Simple Synthesis of a Heterocyclophane Exhibiting Anti-c-Met Activity by Acting as a Hatch Blocking Access to the Active Site*.

A simple approach to the synthesis of heterocyclophane consisting of two 4,4'-bithiazoles has been developed in mild conditions. The heterocyclophane with two short chains was conveniently prepared by Hantzsch thiazoles synthesis using the reaction of 3-tert-butoxycarbonyl-3-azapentanethiocarboxamide with 1,4-dibromobutane-2,3-dione in methanol under reflux for only 15 min. Amino groups at the linkers of this heterocyclophane can be functionalized to give acylated and carbamate derivatives. Their properties as protein kinase inhibitors were investigated, and one of the heterocyclophanes exhibited specific anti-activity for c-mesenchymal epithelial transition factor (IC50 =603 nm), among seven types of protein kinases investigated. The computational site identification by ligand competitive saturation method was used to determine why the one heterocyclophane exhibited strong anti-activity for c-mesenchymal epithelial transition factor.

A Novel Mechanism of Preferential Enrichment Phenomenon Observed for the Cocrystal of (RS)-2-{4-[(4-Chlorophenoxy)methyl]phenoxy}propionic Acid and Isonicotinamide.

A new entry of chiral anti-hyperlipoproteinemia drug is reported, showing an excellent preferential enrichment (PE) phenomenon which is not caused by a polymorphic transition during crystallization, but is proposed to occur by a novel mechanism involving partially irregular stacking of R and S homochiral two-dimensional (2D) sheets with a large dipole moment, followed by selective redissolution of one homochiral 2D sheet into the mother liquor during crystallization. The cocrystal composed of (RS)-2-{4-[(4-chlorophenoxy)methyl]phenoxy}propionic acid (CPPPA) and achiral isonicotinamide exhibited a substantial enrichment in the mother liquor up to 93 % ee by simply repeating recrystallization under nonequilibrium conditions using high supersaturation. Furthermore, the deposited crystals with low ee values obtained at the end of PE experiment were second harmonic generation (SHG)-positive, indicating the formation of homochiral domains in the deposited crystals, which reflects the proposed mechanism of PE.

Preparation, characterization and magnetic behavior of a spin-labelled physical hydrogel containing a chiral cyclic nitroxide radical unit fixed inside the gelator molecule.

An optically active amphiphilic nitroxide radical compound [(S,S,R)-], which contains a paramagnetic (2S,5S)-2,5-dimethyl-2,5-diphenylpyrrolidine-N-oxyl radical group fixed in the inner position together with a hydrophobic long alkyl chain and a hydrophilic (R)-alanine residue in the opposite terminal positions, was found to serve as a low-molecular-weight gelator in H2O to give rise to a spin-labelled physical hydrogel. Characterization of the hydrogel was performed by microscopic (SEM, TEM and AFM) techniques, XRD and SAXS measurements, and IR, UV and CD spectroscopies. The gel-sol transition temperature was determined by EPR spectral line-width (ΔHpp) analysis. Measurement of the temperature dependence of relative paramagnetic susceptibility (χrel) for the hydrogel and sol phases was achieved by means of the double-integration of VT-EPR spectra.

Preferential Enrichment of DL-Leucine Using Cocrystal Formation With Oxalic Acid Under Nonequilibrium Crystallization Conditions.

By utilizing the preferential enrichment (PE) technique, we achieved an improved enantiomeric resolution of DL-leucine (Leu) using a 1:1 cocrystal (DL-) of DL-Leu and oxalic acid. The crystal structure analysis of DL- indicated the occurrence of a novel type of phase transition and subsequent preferential redissolution of one enantiomer from the resulting crystals into solution.

Highly efficient chiral resolution of DL-arginine by cocrystal formation followed by recrystallization under preferential-enrichment conditions.

An excellent chiral symmetry-breaking spontaneous enantiomeric resolution phenomenon, denoted preferential enrichment, was observed on recrystallization of the 1:1 cocrystal of dl-arginine and fumaric acid, which is classified as a racemic compound crystal with a high eutectic ee value (>95 %), under non-equilibrium crystallization conditions. On the basis of temperature-controlled video microscopy and in situ time-resolved solid-state (13) C NMR spectroscopic studies on the crystallization process, a new mechanism of phase transition that can induce preferential enrichment is proposed.

Azacalix[4]arene cation radicals: spin-delocalised doublet- and triplet-ground states observed in the macrocyclic m-phenylene system connected with nitrogen atoms.

Electron paramagnetic resonance spectroscopy has unmasked for the first time the spin-delocalised doublet- and triplet-ground states of azacalix[4]arene cation radicals.

Azacalix[7]arene heptamethyl ether: preparation, nanochannel crystal structure, and selective adsorption of carbon dioxide.

To investigate the solid-state complexation of nitrogen-bridged calixarene analogues, azacalix[7]arene heptamethyl ether 1 has been prepared by applying a "5 + 2"-fragment coupling approach using Buchwald-Hartwig aryl amination reaction aided by our previously devised temporal N-silylation protocol. X-ray crystallographic analysis revealed that azacalix[7]arene 1 adopted a highly distorted 1,2-alternate conformation in the solid state as a result of intramolecular NH/O hydrogen bonding interactions and steric repulsion between the methoxy groups. In the crystal, molecules of 1 are mutually interacted by intermolecular NH/O and CH/pi interactions to establish one-dimensional (1D) hexane-filled nanochannel crystal architecture. Similarly to our recently reported azacalix[6]arene 2, the desolvated crystalline powder material of 1 was capable of selectively and rapidly adsorbing CO2 among the four main components of the atmosphere. The adsorption capacity of 1 for CO2 nearly doubled as compared to that of 2 because of the formation of the 1D nanochannel with almost twice the volume of the latter.

Regioselectively N-methylated azacalix[8]arene octamethyl ether prepared by catalytic aryl amination reaction using a temporal N-silylation protocol.

[Structure: see text] A temporal N-silylation protocol in the catalytic aryl amination reaction has been devised to prepare nitrogen-bridged calixarene analogues. The protocol involves a smooth in situ N-silylation before aryl amination reaction, followed by spontaneous cleavage of the N-Si bond in the usual workup process, to furnish secondary aromatic amines as the cross-coupled product with no silyl group on the nitrogen atom. A successful application to the preparation of regioselectively N-methylated azacalix[8]arene is described, together with the crystallographic analysis.

Exhaustively methylated azacalix[4]arene: preparation, conformation, and crystal structure with exclusively CH/pi-controlled crystal architecture.

[structure: see text]. Described are the preparation, conformation, and crystal structure of exhaustively methylated azacalix[4]arene involving nitrogen atoms as bridging units. NMR and X-ray crystallographic analysis have demonstrated that this novel azacalix[4]arene adopts a 1,3-alternate conformation both in solution and in the solid state. The crystal structure has been characterized solely by intermolecular CH/pi interactions, by which the azacalix[4]arenes mutually interact with each other outside the cavity to furnish a two-dimensional network structure.

Spontaneous racemization and epimerization behavior in solution of chiral nitroxides.

[reaction: see text] Enantiomerically enriched samples of chiral cyclic nitroxides with a 4-hydroxyphenyl group on the stereogenic center bearing the NO radical group undergo unprecedented spontaneous racemization and/or epimerization in aprotic solvents, which can be well accounted for by the multistep equilibrations involving planar quinoid intermediates.

Occurrence of spontaneous resolution of ketoprofen with a racemic crystal structure by simple crystallization under nonequilibrium preferential enrichment conditions.

Nearly racemic ketoprofen, which satisfies the requirements for the occurrence of preferential enrichment, was spontaneously resolved into the two enantiomers by simple crystallization under nonequilibrium conditions using high concentrations.

Spontaneous and selective CO2 sorption under ambient conditions in seemingly nonporous molecular crystal of azacalix[5]arene pentamethyl ether.

Described are the syntheses, crystal structures, and solid-gas adsorption behaviors of azacalix[4]arene tetramethyl ether and azacalix[5]arene pentamethyl ether. While the former compound exhibited no adsorption of four main atmospheric components, the latter selectively and rapidly adsorbed CO(2) at ambient temperature and pressure. X-ray crystallographic and potential energy distribution analysis revealed that azacalix[5]arene created an energetically favorable space for CO(2) in its seemingly nonporous crystal, leading to the observed selective CO(2) uptake under ambient conditions.

Azacalix[6]arene hexamethyl ether: synthesis, structure, and selective uptake of carbon dioxide in the solid state.

To investigate dynamic solid-state complexation hitherto unexplored in nitrogen-bridged calixarene analogues, azacalix[6]arene hexamethyl ether has been prepared in three steps by applying a 5+1 fragment-coupling approach by using a Buchwald- Hartwig aryl amination reaction with the aid of our previously devised temporal N-silylation protocol. X-ray crystallographic analysis and NMR spectroscopic measurements have revealed that the azacalix[6]arene is well endowed with hydrogen-bonding ability, by which both the molecular and crystal structures are controlled. The azacalix[6]arene is conformationally flexible in solution on the NMR time scale, whereas it adopts a definite 1,2,3-alternate conformation with S2 symmetry in the solid state as a result of intramolecular bifurcated hydrogen-bonding interactions. In the crystal, molecules of the azacalix[6]arene are mutually interacted by intermolecular hydrogen bonds to establish one-dimensional hexane-filled nanochannel crystal architecture. Although the single crystal was broken after desolvation, the resultant polycrystalline powder material was capable of selectively adsorbing CO2 among the four main gaseous components of the atmosphere. In contrast, carbocyclic p-tert-butylcalix[6]arene hexamethyl ether, the crystal structure of which was also elucidated for the first time in the present study, gave rise to almost no uptake of CO2. Additional solid-gas adsorption experiments for another three gases, such as N2, O2, and Ar, suggested that quadrupole/induced-dipole interactions and/or hydrogen-bonding interactions played an important role in permitting the observed selective uptake of CO2 by this new azacalix[6]arene in the solid state.

Partial resolution of racemic trans-4-[5-(4-alkoxyphenyl)-2,5-dimethylpyrrolidine-1-oxyl-2-yl]benzoic acids by the diastereomer method with (R)- or (S)-1-phenylethylamine.

The partial resolution is described of a series of racemic trans-4-[5-(4-alkoxyphenyl)-2,5-dimethylpyrrolidine-1-oxyl-2-yl]benzoic acids (1), which are the key intermediates for the synthesis of chiral organic radical liquid crystalline compounds and are crystallized to give racemic compounds. Racemic acid 1 [(+/-)-1] with a long alkyl chain (C7 to C13) could be resolved by the conventional diastereomeric salt formation using (R)- or (S)-1-phenylethylamine (2) as the resolving agent, whereas resolution of (+/-)-1 with a short alkyl chain (C4 to C6) was unsuccessful. Use of six equiv of (R)- or (S)-2 for the initial diastereomeric salt formation of (+/-)-1 with a C7-C13 alkyl chain, followed by recrystallization of the resulting salts once or twice, gave 2S,5S- or 2R,5R-enriched 1, respectively, in an ee range of 75-92% and with an overall recovery of 11-27%, based on the original quantity of (+/-)-1.

Induction and inhibition of preferential enrichment by controlling the mode of the polymorphic transition with seed crystals.

Both induction and inhibition of "preferential enrichment", an unusual symmetry-breaking enantiomeric-resolution phenomenon observed upon simple recrystallization of a certain kind of racemic crystals from organic solvents, have been successfully achieved by controlling the mode of the polymorphic transition during crystallization with appropriate seed crystals. Such control of the polymorphic transition can be interpreted in terms of a novel phenomenon consisting of 1) the adsorption of prenucleation aggregates, 2) the heterogeneous nucleation and crystal growth of a metastable crystalline form, and 3) the subsequent polymorphic transition into the more stable form; these three processes occur on the same surface of a seed crystal. We refer to this phenomenon as an "epitaxial transition", which has been confirmed by means of in situ attenuated total reflection (ATR) FTIR spectroscopy in solution and the solid state, differential scanning calorimetry (DSC) measurements of the deposited crystals, and X-ray crystallographic analysis of the single crystals or the direct-space approach employing the Monte Carlo method with the Rietveld refinement for the structure solution from the powder X-ray diffraction data.

A new and selective capillary column coated with cationic diazacrown ether for separation of organic and inorganic anions by capillary electrophoresis.

A new coated capillary has been introduced for capillary electrophoretic separation of anions by using a positively charged diazacrown ether with a 12-membered ring. A positive charge spread over the inner capillary surface led to a substantial anodic electroosmotic flow (EOF) over the range of migrating buffer of pH 2-11. Under the optimum conditions of 25 mM phosphate buffer at pH 7, the diazacrown-coated capillary showed a successful simultaneous separation of 7 inorganic anions and 13 aromatic anions (including positional isomers) in less than 15 min. The migration times of the sample anions and EOF marker for consecutive runs on a single column were highly reproducible, giving a relative standard deviation of 1%. Theoretical treatment of the migration behavior clearly demonstrated that ion association between the diazacrown and analyte anions is strongly dependent on the nature of the functional groups of anions (e.g., sulfonate groups > carboxyl groups) and the number of negative charges (e.g., trivalent anions > divalent anions > monovalent anions) on the analyte.

Capillary electrophoresis using high ionic strength background electrolytes containing zwitterionic and non-ionic surfactants and its application to direct determination of bromide and nitrate in seawater.

In capillary electrophoresis, it is commonly considered that even a moderately high ionic concentration in the background electrolyte (BGE) leads to high currents, resulting in Joule heating and serious peak distortion. As a new approach to overcome this problem, zwitterionic (Zwittergent-3-14) and/or non-ionic (Tween 20) surfactants have been added to BGEs containing high salt concentrations (e.g. 0.3 M NaCl) and have been shown to result in acceptable separation currents (<200 microA). In turn, these BGEs could be applied to the separation of samples containing high salt concentrations (such as undiluted seawater) without the occurrence of any significant peak broadening due to electrodispersion of the sample. For example, a BGE comprising 10 mM Zwittergent-3-14, 50 mM Tween 20, 0.3 M NaCl and 5 mM phosphate (ph 7) could be used for the determination of UV-absorbing anions in seawater, giving good peak shapes and detection limits of 0.8 microM and 0.6 microM for nitrate and bromide, respectively. The beneficial effects of the non-ionic surfactant on the separation were attributed largely to suppression of the electro-osmotic flow. On the other hand, the zwitterionic surfactant was found to be capable of the incorporation of some anions in accordance with the behaviour of these same surfactants in electrostatic ion chromatography. This incorporation resulted in a decreased conductivity of the BGE and also a change in the separation selectivity of the system.