Enantiopure O-ethyl phenylphosphonothioic acid: a solvating agent for the determination of enantiomeric excesses.

An improved method, which is highly reproducible, was developed for the enantioseparation of racemic O-ethyl phenylphosphonothioic acid (1a) with brucine by introducing seeding to a supersaturated solution of the diastereomeric salt mixture. The present method gave both diastereomeric salts in high yields with a diastereomeric ratio of >99.5:0.5 upon choosing the crystallization solvent (MeOH for the (R)-1a salt and MeOH/H2 O for the (S)-1a salt). The enantiopure acid showed a good chirality recognition ability for not only strong bases, such as amines and amino alcohols, but also weakly basic alcohols and was applicable as a solvating agent to the (1) H NMR determination of the enantiomeric excess of chiral amines, amino alcohols, and alcohols, including aliphatic substrates.

Metastable liquid crystal as time-responsive reaction medium: aging-induced dual enantioselective control.

A metastable liquid crystal (LC) was found to serve as a time-responsive reaction medium, in which the enantioselectivity of a photoreaction was perfectly switched through isothermal annealing of the reaction system. When the LC salt of an enantiopure amine with a photoreactive acid was irradiated with UV/vis light, in situ photodimerization of the acid moiety proceeded smoothly to afford the (+)-isomer of the photodimer with high enantioselectivity (+86% ee). In contrast, photoirradiation of an aged sample, isothermally annealed for 20 h, gave predominantly the (-)-isomer (-94% ee). Systematic studies revealed that the reversal in selectivity originated from metastability of the LC system, which gradually transformed into a crystalline phase during annealing. This finding demonstrates the potential use of metastable aggregates as dynamic time-responsive media, reminiscent of biological systems.

One-step synthesis of differently bis-functionalized isoxazoles by cycloaddition of carbamoylnitrile oxide with ß-keto esters.

A new protocol for synthesizing different functionalized isoxazoles is provided. Carbamoylnitrile oxide generated from nitroisoxazolone underwent inverse electron-demand 1,3-dipolar cycloaddition with 1,3-dicarbonyl compounds in the presence of magnesium acetate that formed magnesium enolate in situ. Although electron-deficient trifluoroacetoacetate did not undergo this cycloaddition under the same conditions, conversion to sodium enolate furnish the corresponding bis-functionalized trifluoromethylisoxazole. The DFT calculations using B3LYP 6-31G+(d,p) also supported the aforementioned reactivity.

Guest-responsive covalent frameworks by the cross-linking of liquid-crystalline salts: tuning of lattice flexibility by the design of polymerizable units.

Cross-linked polymers prepared by the in-situ polymerization of liquid-crystalline salts were found to work as solid-state hosts with a flexible framework. As a component of such hosts, four kinds of polymerizable amphiphilic carboxylic acids bearing alkyl chains with acryloyloxy (A), dienyl (D), and/or nonreactive (N) chain ends (monomeric carboxylic acids; M(AAA), M(ANA), M(DDD), and M(DND)) were used. The carboxylic acids were mixed with an equimolar amount of a template unit, (1R,2S)-norephedrine (guest amine; G(RS)), to form the corresponding salts. Every salt exhibited a rectangular columnar LC phase at room temperature, which was successfully polymerized by (60)Co γ-ray-induced polymerization without serious structural disordering to afford the salt of cross-linked carboxylic acid (polymeric carboxylic acid; P(AAA), P(ANA), P(DDD), and P(DND)) with G(RS) . Owing to the noncovalency of the interactions between the polymer framework P and the template G(RS), the cross-linked polymers could reversibly release and capture a meaningful amount of G(RS). In response to the desorption and adsorption of G(RS), the cross-linked polymers dramatically switched their nanoscale structural order. A systematic comparison of the polymers revealed that the choice of polymerizable groups has a significant influence on the properties of the resultant polymer frameworks as solid-state hosts. Among these polymers, P(DDD) was found to be an excellent solid-state host, in terms of guest-releasing/capturing ability, guest-recognition ability, durability to repetitive usage, and unique structural switching mode.

Inverse electron-demand 1,3-dipolar cycloaddition of nitrile oxide with common nitriles leading to 3-functionalized 1,2,4-oxadiazoles.

A carbamoyl-substituted nitrile oxide was generated upon treatment of easily available 2-methyl-4-nitro-3-isoxazolin-5(2H)-one with THF (not dried); the reaction proceeded efficiently even in the absence of any special reagents and reaction conditions. The nitrile oxide caused 1,3-dipolar cycloaddition with common aliphatic nitriles or electron-rich aromatic nitriles to afford 3-functionalized 1,2,4-oxadiazoles, which are expected to serve as precursors for the preparation of a variety of functional materials by the chemical transformation of the carbamoyl group. While conventional preparative methods for 1,2,4-oxadiazoles involve the cycloaddition of an electron-rich nitrile oxide with an electron-deficient nitrile or a nitrile activated by a Lewis acid, our method employs the complementary combination of an electron-rich nitrile and an electron-deficient nitrile oxide- the inverse electron-demand 1,3-cycloaddition. The DFT calculations using B3LYP 6-31G* supported the abovementioned inverse reactivity, and also suggested the presence of an accelerating effect by the carbamoyl group as a result of hydrogen bond formation with a dipolarophilic nitrile.

An anomalous hydration/dehydration sequence for the mild generation of a nitrile oxide.

A nitrile oxide containing a carbamoyl group is readily generated upon the treatment of 2-methyl-4-nitro-3-isoxazolin-5(2H)-one with water under mild reaction conditions, even in the absence of special reagents. The obtained nitrile oxide undergoes cycloaddition with dipolarophiles, alkynes and alkenes, to afford the corresponding isoxazol(in)es, which are useful intermediates in the synthesis of polyfunctionalized compounds. A plausible mechanism underlying the formation of the nitrile oxide is proposed, which involves an anomalous hydration/dehydration sequence. DFT calculations were also performed to support this mechanism.

Enantiopure cyclic O-substituted phenylphosphonothioic acid: synthesis and chirality-recognition ability.

As a new acidic selector (resolving agent), we synthesized an enantiopure O-alkyl phenylphosphonothioic acid with a seven-membered ring ((R)-5), which was designed on the basis of the results for the enantioseparation of 1-arylethylamine derivatives with acyclic O-ethyl phenylphosphonothioic acid (I). The phosphonothioic acid (R)-5 showed unique chirality-recognition ability in the enantioseparation of 1-naphthylethylamine derivatives, aliphatic secondary amines, and amino alcohols; the ability was complementary to that of I. The X-ray crystallographic analyses of the less- and more-soluble diastereomeric salts showed that hydrogen-bonding networks in the salt crystals are 2(1) -column-type with a single exception which is cluster-type. In the cases of the 2(1) -column-type crystals, stability of the crystals is firstly governed by hydrogen bonds to form a 2(1) -column and secondly determined by intra-columnar T-shaped CH/π interaction(s), intra-columnar hydrogen bond(s), inter-columnar van der Waals interaction and/or inter-columnar T-shaped CH/π interaction(s). In contrast, the cluster-type salt crystal is stabilized by the assistance of inter-cluster T-shaped CH/π and van der Waals interactions. To realize still more numbers of intra- and inter-columnar and -cluster T-shaped CH/π interactions, the seven-membered ring of (R)-5 plays a considerable role.

Tunable chiral reaction media based on two-component liquid crystals: regio-, diastereo-, and enantiocontrolled photodimerization of anthracenecarboxylic acids.

Three kinds of enantiopure amphiphilic amino alcohols (1a-c) were newly synthesized, of which the stereochemistry of the stereogenic carbons adjacent to the amino (C2) and hydroxy (C1) groups was systematically varied. By using these amino alcohols and four photoreactive carboxylic acids, 12 kinds of salts were prepared. The structure and thermal behavior of the salts were thoroughly investigated by various techniques, which revealed that the stereochemistry of the amino alcohol unit has significant effects on the properties of the salts; the salts of 1a with (1R,2S)-configuration did not exhibit any liquid crystal (LC) phase but showed high crystallinity, whereas 1b and 1c with (1S,2S)- and (1S)-configurations, respectively, generally afforded stable LC salts with smectic structure(s). Within the matrix of these amphiphilic salts, the in situ photodimerizations of 2-anthracenecarboxylic acid (2c) and 1-anthracenecarboxylic acid (2d) were conducted by the irradiation with UV/vis light (500 W, a high-pressure mercury arc lamp, >380 nm). Concerning reactivity and regio-/diastereo-/enantioselectivities, the LC phases were found to be superior to isotropic and crystalline phases. For the two substrates 2c and 2d, every LC phase promoted the photodimerization with unprecedentedly high head-to-head selectivity. Particularly in the case of 2c, diastereoselecitivity (syn(HH) vs anti(HH)) could be rationally controlled by the choice of the amino alcohol unit and mesophase (syn(HH):anti(HH) = 61:37 to 26:72). Moreover, one of the LC phases exhibited by 1b·2c afforded the anti(HH)-dimer of 2c with excellent enantioselectivity (up to 86% ee). On the basis of the hypothesis that the present photochemical outcome arises from the preorientation of the substrates, a preliminary structural model of these LCs was proposed.

Collaborative study on fifteen compounds in the rat-liver Comet assay integrated into 2- and 4-week repeat-dose studies.

A collaborative trial was conducted to evaluate the possibility of integrating the rat-liver Comet assay into repeat-dose toxicity studies. Fourteen laboratories from Europe, Japan and the USA tested fifteen chemicals. Two chemicals had been previously shown to induce micronuclei in an acute protocol, but were found negative in a 4-week Micronucleus (MN) Assay (benzo[a]pyrene and 1,2-dimethylhydrazine; Hamada et al., 2001); four genotoxic rat-liver carcinogens that were negative in the MN assay in bone marrow or blood (2,6-dinitrotoluene, dimethylnitrosamine, 1,2-dibromomethane, and 2-amino-3-methylimidazo[4,5-f]quinoline); three compounds used in the ongoing JaCVAM (Japanese Center for the Validation of Alternative Methods) validation study of the acute liver Comet assay (2,4-diaminotoluene, 2,6-diaminotoluene and acrylamide); three pharmaceutical-like compounds (chlordiazepoxide, pyrimethamine and gemifloxacin), and three non-genotoxic rodent liver carcinogens (methapyrilene, clofibrate and phenobarbital). Male rats received oral administrations of the test compounds, daily for two or four weeks. The top dose was meant to be the highest dose producing clinical signs or histopathological effects without causing mortality, i.e. the 28-day maximum tolerated dose. The liver Comet assay was performed according to published recommendations and following the protocol for the ongoing JaCVAM validation trial. Laboratories provided liver Comet assay data obtained at the end of the long-term (2- or 4-week) studies together with an evaluation of liver histology. Most of the test compounds were also investigated in the liver Comet assay after short-term (1-3 daily) administration to compare the sensitivity of the two study designs. MN analyses were conducted in bone marrow or peripheral blood for most of the compounds to determine whether the liver Comet assay could complement the MN assay for the detection of genotoxins after long-term treatment. Most of the liver genotoxins were positive and the three non-genotoxic carcinogens gave negative result in the liver Comet assay after long-term administration. There was a high concordance between short- and long-term Comet assay results. Most compounds when tested up to the maximum tolerated dose were correctly detected in both short- and long-term studies. Discrepant results were obtained with 2,6 diaminotoluene (negative in the short-term, but positive in the long-term study), phenobarbital (positive in the short-term, but negative in the long-term study) and gemifloxacin (positive in the short-term, but negative in the long-term study). The overall results indicate that the liver Comet assay can be integrated within repeat-dose toxicity studies and efficiently complements the MN assay in detecting genotoxins. Practical aspects of integrating genotoxicity endpoints into repeat-dose studies were evaluated, e.g. by investigating the effect of blood sampling, as typically performed during toxicity studies, on the Comet and MN assays. The bleeding protocols used here did not affect the conclusions of the Comet assay or of the MN assays in blood and bone marrow. Although bleeding generally increased reticulocyte frequencies, the sensitivity of the response in the MN assay was not altered. These findings indicate that all animals in a toxicity study (main-study animals as well as toxicokinetic (TK) satellite animals) could be used for evaluating genotoxicity. However, possible logistical issues with scheduling of the necropsies and the need to conduct electrophoresis promptly after tissue sampling suggest that the use of TK animals could be simpler. The data so far do not indicate that liver proliferation or toxicity confound the results of the liver Comet assay. As was also true for other genotoxicity assays, criteria for evaluation of Comet assay results and statistical analyses differed among laboratories. Whereas comprehensive advice on statistical analysis is available in the literature, agreement is needed on applying consistent criteria.

Hydrogen-bonding-assisted self-doping in tetrathiafulvalene (TTF) conductor.

The synthesis, characterization, and carrier generation mechanism of self-doping in a tetrathiafulvalene (TTF) conductor, ammonium tetrathiafulvalene-2-carboxylate (TTFCOO(-)NH(4)(+)), are described together with molecular orbital characteristics. Insulating TTFCOOH changes into a hole-doped conductor TTFCOO(-)NH(4)(+) with a conductivity of sigma = 2.0 x 10(-4) S/cm (300 K), upon salt formation with NH(3). A radical species, TTF(*+)COO(-)NH(4)(+), is generated via protonation of the TTF moiety as demonstrated by UV-vis, ESR, and (1)H NMR spectra. The X-ray crystallographic structure of TTFCOO(-)NH(4)(+) reveals supramolecular arrays of TTFCOO(-) moieties with short S...S contact, assisted by the one-dimensional hydrogen-bonding network composed of the ammonium and carboxylate ions. Molecular orbital calculations of cluster models show that the singly occupied molecular orbital (SOMO) of TTF(*+)COO(-)NH(4)(+) in the supramolecular array is not at the highest energy level, which is characterized as a quasi-closed-shell state. The ab initio periodic calculation with a one-dimensional boundary condition reveals that TTF(*+)COO(-)NH(4)(+) behaves as a dopant leading to the semiconducting behavior of the stacked TTF moieties assembled by the hydrogen-bonding network. Namely, TTFCOO(-)NH(4)(+) can be described as a "hydrogen-bonding-assisted self-doped conductor". The contribution of the hydrogen-bonding interaction to the electron conduction is experimentally supported by a large isotope effect in the ac conductivity of TTFCOO(-)NH(4)(+) at low temperature.

An enantiopure cyclophane-type imidazole with no central but planar chirality.

An enantiopure cyclophane-type imidazole with planar chirality was synthesized, which was expected to serve as a useful component for the development of novel chiral molecular devices, such as ligands, organocatalysts, and receptors.

Ring-opening reaction of cyclopropanated [60]fullerenes: unexpected transformation of methano[60]fullerenes having an electron-donating group on the methano-bridge carbon.

A series of novel transformations of [60]fullerene derivatives were found, starting from methano[60]fullerenes with an electron-donating group on the methano-bridge carbon. Aminomethano[60]fullerenes, in situ generated by the treatment of their trifluoromethanesulfonic acid salts with a base, were readily converted into 1-acyl-1,2-dihydro[60]fullerenes via the ring opening of the cyclopropane moiety. The aldehyde/ketones thus obtained were easily hydrolyzed to give 1,2-dihydro[60]fullerene in the presence of hydroxide anions.

Magnesium stearate, a widely-used food additive, exhibits a lack of in vitro and in vivo genotoxic potential.

Magnesium stearate is widely used in the production of dietary supplement and pharmaceutical tablets, capsules and powders as well as many food products, including a variety of confectionery, spices and baking ingredients. Although considered to have a safe toxicity profile, there is no available information regarding its potential to induce genetic toxicity. To aid safety assessment efforts, magnesium sulfate was evaluated in a battery of tests including a bacterial reverse mutation assay, an in vitro chromosome aberration assay, and an in vivo erythrocyte micronucleus assay. Magnesium stearate did not produce a positive response in any of the five bacterial strains tested, in the absence or presence of metabolic activation. Similarly, exposure to magnesium stearate did not lead to chromosomal aberrations in CHL/IU Chinese hamster lung fibroblasts, with or without metabolic activation, or induce micronuclei in the bone marrow of male CD-1 mice. These studies have been used by the Japanese government and the Joint FAO/WHO Expert Committee on Food Additives in their respective safety assessments of magnesium stearate. These data indicate a lack of genotoxic risk posed by magnesium stearate consumed at current estimated dietary exposures. However, health effects of cumulative exposure to magnesium via multiple sources present in food additives may be of concern and warrant further evaluation.

The first synthesis of a methano[60]fullerene with an electron-donating group at the methano-bridge carbon: synthesis and reaction of aminomethano[60]fullerene.

[reaction: see text] Aminomethano[60]fullerene was synthesized for the first time as a trifluoromethanesulfonic acid salt by applying the Curtius rearrangement of azidocarbonylmethano[60]fullerene as the key reaction. Aminomethano[60]fullerene thus obtained was found to be able to react with various acyl chlorides to afford the corresponding amides.

A new hydrogen-bonding motif for chiral recognition in the diastereomeric salts of racemic 1-phenylethylamine derivatives with enantiopure O-ethyl phenylphosphonothioic acid.

An enantiopure phosphonothioic acid showed a unique and superior chiral recognition ability, arising from its P-stereogenicity, for racemic 1-phenylethylamine derivatives through diastereomeric crystallization. Spherical molecular clusters, associated by hydrogen bonds and CH/pi interactions, aggregated with high symmetry in the less-soluble diastereomeric salts.

Supramolecular architecture consisting of an enantiopure amine and an achiral carboxylic acid: application to the enantioseparation of racemic alcohols.

Three-dimensionally dissymmetric cavities are created from an enantiopure amine and an achiral carboxylic acid, which can incorporate the third components to realize the formation of closely packed crystals. The combination demonstrates enantioselective inclusion for 20 kinds of racemic alcohols. The inclusion phenomenon occurs not only during crystallization but also in the solid state.

[60]fullerenoacetyl chloride as a versatile precursor for fullerene derivatives: efficient ester formation with various alcohols.

[reaction: see text] [60]Fullerenoacetyl chloride, one of the reactive derivatives of [60]fullerenoacetic acid, was isolated and identified for the first time. This acid chloride was easily synthesized in good yield from tert-butyl [60]fullerenoacetate through two steps. In the presence of 4-(dimethylamino)pyridine as a base, the acid chloride smoothly reacted with various alcohols under mild conditions to give the corresponding esters including [60]fullerene-biomolecule hybrids in moderate to high yields.

Unexpected switch in regioselectivity of tether-directed Bingel-type biscyclopropanations depending on the leaving groups at tethered active ethylene moieties.

The regioselectivity of tether-directed Bingel-type biscyclopropanations of [60]fullerene was switched depending on the leaving groups at tethered active methylene moieties; the reactions of [60]fullerene with unhalogenated tethered bis(active methylene) derivatives/I2 and with brominated derivatives in the presence of 1,7-diazabicyclo[5.4.0]undec-7-ene gave trans-4-adducts predominantly, while the reactions with chlorinated derivatives afforded equatorial-adducts almost exclusively.

Template polymerization of columnar architectures based on the salts of a carboxylic acid and 2-amino alcohols: application to the molecular recognition of 2-amino alcohols.

The salts of trialkoxybenzoic acids and 2-amino alcohols showed a columnar liquid crystalline phase; in the case of the salt of a polymerizable acid and norephedrine, the photopolymerization proceeded efficiently in the liquid crystalline state, and the resultant solid adsorbed 2-amino alcohols size, regio-, and enantio-selectively.