Nickel-catalyzed Nucleophilic C-Borylation of Imines.

Application of bioisostere plays an important role in drug discovery. α-Aminoboronic acid is the familiar bioisostere of α-amino acid. Developing reactions for the synthesis of a wide variety of α-aminoboronic acid is one important task for synthetic chemistry. Herein, we report the development of nucleophilic C-borylation chemistry for N-arylimines catalyzed by nickel. The reaction proceeds through the insertion of a borylnickel species into the C=N bond to afford the corresponding α-aminoboronate, which was isolated as acetamide after trapping with acetic anhydride. N-Benzyl imine is also tolerated by the developed reaction.

Possible Role of Bent Structure of Methylated Lithocholic Acid on Artificial and Plasma Membranes.

Bile acids form micelles that are essential for the absorption of dietary lipids. However, excessive bile acid micelles can disrupt the plasma membrane by removing phospholipids, resulting in cell death. We hypothesized that the bent geometrical structure of the steroid scaffold of bile acids decreases the lipid order (similar to unsaturated phospholipids with cis double bonds), disrupting the plasma membrane. Here, lithocholic acid (LCA), a bile acid, was methylated to prevent micellization. Methylated lithocholic acid (Me-LCA) was mixed with a thin phase-separated lipid bilayer comprising 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and cholesterol (Chol). Me-LCA was not localized in the DPPC-rich rigid phase but localized in the DOPC-rich fluid phase, and excess Me-LCA did not affect the phase separation. Me-LCA is distributed in the plasma and organelle membranes. However, Me-LCA with bent structure did not affect the membrane properties, membrane fluidity, and hydrophobicity of liposomes composed of DOPC, DPPC, and Chol and also did not affect the proliferation of cells.

Quantitative Determination of Relative Permittivity Based on the Fluorescence Property of Pyrene Derivatives: An Interpretation of Hydrophobicity in Self-Assembled Aggregates of Nonionic Amphiphiles.

Aggregates in aqueous solutions can embed hydrophobic molecules, and their interactions depend on the properties of the aggregates. The electric surface potential, molecular mobility, and gradual hydrophobicity are the properties that regulate the interactions, and it is essential to understand these to quantify the properties. Electric surface potential and molecular mobility are quantified using the zeta potential and NMR measurements. In this study, the quantification of gradual hydrophobicity within the aggregate based on the relative permittivity, also called the dielectric constant, has been estimated from fluorescence spectra of pyrene-dicarboxylic acid conjugates. The localization of the pyrene moiety was modified by conjugation with succinic acid, suberic acid, or dodecanedioic acid, and the conjugates were evaluated in the shallow, middle, and deep regions of the aggregates. Span and Tween surfactants have been employed to prepare these aggregates, because they form various kinds of aggregates such as micelles and vesicles. It was realized that the hydrophobicity gradually increased from the interface to the hydrophobic core. Alternatively, a comparison of hydrophobicity within the aggregates showed no remarkable difference. Moreover, the analyses suggested that there are a few water molecules in the deep region. These results support the idea of the localization of embedded molecules in aggregates.

Nickel-Catalyzed Ring-Opening C-O Functionalization of peri-Xanthenoxanthenes for 8-Substituted Binaphthol Synthesis.

Herein, we disclose the Ni-catalyzed ring-opening C-O functionalization of peri-xanthenoxanthenes using Grignard reagents that forms 8-monofunctionalized binaphthols. 1,2-Bis(dicyclohexylphosphino)ethane was the best ligand for alkylations and ICy for arylation. After mechanistic investigations, we assumed that the reaction proceeds via C-O reduction and subsequent C-O functionalization. To verify the mechanism, the intermediate after reduction was isolated. Moreover, the asymmetric addition, using 8-octylbinaphthol after optical resolution, was studied.

Ni-Catalyzed α-Selective C-H Borylations of Naphthalene-Based Aromatic Compounds.

The ability of α-borylated naphthalene-based aromatic compounds is important because it provides ready access to interesting novel extended π-systems. In this report, we disclose the Ni-catalyzed α-selective C-H borylations of naphthalene-based aromatic compounds. The reaction proceeds with peri-xanthenoxanthene and other aromatic compounds to regioselectively afford the α-borylated products without directing groups. The selectivities of these transformations are different from those of Ir-catalyzed C-H borylation reactions and can be used in a complementary manner.

C-H Triflation of BINOL Derivatives Using DIH and TfOH.

C-H trifluoromethanesulfonyloxylation (triflation) of 1,1'-bi-2-naphthol (BINOL) derivatives has been established under mild conditions using 1,3-diiodo-5,5-dimethylhydantoin (DIH) and trifluoromethanesulfonic acid (TfOH). Up to eight TfO groups can be introduced in a single operation. The resulting highly oxidized BINOL derivatives can be successfully converted to 8,8'-dihydroxy BINOL and bisnaphthoquinone compounds. Mechanistic studies suggested that C-H triflation occurs in the form of an aromatic substitution reaction via the in situ formation of a radical cation.

Effect of dehydrocholic acid conjugated with a hydrocarbon on a lipid bilayer composed of 1,2-dioleoyl-sn-glycero-3-phosphocholine.

The effects of bile acids, dehydrocholic acid (DHA) and DHA conjugated with a hydrocarbon (6-aminohexanoate; 6A-DHA) were evaluated using a lipid bilayer composed of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). DOPC formed a homogenous thin membrane in presence or absence of the DHA, while 20 mol% 6A-DHA induced phase separation on the DOPC thin membrane. It was observed formation of a stomatocyte-like liposomes when these membranes were suspended in a basic solvent. Generally, liposome formation can be prevented by some bile acids. It was found that DHA and 6A-DHA did not disrupt liposome formation, while DHA and 6A-DHA perturbed the liposomal membrane, resulting in increased local-fluidity due to the bent structure of DHA and 6A-DHA. DHA and 6A-DHA showed completely different effects on the hydrophobicity of the boundary surface of DOPC liposome membranes. The steroidal backbone of DHA was found to prevent the insertion of water molecules into the liposomal membrane, whereas 6A-DHA did not show the same behavior which was attributed to its conjugated hydrocarbon.

Design of Pyrene-Fatty Acid Conjugates for Real-Time Monitoring of Drug Delivery and Controllability of Drug Release.

Fluorescence probes are usually employed to analyze pharmacokinetics of drug carriers; however, this method using usual probes is not suitable to monitor drug carriers in detail because fluorescence spectra do not change by the disruption of drug carriers. In this study, pyrene-fatty acid conjugates were investigated as probes to monitor the state of drug carriers in real time. 1-Pyrenemethanol was conjugated with fatty acids, such as lauric acid, stearic acid, and behenic acid, and the conjugates were stirred in ethanol, resulting in the formation of submicron particles; these particles exhibited excimer emission. When J774.1 and Colon 26 cells were treated with these particles, the associated fluorescence spectra shifted from excimer emission to monomer emission. Moreover, the degree of change was controlled by the type of fatty acid. These results support the design of drug carriers that can be used to monitor pharmacokinetics in real time and to control the disruption time.

Cu-Catalyzed Aerobic Oxidative C-H/C-O Cyclization of 2,2'-Binaphthols: Practical Synthesis of PXX Derivatives.

Cu-catalyzed C-H/C-O cyclization of 2,2'-binaphthol, using air as an oxidant, was developed. C-H functionalization of binaphthols occurred at the 8,8'-position to form peri-xanthenoxanthenes that exhibit high charge-carrier mobility. The reaction can tolerate a wide variety of functional groups and afforded the corresponding peri-xanthenoxanthene derivatives via an efficient procedure.

Tailor-made drug carrier: Comparison of formation-dependent physicochemical properties within self-assembled aggregates for an optimal drug carrier.

Self-assembled surfactant aggregates, such as micelles and vesicles, have been investigated for their application as drug carriers in the treatment of various diseases. However, the characteristics that decide which aggregate is the best drug carrier for each disease have not yet been clarified. In order to design an optimal drug carrier for each disease, various kinds of self-assembled aggregates, such as spherical micelles, lens-like vesicles, and tube-like vesicles, were evaluated by "multiple techniques" including dynamic light scattering, differential scanning calorimetry, nuclear magnetic resonance spectroscopy, and fluorescence measurement using the Laurdan probe. These studies led to the compilation of a database on the formation-dependent properties of self-assembled aggregates. As the relationship between physicochemical properties of self-assembled aggregates and their functions as drug carriers have been extensively reported, this database can be utilized for designing an optimal drug carrier, i.e., a tailor-made drug carrier.

Amine/Hydrido Bifunctional Nanoporous Silica with Small Metal Nanoparticles Made Onsite: Efficient Dehydrogenation Catalyst.

Multifunctional catalysts are of great interest in catalysis because their multiple types of catalytic or functional groups can cooperatively promote catalytic transformations better than their constituents do individually. Herein we report a new synthetic route involving the surface functionalization of nanoporous silica with a rationally designed and synthesized dihydrosilane (3-aminopropylmethylsilane) that leads to the introduction of catalytically active grafted organoamine as well as single metal atoms and ultrasmall Pd or Ag-doped Pd nanoparticles via on-site reduction of metal ions. The resulting nanomaterials serve as highly effective bifunctional dehydrogenative catalysts for generation of H2 from formic acid.

Grafted Polymethylhydrosiloxane on Hierarchically Porous Silica Monoliths: A New Path to Monolith-Supported Palladium Nanoparticles for Continuous Flow Catalysis Applications.

Polymethylhydrosiloxane has been grafted on the surface of a hierarchically porous silica monolith using a facile catalytic reaction between Si-H and silanol to anchor the polymer. This easy methodology leads to the functionalization of the surface of a silica monolith, where a large amount of free Si-H bonds remain available for reducing metal ions in solution. Palladium nanoparticles of 15 nm have been synthesized homogeneously inside the mesopores of the monolith without any stabilizers, using a flow of a solution containing Pd2+. This monolith was used as column-type fixed bed catalyst for continuous flow hydrogenation of styrene and selective hydrogenation of 3-hexyn-1-ol, in each case without a significant decrease of the catalytic activity after several hours or days. Conversion, selectivity, and stereoselectivity of the alkyne hydrogenation can be tuned by flow rates of hydrogen and the substrate solution, leading to high productivity (1.57 mol g(Pd)-1 h-1) of the corresponding cis-alkene.

An Analytical Method to Measure Free-Water Tritium in Foods using Azeotropic Distillation.

A series of accidents at the Fukushima Dai-ichi Nuclear Power Plant has raised concerns about the discharge of contaminated water containing tritium ((3)H) from the nuclear power plant into the environment and into foods. In this study, we explored convenient analytical methods to measure free-water (3)H in foods using a liquid scintillation counting and azeotropic distillation method. The detection limit was 10 Bq/L, corresponding to about 0.01% of 1 mSv/year. The (3)H recoveries were 85-90% in fruits, vegetables, meats and fishes, 75-85% in rice and cereal crops, and less than 50% in sweets containing little water. We found that, in the case of sweets, adding water to the sample before the azeotropic distillation increased the recovery and precision. Then, the recoveries reached more than 75% and RSD was less than 10% in all food categories (13 kinds). Considering its sensitivity, precision and simplicity, this method is practical and useful for (3)H analysis in various foods, and should be suitable for the safety assessment of foods. In addition, we examined the level of (3)H in foods on the Japanese market. No (3)H radioactivity was detected in any of 42 analyzed foods.

Characterization of sorbitan surfactant-based vesicles at the molecular scale using NMR: Effect of acyl chain length vs. phospholipid composition.

We focused on the characterization of the hydrophobic-hydrophilic interface of the membrane of vesicles prepared with various sorbitan surfactants using two evaluation methods: Laurdan fluorescence intensity (GP(340) value) and NMR analysis (half linewidth). Laurdan fluorescence intensity analysis, used to evaluate the hydrophobicity of the interior of the vesicular membrane, indicated a similarity between Span vesicles and liposomes in terms of hydrophobicity, while NMR analysis, used to assess the mobility of lipid molecules, indicated a large difference between Span vesicles and liposomes in terms of molecular mobility at the interface. These results suggest that the physicochemical properties of Span vesicles and liposomes are roughly similar at the "meso-scale" but not completely similar at the "molecular scale."

Surface functionalization of silica by Si-H activation of hydrosilanes.

Inspired by homogeneous borane catalysts that promote Si-H bond activation, we herein describe an innovative method for surface modification of silica using hydrosilanes as the modification precursor and tris(pentafluorophenyl)borane (B(C6F5)3) as the catalyst. Since the surface modification reaction between surface silanol and hydrosilane is dehydrogenative, progress and termination of the reaction can easily be confirmed by the naked eye. This new metal-free process can be performed at room temperature and requires less than 5 min to complete. Hydrosilanes bearing a range of functional groups, including alcohols and carboxylic acids, have been immobilized by this method. An excellent preservation of delicate functional groups, which are otherwise decomposed in other methods, makes this methodology appealing for versatile applications.

Recyclable functionalization of silica with alcohols via dehydrogenative addition on hydrogen silsesquioxane.

Synthesis of class II hybrid silica materials requires the formation of covalent linkage between organic moieties and inorganic frameworks. The requirement that organosilylating agents be present to provide the organic part limits the synthesis of functional inorganic oxides, however, due to the water sensitivity and challenges concerning purification of the silylating agents. Synthesis of hybrid materials with stable molecules such as simple alcohols, rather than with these difficult silylating agents, may therefore provide a path to unprecedented functionality. Herein, we report the novel functionalization of silica with organic alcohols for the first time. Instead of using hydrolyzable organosilylating agents, we used stable organic alcohols with a Zn(II) catalyst to modify the surface of a recently discovered highly reactive macro-mesoporous hydrogen silsesquioxane (HSQ, HSiO1.5) monolith, which was then treated with water with the catalyst to form surface-functionalized silica. These materials were comprehensively characterized with FT-IR, Raman, solid-state NMR, fluorescence spectroscopy, thermal analysis, elemental analysis, scanning electron microscopy, and nitrogen adsorption-desorption measurements. The results obtained from these measurements reveal facile immobilization of organic moieties by dehydrogenative addition onto surface silane (Si-H) at room temperature with high loading and good tolerance of functional groups. The organic moieties can also be retrieved from the monoliths for recycling and reuse, which enables cost-effective and ecological use of the introduced catalytic/reactive surface functionality. Preservation of the reactivity of as-immobilized organic alcohols has been confirmed, moreover, by successfully performing copper-catalyzed azide-alkyne cycloaddition (CuAAC) "click" reactions on the immobilized silica surfaces.

Generation of pyridyl coordinated organosilicon cation pool by oxidative Si-Si bond dissociation.

An organosilicon cation stabilized by intramolecular pyridyl coordination was effectively generated and accumulated by oxidative Si-Si bond dissociation of the corresponding disilane using low temperature electrolysis, and was characterized by NMR and CSI-MS.

Palladium-catalyzed cross-coupling reactions of (2-pyridyl)allyldimethylsilanes with aryl iodides.

[reaction: see text] (2-Pyridyl)allyldimethylsilanes were found to be novel pyridyl transfer reagents in palladium-catalyzed cross-coupling reactions of various aryl iodides in the presence of silver(I) oxide as an activator.

Copper-catalyzed allylation of carbonyl derivatives using allyl(2-pyridyl)silanes.

[reaction: see text] We have developed an efficient copper-catalyzed allylation of carbonyl derivatives using allyl(2-pyridyl)silanes, in which the strong directing effect of the 2-pyridyl group was observed. A useful synthesis and allylation of substituted allyl(2-pyridyl)silanes is also described.

Diversity-oriented synthesis of tamoxifen-type tetrasubstituted olefins.

A general synthetic scheme for tamoxifen-type tetrasubstituted olefins based on the novel Cu-catalyzed carbomagnesation across alkynyl(2-pyridyl)silane has been developed. A wide array of electronically and structurally diverse tetrasubstituted olefins can be prepared in a regiocontrolled, stereocontrolled, and diversity-oriented manner. Noteworthy features are that (i) the three aryl groups, which are believed to be important (essential) for anti-estrogenic activity, can be varied at will because they all stem from readily available aryl iodides, and (ii) any stereo- and regioisomers can, in principle, be prepared by simply changing the applying order of aryl iodides into the sequence.