known as 2-phenyl-1,2-benzisoselenazol-3(2H)-one. In studies examining its numerous pharmacological activities, including antioxidant, anticancer, antiviral, and anti- Alzheimer's, ebselen has demonstrated promising results. This review's primary objective was to emphasize the numerous synthesis pathways of ebselen and their efficacy in fighting cancer. The data were collected from multiple sources, including Scopus, PubMed, Google Scholar, Web of Science, and Publons. The starting reagents for the synthesis of ebselen are 2-aminobenzoic acid and N-phenyl benzamide. It was discovered that ebselen has the ability to initiate apoptosis in malignant cells and prevent the formation of new cancer cells by scavenging free radicals. In addition, ebselen increases tumor cell susceptibility to apoptosis by inhibiting TNF-α mediated NF-kB activation. Ebselen can inhibit both doxorubicin and daunorubicin-induced cardiotoxicity. Allopurinol and ebselen administered orally can be used to suppress renal ototoxicity and nephrotoxicity. Due to excessive administration, diclofenac can induce malignancy of the gastrointestinal tract, which ebselen can effectively suppress. Recent research has demonstrated ebselen to inhibit viral function by binding to cysteinecontaining catalytic domains of various viral proteases. It was discovered that ebselen could inhibit the catalytic dyad function of Mpro by forming an irreversible covalent bond between Se and Cys145, thereby altering protease function and inhibiting SARS-CoV-2. Ebselen may also inhibit the activation of endosomal NADPH oxidase of vascular endothelial cells, which is believed to be required for thrombotic complications in COVID-19. In this review, we have included various studies conducted on the anticancer effect of ebselen as well as its inhibition of SARS-CoV-2.

Multiple‐State Control over Supramolecular Chirality through Dynamic Chemistry Mediated Molecular Engineering

AbstractDynamic chemistry utilizing both covalent and noncovalent bonds provides valid protocols in manipulating properties of self‐assemblies and functions. Here we employ dynamic chemistry to realize multiple‐route control over supramolecular chirality up to five states. N‐protected fluorinated phenylalanine in the carboxylate state self‐assembled into achiral nanoparticles ascribed to the amphiphilicity. Protonation promoted one‐dimensional growth into helices with shrunk hydrophilicity, which in the presence of disulfide pyridine undergo chirality inversion promoted by the hydrogen bonding‐directed coassembly. Further interacting with the water‐soluble reductant cleavages the disulfide bond to initiate the rearrangement of coassemblies with a chirality inversion as well. Finally, by tuning the pH environments, aromatic nucleophilic substitution reaction between reduced products and perfluorinated phenylalanine occurs, giving distinct chiral nanoarchitectures with emerged luminescence and circularly polarized luminescence. We thus realized a particular five‐state control by combining dynamic chemistry at one chiral compound, which greatly enriches the toolbox in fabricating responsive chiroptical materials.

Multiple-State Control over Supramolecular Chirality through Dynamic Chemistry Mediated Molecular Engineering.

Dynamic chemistry utilizing both covalent and noncovalent bonds provides valid protocols in manipulating properties of self-assemblies and functions. Here we employ dynamic chemistry to realize multiple-route control over supramolecular chirality up to five states. N-protected fluorinated phenylalanine in the carboxylate state self-assembled into achiral nanoparticles ascribed to the amphiphilicity. Protonation promoted one-dimensional growth into helices with shrunk hydrophilicity, which in the presence of disulfide pyridine undergo chirality inversion promoted by the hydrogen bonding-directed coassembly. Further interacting with the water-soluble reductant cleavages the disulfide bond to initiate the rearrangement of coassemblies with a chirality inversion as well. Finally, by tuning the pH environments, aromatic nucleophilic substitution reaction between reduced products and perfluorinated phenylalanine occurs, giving distinct chiral nanoarchitectures with emerged luminescence and circularly polarized luminescence. We thus realized a particular five-state control by combining dynamic chemistry at one chiral compound, which greatly enriches the toolbox in fabricating responsive chiroptical materials.

Design and synthesis of novel and potent allosteric HIV-1 integrase inhibitors with a spirocyclic moiety

We report herein the design and discovery of novel allosteric HIV-1 integrase inhibitors. Our design concept utilized the spirocyclic moiety to restrain the flexibility of the conformation of the lipophilic part of the inhibitor. Compound 5 showed antiviral activity by binding to the nuclear lens epithelium-derived growth factor (LEDGF/p75) binding site of HIV-1 integrase (IN). The introduction of a lipophilic amide substituent into the central benzene ring resulted in a significant increase in antiviral activity against HIV-1 WT X-ray crystallography of compound 15 in complex with the integrase revealed the presence of a hydrogen bond between the oxygen atom of the amide of compound 15 and the hydroxyl group of the T125 side chain. Chiral compound 17 showed high antiviral activity, good bioavailability, and low clearance in rats.

Axially chiral dihydrophenanthrene dimers from Pholidota yunnanensis with anti-neuroinflammatory activities

Axially chiral compounds are well known in medicinal chemistry of natural products, but their absolute configurations and bioactivities are rarely reported and studied. In this study, eleven undescribed axially chiral dihydrophenanthrene dimers, as well as twenty-five known dihydrophenanthrenes, were isolated from the entire plant of Pholidota yunnanensis. Their structures were elucidated by comprehensive spectroscopic analysis. A method for determining the absolute configurations of enantiomers was developed based on the rotational barriers and calculated ECD spectra. Additionally, the activities of all isolated compounds were assessed in LPS-induced BV-2 microglial cells. Most dihydrophenanthrenes exhibited significant NO inhibitory activities, and compound 7 showed the most potent inhibitory effect with an IC50 value of 1.5 μM, compared to the positive control minocycline. The immunofluorescence and western blot results revealed that compound 7 suppressed the expression of Iba-1, iNOS and COX-2 in LPS-stimulated BV-2 microglial cells.

Asymmetric Mannich/Cyclization Reaction of 2-Benzothiazolimines and 2-Isothiocyano-1-indanones to Construct Chiral Spirocyclic Compounds.

An efficient and practical organocatalyzed asymmetric Mannich/cyclization tandem reaction strategy of 2-benzothiazolimines and 2-isothiocyanato-1-indanones was developed, and novel spirocyclic compounds containing benzothiazolimine and indanone scaffolds were obtained. This chiral thiourea-catalyzed Mannich/cyclization tandem reaction offers chiral spirocyclic compounds with continuous tertiary and quaternary stereocenters in good to high yields (up to 90%) with excellent diastereoselectivities (up to >20:1 dr) and enantioselectivities (up to 98% ee) at -18 °C. Additionally, the scaled-up synthesis was also performed with retained yield and stereoselectivity, and a reaction mechanism was also proposed.

Real-Time Direct Monitoring of Chirality Fixation and Recognition at the Single-Molecule Level.

Chirality, a fundamental attribute of nature, significantly influences a wide range of phenomena related to physical properties, chemical reactions, biological pharmacology, and so on. As a pivotal aspect of chirality research, chirality recognition contributes to the synthesis of complex chiral products from simple chiral compounds and exhibits intricate interplay between chiral materials. However, macroscopic detection technologies cannot unveil the dynamic process and intrinsic mechanisms of single-molecule chirality recognition. Herein, we present a single-molecule detection platform based on graphene-molecule-graphene single-molecule junctions to measure the chirality recognition involving interactions between amines and chiral alcohols. This approach leads to the realization of in situ and real-time direct observation of chirality recognition at the single-molecule level, demonstrating that chiral alcohols exhibit compelling potential to induce the formation of the corresponding chiral configuration of molecules. The amalgamation of theoretical analyses with experimental findings reveals a synergistic action between electrostatic interactions and steric hindrance effects in the chirality recognition process, thus substantiating the microscopic mechanism governing the chiral structure-activity relationship. These studies open up a pathway for exploring novel chiral phenomena from the fundamental limits of chemistry, such as chiral origin and chiral amplification, and offer important insights into the precise synthesis of chiral materials.

Chiral phosphoric acid-catalyzed asymmetric epoxidation of alkenyl aza-heteroarenes using hydrogen peroxide

The synthesis of chiral α-azaheteroaryl oxiranes via enantioselective catalysis is a formidable challenge due to the required complex stereoselectivity and diverse N-heterocyclic structures. These compounds play a crucial role in developing bioactive molecules, where precise chirality significantly influences biological activity. Here we show that using chiral phosphoric acid as a catalyst, our method efficiently addresses these challenges. This technique not only achieves high enantio- and diastereoselectivity but also demonstrates superior chemo- and stereocontrol during the epoxidation of alkenyl aza-heteroarenes. Our approach leverages a synergistic blend of electrostatic and hydrogen-bonding interactions, enabling the effective activation of both substrates and hydrogen peroxide. The resulting chiral oxiranes exhibit enhanced diversity and functionality, aiding the construction of complex chiral azaaryl compounds with contiguous stereocenters. Kinetic and density functional theory studies elucidate the mechanism, highlighting chiral phosphoric acid’s pivotal role in this intricate enantioselective process.