A Comprehensive Study Concerning the Synthesis, Structure, and Reactivity of Terminal Uranium Oxido, Sulfido, and Selenido Metallocenes.

Terminal uranium oxido, sulfido, and selenido metallocenes were synthesized, and their reactivity was comprehensively studied. Heating of an equimolar mixture of [η5-1,2,4-(Me3Si)3C5H2]2UMe2 (2) and [η5-1,2,4-(Me3Si)3C5H2]2U(NH-p-tolyl)2 (3) in the presence of 4-dimethylaminopyridine (dmap) in refluxing toluene forms [η5-1,2,4-(Me3Si)3C5H2]2U═N(p-tolyl)(dmap) (4), which is a useful precursor for the preparation of the terminal uranium oxido, sulfido, and selenido metallocenes [η5-1,2,4-(Me3Si)3C5H2]2U═E(dmap) (E = O (5), S (6), Se (7)) employing a cycloaddition-elimination methodology with Ph2C═E (E = O, S) or (p-MeOPh)2CSe, respectively. Metallocenes 5-7 are inert toward alkynes, but they act as nucleophiles in the presence of alkylsilyl halides. The oxido and sulfido metallocenes 5 and 6 undergo [2 + 2] cycloadditions with isothiocyanate PhNCS or CS2, while the selenido derivative 7 does not. The experimental studies are complemented by density functional theory (DFT) computations.

Platelet Membrane Cloaked Nanotubes to Accelerate Thrombolysis by Thrombus Clot-Targeting and Penetration.

Thrombotic diseases have a high rate of mortality and disability, and pose a serious threat to global public health. Currently, most thrombolytic drugs especially protein drugs have a short blood-circulation time, resulting in low thrombolytic efficiency. Therefore, a platelet membrane (Pm) cloaked nanotube (NT-RGD/Pm) biomimetic delivery system with enhanced thrombolytic efficiency is designed. Nanotubes (NT) with an excellent clot-penetration properties are used to load a protein thrombolytic drug urokinase (Uk). Platelet-targeting arginine glycine-aspartic peptide (RGD) is grafted onto the surface of the nanotubes (NT-RGD) prior to cloaking. Multiple particle tracking (MPT) technique and confocal laser scanning microscope (CLSM) analysis are applied and the results show that the nanotubes possess a strong penetration and diffusion capacity in thrombus clots. After the Pm cloaking on NT-RGD/Uk, it shows a thrombus microenvironmental responsive release property and the half-life of Uk is six times longer than that of free Uk. Most importantly, NT-RGD-Uk/Pm exhibits a 60% thrombolytic efficiency in the FeCl3 -induced thrombosis mouse model, and it is able to significantly reduce the bleeding side effects of Uk. This Pm-cloaked nanotube system is an effective and promising platform for the controlled and targeted delivery of drugs for the thrombus treatment.

Efficient Rh-Catalyzed Chemo- and Enantioselective Hydrogenation of 2-CF3-Chromen/Thiochromen-4-ones.

A Rh-catalyzed highly chemo- and enantioselective hydrogenation of 2-CF3-chromen/thiochromen-4-ones was successfully established achieving excellent selectivity and high turnover numbers. Under mild conditions, a series of 2-CF3-chromen-4-ones were hydrogenated to provide the corresponding chiral 2-CF3-chroman-4-ones with excellent enantioselectivities (up to 99.9% ee) and achieve high turnover numbers (TON of up to 11,800). Moreover, the obtained hydrogenation products were also successfully transformed into other derivatives including the important intermediate of plasmepsin inhibitors with maintained enantiopurity.

Uranium versus Thorium: A Case Study on a Base-Free Terminal Uranium Imido Metallocene.

The structure of and bonding in two base-free terminal actinide imido metallocenes, [η5-1,2,4-(Me3C)3C5H2]2An═N(p-tolyl) (An = U (1), Th (1')) are compared and connected to their individual reactivity. While structurally rather similar, the U(IV) derivative 1 is slightly more sterically crowded. Furthermore, density functional theory (DFT) studies imply that the 5f orbital contribution to the bonding within the individual actinide imido An═N(p-tolyl) moieties is significantly larger for 1 than for 1', which makes the bonds between the [η5-1,2,4-(Me3C)3C5H2]2U2+ and [(p-tolyl)N]2- fragments more covalent. Therefore, steric and electronic factors impact the reactivity of these imido complexes. For example, complex 1 is inert toward internal alkynes, but it readily forms Lewis base adducts [η5-1,2,4-(Me3C)3C5H2]2U═N(p-tolyl)(L) (L = OPMe3 (6), dmap (9), PhCN (14), and 2,6-Me2PhNC (17)) with Me3PO, 4-dimethylaminopyridine (dmap), nitrile, PhCN, or isonitrile 2,6-Me2PhNC. It may also react as a nucleophile or undergo a [2 + 2] cycloaddition with CS2, isothiocyanates, thio-ketones, ketones, lactides, and acyl nitriles, forming the four- or five-membered metallaheteroacycles, terminal sulfido, or oxido complexes, and cyanide amidate complexes, respectively. In contrast, after the addition of aldehyde p-tolylCHO, the tetranuclear complex [η5-1,2,4-(Me3C)3C5H2]4[OCH(p-tolyl)CH(p-tolyl)O]2U4O4 (10) is isolated. However, while 1 is unreactive toward dicyclohexylcarbodiimide (DCC), an equilibrium exists in benzene solution between N,N'-diisopropylcarbodiimide (DIC), 1, and the four-membered metallaheterocycle [η5-1,2,4-(Me3C)3C5H2]2U[N(p-tolyl)C(═NiPr)N(iPr)] (12). Furthermore, 1 may also engage in single- and two-electron transfer processes. It is singly oxidized by Ph3CN3, CuI, Ph2S2, and Ph2Se2, yielding the uranium(V) imido complexes [η5-1,2,4-(Me3C)3C5H2]2U═N(p-tolyl)(X) (X = N3 (20), I (22), PhS (23), and PhSe (24)), or is doubly oxidized by organic azides (RN3) and 9-diazofluorene, forming the uranium(VI) bis-imido metallocenes [η5-1,2,4-(Me3C)3C5H2]2U═N(p-tolyl)(=NR) (R = p-tolyl (18), mesityl (19)) and [η5-1,2,4-(Me3C)3C5H2]2U=N(p-tolyl)[=NN=(9-C13H8)] (21), respectively.

Experimental and Computational Studies on Uranium Diazomethanediide Complexes.

Uranium diazomethanediide complexes can be prepared and their synthesis, structure and reactivity were explored. Reaction of the uranium imido compound [η5 -1,2,4-(Me3 Si)3 C5 H2 ]2 U=N(p-tolyl)(dmap) (1) or [η5 -1,3-(Me3 C)2 C5 H3 ]2 U=N(p-tolyl)(dmap) (4) with Me3 SiCHN2 cleanly yields the first isocyanoimido metal complexes [η5 -1,2,4-(Me3 Si)3 C5 H2 ]2 U(=NNC)(µ-CNN=)U(dmap)[η5 -1,2,4-(Me3 Si)3 C5 H2 ]2 (2) and {[η5 -1,3-(Me3 C)2 C5 H3 ]2 U[µ-(=NNC)]}6 (5), respectively. Both compounds exhibit remarkable thermal stability and were fully characterized. According to density functional theory (DFT) studies the bonding between the Cp2 U2+ and [NNC]2- moieties is strongly polarized with a significant 5 f orbital contribution, which is also reflected in the reactivity of these complexes. For example, complex 5 acts as a nucleophile toward alkylsilyl halides and engages in a [2+2] cycloaddition with CS2 , but no reaction occurs in the presence of internal alkynes.

Small-Molecule Activation Mediated by [η5-1,3-(Me3Si)2C5H3]2U(bipy).

The uranium bipyridyl metallocene, [η5-1,3-(Me3Si)2C5H3]2U(bipy) (2), is readily accessible in good yield by adding potassium graphite (KC8) to a mixture of [η5-1,3-(Me3Si)2C5H3]2UCl2 (1) and 2,2'-bipyridine. Compound 2 was fully characterized and employed for small-molecule activation. It has been demonstrated that 2 may serve as a synthon for [η5-1,3-(Me3Si)2C5H3]2U(II) fragment in the presence of Ph2E2 (E = S, Se), alkynes, and a variety of hetero-unsaturated molecules such as diazabutadienes, azine (Ph2C═N)2, o-benzoquinone, pyridine N-oxide, CS2, isothiocyanates, and organic azides. However, upon exposure of 2 to thio-ketone Ph2CS, aldehyde p-MePhCHO, ketone Ph2CO, imine PhCH═NPh, azine (PhCH═N)2, and nitrile PhCN, it may also promote C-C coupling reactions forming [η5-1,3-(Me3Si)2C5H3]2U[(bipy)(Ph2CS)] (16), [η5-1,3-(Me3Si)2C5H3]2U[(bipy)(p-MePhCHO)] (17), [η5-1,3-(Me3Si)2C5H3]2U[(bipy)(Ph2CO)] (18), [η5-1,3-(Me3Si)2C5H3]2U[(bipy)(PhCHNPh)] (19), [η5-1,3-(Me3Si)2C5H3]2U[(bipy)(PhCHNN═CHPh)] (20), and [η5-1,3-(Me3Si)2C5H3]2U[(N2C10H7C(Ph)NH)] (22), respectively, in quantitative conversion. Furthermore, in the presence of CuI, a single-electron transfer (SET) process is observed to yield the uranium(III) iodide complex [η5-1,3-(Me3Si)2C5H3]2U(I)(bipy) (15).

Uranium versus Thorium: Synthesis and Reactivity of [η5 -1,2,4-(Me3 C)3 C5 H2 ]2 U[η2 -C2 Ph2 ].

The synthesis, electronic structure, and reactivity of a uranium metallacyclopropene were comprehensively studied. Addition of diphenylacetylene (PhC≡CPh) to the uranium phosphinidene metallocene [η5 -1,2,4-(Me3 C)3 C5 H2 ]2 U=P-2,4,6-tBu3 C6 H2 (1) yields the stable uranium metallacyclopropene, [η5 -1,2,4-(Me3 C)3 C5 H2 ]2 U[η2 -C2 Ph2 ] (2). Based on density functional theory (DFT) results the 5f orbital contributions to the bonding within the metallacyclopropene U-(η2 -C=C) moiety increases significantly compared to the related ThIV compound [η5 -1,2,4-(Me3 C)3 C5 H2 ]2 Th[η2 -C2 Ph2 ], which also results in more covalent bonds between the [η5 -1,2,4-(Me3 C)3 C5 H2 ]2 U2+ and [η2 -C2 Ph2 ]2- fragments. Although the thorium and uranium complexes are structurally closely related, different reaction patterns are therefore observed. For example, 2 reacts as a masked synthon for the low-valent uranium(II) metallocene [η5 -1,2,4-(Me3 C)3 C5 H2 ]2 UII when reacted with Ph2 E2 (E=S, Se), alkynes and a variety of hetero-unsaturated molecules such as imines, ketazine, bipy, nitriles, organic azides, and azo derivatives. In contrast, five-membered metallaheterocycles are accessible when 2 is treated with isothiocyanate, aldehydes, and ketones.

Enantioselective Synthesis of Chiral Phosphonates via Rh/f-spiroPhos Catalyzed Asymmetric Hydrogenation of ß,ß-Disubstituted Unsaturated Phosphonates.

The first asymmetric hydrogenation of ß,ß-diaryl unsaturated phosphonates has been realized for synthesis of ß,ß-diaryl chiral phosphonates with excellent enantioselectivities (up to 99.9% ee) catalyzed by the Rh-(R,R)-f-spiroPhos complex. Furthermore, this catalyst also exhibits comparably excellent performance for ß-aryl-ß-alkyl unsaturated phosphonates providing the corresponding chiral phosphonates with up to 99.9% ee values. This methodology provides a straightforward access to asymmetric synthesis of chiral phosphonates.

Experimental and Computational Studies on a Base-Free Terminal Uranium Phosphinidene Metallocene.

The first stable base-free terminal uranium phosphinidene metallocene is presented; and its structure and reactivity have been studied in detail and compared to that of the corresponding thorium derivative. Salt metathesis reaction of the methyl iodide uranium metallocene Cp'''2 U(I)Me (2, Cp'''=η5 -1,2,4-(Me3 C)3 C5 H2 ) with Mes*PHK (Mes*=2,4,6-(Me3 C)3 C6 H2 ) in THF yields the base-free terminal uranium phosphinidene metallocene, Cp'''2 U=PMes* (3). In addition, density functional theory (DFT) studies suggest substantial 5f orbital contributions to the bonding within the uranium phosphinidene [U]=PAr moiety, which results in a more covalent bonding between the [Cp'''2 U]2+ and [Mes*P]2- fragments than that for the related thorium derivative. This difference in bonding besides steric reasons causes different reactivity patterns for both molecules. Therefore, the uranium derivative 3 may act as a Cp'''2 U(II) synthon releasing the phosphinidene moiety (Mes*P:) when treated with alkynes or a variety of hetero-unsaturated molecules such as imines, thiazoles, ketazines, bipy, organic azides, diazene derivatives, ketones, and carbodiimides.

Rh-Catalyzed Asymmetric Hydrogenation of α,ß- and ß,ß-Disubstituted Unsaturated Boronate Esters.

A highly enantioselective hydrogenation of α,ß-unsaturated boronate esters catalyzed by Rh-(S)-DTBM-Segphos complex has been developed. Both (Z)-α,ß- and ß,ß-disubstituted substrates can be successfully hydrogenated to afford chiral boronates with excellent enantioselectivities, up to 98 % ee. Furthermore, the obtained chiral boronate esters, as important versatile synthetic intermediates are successfully transformed to the corresponding chiral alcohols, amines and other important derivatives with maintained enantioselectivities.

A Lewis Base Supported Terminal Uranium Phosphinidene Metallocene.

A Lewis base supported terminal uranium phosphinidene, [η5-1,3-(Me3C)2C5H3]2U(═P-2,4,6-tBu3C6H2)(OPMe3) (5), is isolated from the reaction of the uranium methyl chloride [η5-1,3-(Me3C)2C5H3]2U(Cl)Me (4) with 2,4,6-(Me3C)3C6H2PHK in toluene in the presence of Me3PO. Moreover, the reactivity of uranium phospinidene 5 toward a series of small molecules was comprehensively explored. While no reactivity of 5 with internal alkynes is observed attributed to steric hindrance, it readily reacts in good yields with various small molecules including isothiocyanates, aldehydes, imines, diazenes, carbodiimides, nitriles, isonitriles, and organic azides, yielding uranium sulfidos, oxidos, metallaheterocycles, and imido complexes.

Mechanism of bioactive polysaccharide from Lachnum sp. acts synergistically with 5-fluorouracil against human hepatocellular carcinoma.

The antimetabolite 5-fluorouracil (5-FU) is a widely used antitumor agent, however the overall response rate to 5-FU as a single agent is usually limited. Herein, how Lachnum expolysaccharide (LEP-2a), a type of active polysaccharide isolated from Lachnum sp., acted synergistically with 5-FU on HepG2 cells was investigated. It was found that LEP-2a notably enhanced 5-FU sensitivity in HepG2 cells in a synergistic manner. After combination treatment of 5-FU and LEP-2a, Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathway were inactivated. In addition, combination treatment induced generation of reactive oxygen species, decreased the levels of intracellular antioxidant enzymes and triggered mitochondrial apoptosis pathway. Furthermore, 5-FU combined with LEP-2a also resulted in p53 activation and NF-κB inhibition, and cell cycle arrest in the S phase as well as cell metastasis stagnation. Interestingly, LEP-2a treatment also blocked the DNA damage repair procedure. These findings demonstrate that LEP-2a enhanced 5-FU sensitivity and combination of 5-FU and LEP-2a exerts synergistic antitumor efficiency through multiple approaches.

Highly Efficient Enantioselective Synthesis of Chiral Sulfones by Rh-Catalyzed Asymmetric Hydrogenation.

A highly efficient and enantioselective Rh-( R, R)-f-spiroPhos complex catalyzed hydrogenation of a series of unsaturated sulfones has been developed. With Rh-( R, R)-f-spiroPhos catalyst under mild conditions, not only the asymmetric hydrogenation of both the 3,3-diaryl and exocyclic α,ß-unsaturated sulfones was first realized with up to 99.9% ee but also 3-alkyl-3-aryl and benzo[ b]thiophene-1,1-dioxides were successfully hydrogenated to the corresponding chiral sulfones with excellent enantioselectivities (up to 99.4% ee) regardless of the steric hindrance, electronic property, and geometry of the substrates. Moreover, this reaction offers a route to ( S)-(+)- ar-turmerone as a spice flavor, which is an important synthetic intermediate of pharmaceuticals.

Cu-Catalyzed Asymmetric Hydroboration of Naphthylallylic Compounds for Enantioselective Synthesis of Chiral Boronates.

A Cu-catalyzed regio- and enantioselective hydroboration of various naphthylallylic compounds affording chiral boronates with high yields and excellent enantioselectivities (up to 96% ee) was presented. The utility of the boronated products is further illustrated by other stereospecific C-B bond transformations to produce amino alcohols and other useful compounds.

Copper-Catalyzed Asymmetric Hydroboration of 2 H-Chromenes Using a Chiral Diphosphine Ligand.

A highly regioselective asymmetric hydroboration of 2 H-chromenes catalyzed by the complex of CuCl and diphosphine ligand ( S, R)-DuanPhos has been realized under mild conditions to produce 3-boryl chromans, achieving good yields and excellent enantioselectivities up to 96% ee. This work provides an efficient approach to the synthesis of chiral 3-boryl chromans and derivatives.

An Alkali-Metal Halide-Bridged Actinide Phosphinidiide Complex.

The salt metathesis reaction of the thorium methyl chloride complex [η5-1,3-(Me3C)2C5H3]2Th(Cl)Me (3) with 2,4,6-(Me3C)3C6H2PHK in benzene furnishes an alkali-metal halide-bridged phosphinidiide actinide metallocene, {[η5-1,3-(Me3C)2C5H3]2Th(═P-2,4,6- tBu3C6H2)(ClK)}2 (4), whose structure and reactivity was investigated in detail. On the basis of density functional theory (DFT) studies, the 5f orbitals in the model complex [η5-1,3-(Me3C)2C5H3]2Th(═P-2,4,6- tBu3C6H2) (4') contribute significantly to the bonding of the phosphinidene Th═P(2,4,6- tBu3C6H2) moiety. Furthermore, compared to the related thorium imido complex, the bonds between the [η5-1,3-(Me3C)3C5H2]2Th2+ and [P-2,4,6- tBu3C6H2]2- fragments are more covalent. The reactivity of compound 4 toward alkynes and a variety of heterounsaturated molecules such as nitriles, isonitriles, carbodiimides, imines, isothiocyanates, aldehydes, ketones, thiazoles, quinolines, organic azides, pyridines, and imidazoles, forming metallacycles, phospholes, imidos, metallaheterocycles, sulfidos, oxidos, pinacolates, pseudophosphinimidos, and phosphidos, was comprehensively studied. Moreover, complex 4 reacts with elemental selenium and PhSSPh, yielding selenido and sulfido compounds, respectively. DFT computations were performed to complement these experimental investigations and to provide further insights.

A Base-Free Terminal Actinide Phosphinidene Metallocene: Synthesis, Structure, Reactivity, and Computational Studies.

The synthesis, structure, and reactivity of a base-free terminal actinide phosphinidene metallocene have been comprehensively studied. The salt metathesis reaction of the thorium methyl iodide complex Cp‴2Th(I)Me (2; Cp‴ = η5-1,2,4-(Me3C)3C5H2) with Mes*PHK (Mes* = 2,4,6-(Me3C)3C6H2) in THF furnishes the first stable base-free terminal phosphinidene actinide metallocene, Cp‴2Th═PMes* (3). Density functional theory (DFT) shows that the bonds between the Cp‴2Th2+ and [PMes*]2- fragments are more covalent than those in the related thorium imido complex. While the phosphinidene complex 3 shows no reactivity toward alkynes, it reacts with a variety of heterounsaturated molecules such as CS2, isothiocyanate, nitriles, isonitriles, and organic azides, forming carbodithioates, imido complexes, metallaaziridines, and azido compounds. These experimental observations are complemented by DFT computations.

Enantioselective Synthesis of Boryl Tetrahydroquinolines via Cu-Catalyzed Hydroboration.

A Cu-catalyzed regio- and enantioselective hydroboration of 1,2-dihydroquinolines with high yields and excellent enantioselectivities (up to 98% ee) was presented. This method could be applied in the asymmetric synthesis of the important intermediates used in the enantioselective synthesis of the potential agent Sumanirole for the treatment of Parkinson's disease and of the potentially interesting positive inotropic agent (S)-903.

Heavy Metal Pollution Characteristics in the Modern Sedimentary Environment of Northern Jiaozhou Bay, China.

The particle size distribution characteristics of sediments and the concentrations of heavy metals in Jiaozhou Bay were investigated in this study. The average concentrations of Cu, Pb, Zn, Cr, Cd, Hg and As were 36.88, 29.60, 82.08, 77.48, 0.083, 0.048 and 11.00 mg/kg, respectively. The heavy metal concentrations were highest in the eastern sediments, followed by those at the top of the bay, and the lowest concentrations were observed in the central region. Overall, a decreasing trend from the center of the bay to the periphery was observed. Additionally, the distribution of heavy metals in sediments was not completely controlled by sediment particle size. The degree of heavy metal contamination was evaluated using the geoaccumulation index and Hakanson's method. The results revealed that the level of heavy metal pollution in the sediments was relatively low and that the main pollution elements were Cu and Hg. In addition, the sediments are associated with various levels of potential ecological risk due to the high pollution levels of Hg and Cd.

Rh-Catalyzed Asymmetric Hydrogenation of 1,2-Dicyanoalkenes.

A highly efficient enantioselective hydrogenation of 1,2-dicyanoalkenes catalyzed by the complex of rhodium and f-spiroPhos has been developed. A series of 1,2-dicyanoalkenes were successfully hydrogenated to the corresponding chiral 1,2-dicyanoalkanes under mild conditions with excellent enantioselectivities (up to 98% ee). This methodology provides efficient access to the asymmetric synthesis of chiral diamines.