Chiral Ruthenium Complexes Research Articles

Ruthenium(II)‐Catalyzed Enantioselective Synthesis of 1,2‐trans‐Disubstituted PhSO2CF2‐containing Cyclopropanes

AbstractThe direct diastereo‐ and enantioselective Ru(II)‐ catalyzed cyclopropanation reaction of alkenes with ((2‐diazo‐1,1‐difluoroethyl)sulfinyl)benzene was described. The desired enantioenriched PhSO2CF2‐cyclopropanes were obtained in high yields with high diastereo‐ and enantioselectivities in the presence of a chiral ruthenium complex Ru(II)‐Pheox (17–94% yields, >20:1 d.r. and 83:17–98:2 e.r.). The robustness of the approach was showcased and This methodology gave access to chiral 1,2‐trans difluoro‐methylcyclopropanes.

Experimental and Computational Studies for the Synthesis of Functionalized Cyclopropanes from 2-Substituted Allylic Derivatives with Ethyl Diazoacetate.

The catalytic asymmetric synthesis of highly functionalized cyclopropanes from 2-substituted allylic derivatives is reported. Using ethyl diazo acetate, the reaction, catalyzed by a chiral ruthenium complex (Ru(II)-Pheox), furnished the corresponding easily separable cis and trans cyclopropanes in moderate to high yields (32-97 %) and excellent ee (86-99 %). This approach significantly extends the portfolio of accessible enantioenriched cyclopropanes from an underexplored class of olefins. DFT calculations suggest that an outer-sphere mechanism is operative in this system.

Binding and stabilizations effects of RNA triplex poly(U*A-U) by enantiomers of ruthenium(II) polypyridyl complex [Ru(bpy)2(10-OH-dppz)]2+

Two new chiral ruthenium (II) complexes, Δ-[Ru (bpy)2 (10-OH-dppz)]2+ (Δ-1; bpy = 2,2ʹ-bipyridine, 10-OH-dppz = 10-hydroxyl-dipyrido [3,2-a:2′,3′-c]phenazine) and Λ-[Ru (bpy)2 (10-OH-dppz)]2+ (Λ-1), have been synthesized and characterized in this work. The binding properties of the two enantiomers with an RNA triplex poly (U*A-U) [in text, dash (−) denotes the Watson-Crick base pairing and the asterisk (*) denotes the Hoogsteen base pairing] have been studied. Analysis of the absorption and fluorescence spectra suggest that the binding constant of enantiomer Λ-1 toward the triplex is somewhat smaller than that of enantiomer Δ-1, which is further supported by viscosity experiments. Viscosity experiments showed that although the two enantiomers were intercalated to the triplex, the Δ-enantiomer was a better intercalator than the Λ-enantiomer. Furthermore, thermal denaturation experiments demonstrate that although the two enantiomers can significantly increase the triplex stabilization, unlike enantiomer Λ-1, enantiomer Δ-1 stabilizes the Watson-Crick base-paired duplex and the Hoogsteen base-paired third strand of the triplex with obvious selectivity. In addition, the triplex stabilization by enantiomer Δ-1 was significantly stronger than that by Λ-1. The obtained results indicate that the binding ability of enantiomers Δ-1 and Λ-1 to the triplex is dependent on the chirality of enantiomers.

Chiral Atropisomeric-NHC Catechodithiolate Ruthenium Complexes for Z-Selective Asymmetric Ring-Opening Cross Metathesis of Exo-Norbornenes.

A set of 16 chiral ruthenium complexes containing atropisomerically stable N-Heterocyclic Carbene (NHC) ligands was synthesized from prochiral NHC precursors. After a rapid screening in asymmetric ring-opening-cross metathesis (AROCM), the most effective chiral atrop BIAN-NHC Ru-catalyst (up to 97 : 3 er) was then converted to a Z-selective catechodithiolate complex. The latter proved to be highly efficient in Z-selective AROCM of exo-norbornenes affording valuable trans-cyclopentanes with excellent Z-selectivity (>98 %) and high enantioselectivity (up to 96.5 : 3.5 er).

Novel Chiral Ru(II) Complexes as Potential c-myc G-quadruplex DNA Stabilizers Inducing DNA Damage to Suppress Triple-Negative Breast Cancer Progression.

Currently, effective drugs for triple-negative breast cancer (TNBC) are lacking in clinics. c-myc is one of the core members during TNBC tumorigenesis, and G-rich sequences in the promoter region can form a G-quadruplex conformation, indicating that the c-myc inhibitor is a possible strategy to fight cancer. Herein, a series of chiral ruthenium(II) complexes ([Ru(bpy)2(DPPZ-R)](ClO4)2, Λ/Δ-1: R = -H, Λ/Δ-2: R = -Br, Λ/Δ-3: R = -C≡C(C6H4)NH2) were researched based on their interaction with c-myc G-quadruplex DNA. Λ-3 and Δ-3 show high affinity and stability to decrease their replication. Additional studies showed that Λ-3 and Δ-3 exhibit higher inhibition against different tumor cells than other molecules. Δ-3 decreases the viability of MDA-MB-231 cells with an IC50 of 25.51 μM, which is comparable with that of cisplatin, with an IC50 of 25.9 μM. Moreover, Δ-3 exhibits acceptable cytotoxic activity against MDA-MB-231 cells in a zebrafish xenograft breast cancer model. Further studies suggested that Δ-3 decreases the viability of MDA-MB-231 cells predominantly through DNA-damage-mediated apoptosis, which may be because Δ-3 can induce DNA damage. In summary, the results indicate that Ru(II) complexes containing alkinyl groups can be developed as c-myc G-quadruplex DNA binders to block TNBC progression.

Chiral ruthenium(II) complexes as stabilizers for an RNA triplex: In contrast to Λ-enantiomer, Δ-enantiomer stabilizes the Watson-Crick duplex and the Hoogsteen strand without significant preference

To further determine the factors governing the triplex stabilization by chiral ruthium(II) polypyridyl complexes, two new dppz-beased binding reagents, Δ-[Ru(bpy)2(6-NO2-dppz)]2+ (Δ-1; bpy = 2,2′-bipyridine; 6-NO2-dppz = 6-nitro-dipyrido-3,2-a,2′,3′-c]phenazine) and Λ-[Ru(bpy)2(6-NO2-dppz)]2+ (Λ-1), have been synthesized and characterized in this work. Binding properties of the two enantiomers Δ-1 and Λ-1 with the RNA poly(U)•poly(A)*poly(U) triplex have been studied by spectroscopic technologies and viscosity measurements as well as melting measurements. Spectral titrations and viscosity experiments as well as light-scattering experiments show that although the two enantiomers bind to the triplex through an intercalative mode, the binding affinity of Δ-1 toward the triplex is slightly higer than that of Λ-1. Moreover, melting measurements show that the two enantiomers exhibit different stabilization effects on the triplex under the same conditions. The enantiomer Δ-1 stabilizes the triplex without significant preference, thereby almost equally stabilizing the Watson-Crick base-paired duplex (the template duplex) and the Hoogsteen base-paired strand (third-strand) of the triplex. In contrast to Δ-1, Λ-1 shows preference for stabilizing the template duplex rather than third-strand to a large extent. This suggests that the racemic complex [Ru(bpy)2(6-NO2-dppz)]2+ is similar as a non-specific metallointercalator for the triplex investigated in this study. The results obtained in this work show that in addition to chiralities of Ru(II) polypyridyl complexes, substituent effects of the main ligands also play important roles in altering the ability and selectivity of the metal complex enantiomers to stabilize the triplex.

Transfer Hydrogenation of Ketones into Alcohols Catalyzed by a Novel Chiral Terpyridine Ruthenium(II) Complex

Transfer Hydrogenation of Ketones into Alcohols Catalyzed by a Novel Chiral Terpyridine Ruthenium(II) Complex

Enantio- and regioselective asymmetric allylic substitution using a chiral aminophosphinite ruthenium complex: an experimental and theoretical investigation.

The design and synthesis of a new chiral aminophosphinite-ligated ruthenium complex is described. The ruthenium complex, [Ru(AMP)2(CH3CN)2][BPh4]2 {AMP = (S)-tert-butyl 1-(diphenylphosphinooxy)-3-methylbutan-2-ylcarbamate}, has been found to catalyze nucleophilic addition of phenol and carboxylic acid to allyl chloride in a highly regioselective fashion with enantiomeric excess ranging from 12 to 90.

On the Cytotoxicity of Chiral Ruthenium Complexes Containing Sulfur Amino Acids against Breast Tumor Cells (MDA-231 and MCF-7).

Breast cancer is one of the most common types among women. Its incidence progressively increases with age, especially after age 50. Platinum compounds are not efficient in the treatment of breast cancer, highlighting the use of other metals for the development of new chemotherapeutic agents. This paper aims to obtain three new ruthenium compounds that incorporate sulfur amino acids in their structures and to investigate their cytotoxic activity in breast tumor cell lines. Complexes with general formula [Ru(AA)(dppb)(bipy)] (complexes 1 and 2) or [Ru(AA)(dppb) (bipy)]PF6 (complex 3), where AA = L-cysteinate (1), D-penicillaminate (2), and L-deoxyalliinate (3), dppb = 1,4-bis(diphenylphosphino)butane and 2,2´-bipyridine, were obtained from the cis-[RuCl2(dppb)(bipy)] precursor. The cytotoxicity of the complexes on MDA-MB-231 (triple negative human breast cancer); MCF-7 (double positive human breast cancer) and V79 (hamster lung fibroblast) was performed by the MTT (4,5- dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide) method. The control agent was the cisplatin, which is a commercially available drug for cancer treatment. In complexes (1) and (2), the ligands are coordinated to the metal center by nitrogen and sulfur atoms, while in complex (3), coordination is through the oxygen and nitrogen atoms. These suggestions are based on the infrared and 31P{1H} NMR data. For complexes (1) and (2), their X-ray structures were determined confirming this suggestion. The three complexes are stable in a mixture of DMSO (80%) and biological medium (20%) for at least 48h and presented cytotoxicity against the MDA-MB-231 and MCF-7 tumor cells with reasonable selectivity indexes. Our work demonstrated that ruthenium complexes containing sulfur amino acids, bipyridines and bisphosphines showed cytotoxicity against the MDA-MB-231 and MCF-7 cancer cell lines, in vitro, and that they interact weakly with the DNA (Deoxyribonucleic Acid) and the HSA (Human Serum Albumin) biomolecules.

Room-Temperature Guerbet Reaction with Unprecedented Catalytic Efficiency and Enantioselectivity.

We report herein an unprecedented highly efficient Guerbet-type reaction at room temperature (catalytic TON up to >6000). This β-alkylation of secondary methyl carbinols with primary alcohols has significant advantage of delivering higher-order secondary alcohols in an economical, redox-neutral fashion. In addition, the first enantioselective Guerbet reaction has also been achieved using a commercially available chiral ruthenium complex to deliver secondary alcohols with moderate yield and up to 92 % ee. In both reactions, the use of a traceless ketone promoter proved to be beneficial for the catalytic efficiency.

Room‐Temperature Guerbet Reaction with Unprecedented Catalytic Efficiency and Enantioselectivity

AbstractWe report herein an unprecedented highly efficient Guerbet‐type reaction at room temperature (catalytic TON up to >6000). This β‐alkylation of secondary methyl carbinols with primary alcohols has significant advantage of delivering higher‐order secondary alcohols in an economical, redox‐neutral fashion. In addition, the first enantioselective Guerbet reaction has also been achieved using a commercially available chiral ruthenium complex to deliver secondary alcohols with moderate yield and up to 92 % ee. In both reactions, the use of a traceless ketone promoter proved to be beneficial for the catalytic efficiency.

Recognizing and stabilizing miR-21 by chiral ruthenium(II) complexes

MiR-21, a non-coding miRNA with 22 nucleotides, plays an important part in the proliferation, invasion, and metastasis of tumor cells. The present study demonstrates that isomers of chiral ruthenium(II) complexes with alkynes (Λ-1 and Δ-1) were synthesized by Songogashira coupling reaction by using microwave-assisted synthetic technology. The isomers can recognize and stabilize miR-21, with the Λ-isomer showing a stronger binding capacity than the Δ-isomer. Further studies showed that both isomers can be uptaken by MDA-MB-231 cells and enriched in the nucleus. Treatment with the Λ-/Δ-isomer downregulated the expression of miR-21. In a word, the development of chiral ruthenium(II) complexes act as potential inhibitors against tumor cells by recognizing, stabilizing, and regulating the expression of miR-21.

Stable Chiral Ruthenium Complex Catalyst Based on Polymer Ionic Liquid for Asymmetric Transfer Hydrogenation of Aliphatic Ketones in Water

The development of heterogeneous chiral metal catalysts which maintain efficiency and stability in the aqueous phase is significant for applications in many industries. On the basis of a series of ...

Chiral Ru(ii) complexes act as a potential non-viral gene carrier for directional transportation to the nucleus and cytoplasm.

Guanine-rich DNA sequences can spontaneously fold into four-stranded structures called G-quadruplexes (G4s). G4s have been identified extensively in the promoter regions of several proto-oncogenes, including c-myc, as well as telomeres. G4s have attracted an increasing amount of attention in the field of nanotechnology because of their use as versatile building blocks of DNA-based nanostructures. In this study, we report the self-assembly of c-myc G-quadruplex DNA controlled by a pair of chiral ruthenium(ii) complexes coordinated by 2-(4-phenyacetylenephenyl)-1H-imidazo[4,5f][1,10]phenanthroline (PBEPIP), Λ-[Ru(bpy)2(PBEPIP)](ClO4)2 (Λ-RM0627, bpy = bipyridine) and Δ-[Ru(bpy)2(PBEPIP)](ClO4)2 (Δ-RM0627). Λ-RM0627 could promote the high-order self-assembly of c-myc G-quadruplex DNA into a nanowire structure, whereas Δ-RM0627 could induce DNA condensation into G-quadruplex aggregates. Moreover, in vitro studies on human liver carcinoma HepG2 cells showed that the nanowire of c-myc G-quadruplex DNA promoted by Λ-RM0627 could be localized in the nuclei of cells, whereas the nanoparticle of c-myc G-quadruplex DNA generated by Δ-RM0627 was taken up and localized in the cytoplasm. This study provides examples of the enantioselective self-assembly of G4 DNA molecules controlled by chiral ruthenium(ii) complexes and suggests the potential applications of assembled nanostructures as non-viral DNA vectors for gene therapy.

Synthesis of Forms of a Chiral Ruthenium Complex Containing a Ru-Colefin(sp2) Bond and Their Application to Catalytic Asymmetric Cyclopropanation Reactions.

Organometallic complexes [Ru-Colefin(sp2)-Ru(II)-Pheox 2a-2d] containing a Ru-Colefin(sp2) bond have been prepared from unsaturated chiral oxazoline derivatives and evaluated for asymmetric cyclopropanation reactions. The corresponding optically active cyclopropanes were obtained with high yields and high stereoselectivities (≥99/<1 trans/cis, 99% trans ee). The enantioselectivities were found to be affected by the geminal substituent on the Ru-C(sp2) bond. In particular, Ru(II)-Prox catalyst 2c, in which there was no geminal substituent on the metal, was shown to have the highest enantioselectivities.

Synthetic approach for optically active polymers through the combination of asymmetric chirogenic polymerization and postpolymerization modification

A new type of asymmetric chirogenic polymerization by asymmetric allylic substitution catalyzed by planar–chiral ruthenium complexes was designed. The polymerization systems function in a highly stereoselective manner to afford optically active polymers with high selectivity. The asymmetric carbon in the main chain is precisely controlled. Each monomer unit of the polymer has a potentially reactive terminal olefin, which can be used for further transformations. Optically active polymers bearing chiral cyclic architecture were prepared by a combination of asymmetric allylic substitution and ring-closing metathesis reaction employing the terminal olefin of the side chains. Additionally, the efficient introduction of a wide range of substituents into the side chain of the optically active polymer without any racemization has been made possible by using the thiol–ene reaction. Poly-N-alkoxyamides obtained by our asymmetric polymerization can be transformed into nonnatural polypeptides containing an aromatic ring on the peptide backbone, called a poly “arylopeptide”, through reductive cleavage of the N–O bond in N-alkoxyamide. The resulting polymer adopts a one-handed stable helical conformation in solution. A new type of asymmetric chirogenic polymerization by asymmetric allylic substitution catalyzed by planar–chiral ruthenium complexes was designed. The polymerization systems function in a highly stereoselective manner. The asymmetric carbon in the main chain is precisely controlled. Each monomer unit of the polymer has a potentially reactive terminal olefin, which can be used for further transformations, ring-closing metathesis and thiol–ene reaction. Additionally, the resulting polymer can be transformed poly “arylopeptide”, through reductive cleavage of the N–O bond in N-alkoxyamide, which adopts a one-handed stable helical conformation in solution.

A Synthetic Route to Chiral Benzo-Fused N-Heterocycles via Sequential Intramolecular Hydroamination and Asymmetric Hydrogenation of Anilino-Alkynes

An efficient sequential intramolecular hydroamination/asymmetric hydrogenation reaction under catalysis of a single chiral ruthenium complex or a binary system consisting of achiral gold complex an...

Chiral ruthenium(II) complex Δ-[Ru(bpy)2(o-FMPIP)] (bpy = bipyridine, o-FMPIP = 2-(2′-trifluoromethyphenyl) imidazo[4,5-f][1,10]phenanthroline) as potential apoptosis inducer via DNA damage

Chiral ruthenium(II) complexes have long been considered as potential anticancer agents. Herein, in vivo inhibitory activity of a chiral ruthenium(II) complex coordinated by ligand 2-(2′-trifluoromethyphenyl) imidazo [4,5-f][1,10]phenanthroline, Δ-[Ru(bpy)2(o-FMPIP)] (D0402) on Kunming(KM) mice bearing tumor (H22 hepatic cancer) has been evaluated, and the results showed that the tumor weight of mice treated with 0.22 mg/(kg·day) D0402 via i.v. administration for 7 days decreased about 31.79% compared to the control group, while the body weight, as well as the thymus, spleen, liver, lung, and kidney indices of mice treated with D0402 observed almost no loss compared to the control group. Furthermore, the mechanism studies on anti-angiogenic showed that D0402 could inhibit the formation of angiogenesis in the transgenic Tg(fli1a: EGFP) zebrafish. After treated with D0402, the sub-intestinal vessels(SIVs) of the zebrafish became disordered and chaotic, and was dosage dependent. Moreover, the TUNEL analysis and comet assays revealed that D0402 can induce apoptosis of HepG2 cell through DNA damage, and this was further demonstrated by immunofluorescence analysis with the number of γ-H2AX increased following the increasing amount of D0402. Besides, in vivo toxicity of D0402 has also been investigated on the development of zebrafish embryo, and the results showed that there were no death or development delay occurred for zebrafish embryo treated with D0402 up to concentration of 60 μM. All in together, this study suggested that D0402 can be developed as a potential inhibitor against liver cancer through co-junction of anti-angiogenesis and apoptosis-inducing via DNA damage in the near future.

Boron Tetrafluoride Anion Bonding Dual Active Species Within a Large-Pore Mesoporous Silica for Two-Step Successive Organic Transformaion to Prepare Optically Pure Amino Alcohols.

Development of a simple and easy handing process for preparation of multifunctional heterogenous catalysts and exploration of their applications in sequential organic transformation are of great significance in heterogeneous asymmetric catalysis. Herein, through the utilization of a anion–bonding strategy, we anchor conveniently both organic bases and chiral ruthenium complex into the nanopores of Me-FDU−12, fabricating a Lewis base/Ru bifunctional heterogeneous catalyst. As we envisaged, cyclic amine as a Lewis base promotes an intermolecular aza–Michael addition between enones and arylamines, affording γ-secondary amino ketones featuring with aryl motif, whereas ruthenium/diamine species as catalytic promoter boosts an asymmetric transfer hydrogenation of γ-secondary amino ketones to γ-secondary amino alcohols. As expected, both enhance synergistically the aza–Michael addition/asymmetric transfer hydrogenation one–pot enantioselective organic transformation, producing chiral γ-secondary amino alcohols with up to 98% enantioselectivity. Unique features, such as operationally simple one–step synthesis of heterogeneous catalyst, homo–like catalytic environment as well as green sustainable process make this heterogeneous catalyst an attracting in a practical preparation of optically pure pharmaceutical intermediates of antidepressants.

Binding properties of chiral ruthenium(II) complexes Λ- and Δ-[Ru(bpy)2dppz-11-CO2Me]2+ toward the triplex RNA poly(U)•poly(A)*poly(U)

Two chiral ruthenium(II) complexes containing ligand dppz-CO2Me (dppz-11-CO2Me = dipyrido[3,2-a,2′,3′-c]phenazine-11-carboxylic acid methyl ester), Δ-[Ru(bpy)2dppz-11-CO2Me]2+ (bpy = 2,2′-bipyridine; Δ-1) and Λ-[Ru(bpy)2dppz-11-CO2Me]2+ (Λ-1), were synthesized and characterized. The binding of the two enantiomers with the triplex RNA poly(U)•poly(A)*poly(U) was carried out by various biophysical techniques. Analysis of the absorption and fluorescence features indicates that the binding strengths of the two enantiomers toward the triplex RNA differ only slightly from each other. The total increase in viscosity and shape of the curves for the triplex RNA with Λ-1 is similar to that with Δ-1, suggesting the binding modes of two enantiomers with the triplex RNA are intercalation. Thermal melting measurements indicate that the stabilization effects clearly depended on the concentrations of Λ-1 and Δ-1. However, the third-strand stabilizing effect of Δ-1 dramatically differs from that of Λ-1 when they interact with the chiral environment of the RNA triple at pH = 7.0 and [Na+] = 35 mM. Combined with the CD (CD = circular dichroism) variations of the triplex RNA with either Λ-1 or Δ-1, the reason for their different triplex stabilization effects may originate from the two enantiomers through different orientations intercalating into nucleobases of the triplex. In addition, effects of higher ionic strengths on the triplex stabilization in the absence and presence of the two enantiomers have also been studied. The results presented here may be useful for understanding the binding properties of the triplex RNA with small molecule, particularly chiral ruthenium(II) complexes.