Organometallic complexes are useful tools in synthetic organic chemistry. We investigated a novel synthetic method for ring construction using organometallic complexes and synthesized natural products and biologically active substances using these methods. Metalacycles formed from an early transition metal and diene, enyne, and diyne are stable under the reaction conditions and they are easily converted into compounds with functional groups by the addition of various agents. We have developed a novel synthetic method of heterocycles from enyne and diene using Cp₂ZrBu₂. The total syntheses of (−)-dendrobine, (±)-mecembrane, and (±)-mecembrine were achieved using this procedure. To synthesize these natural products as a chiral form, a novel palladium-catalyzed asymmetric allylic amination was developed, and chiral 2-arylcyclohexenylamine derivatives were synthesized. From these compounds, the total syntheses of (−)-mesembrane, (−)-mesembrine, (+)-crinamine, (−)-haemanthidine, and (+)-pretazetine were achieved. By further development of this procedure, a chiral 2-siloxymethylcyclohexenylamine derivative could be synthesized and the novel synthesis of indole derivatives was developed from this compound. From this indole derivative, (−)-tsubifoline and (−)-strychnine were synthesized.

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The complexes of chromium(III), scandium(III) and yttrium(III) formed by 1-hydroxy-2-naphthoic acid (1,2-HNA: H₂L) and 3-hydroxy-2-naphthoic acid (3,2-HNA: H₂L) were investigated by potentiometry and spectroscopy at 25±0.1 °C and at an ionic strength of 0.1 M KNO₃ in 50% ethanol–water (v/v) medium. The stoichiometries of these three M(III) complexes formed with these hydroxy-naphthoic acids and with hydroxo ion were defined and their formation constants were determined and compared. Thus, the removing capacities of these ligands could be examined by calculating the equilibrium concentration of Cr(III) that exists in the discharge water of various industries since Cr(III) ions are the main pollutants present during waste water treatment in our city, Bursa.

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A facile one-pot C-benzylation of various sodium enolates derived from methyl malonate, β-ketoesters, a β-cyanoester, a β-cyanosulfone, ketones and a carboxylic ester is reported. Reaction of alkoxydiphenylsulfonium salts formed by treating various benzyl alcohols with diphenyl sulfide bis(trifluoromethanesulfonate) (derived from trifluoromethanesulfonic anhydride and diphenyl sulfoxide) proceeded smoothly, and the corresponding C-benzylated products were afforded in good to high yields.

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This paper describes an improved quality assessment method for Radix Salviae Miltiorrhizae (Root of Salvia miltiorrhiza BGE.) which was established using chromatographic fingerprinting and quantification of multiple marker compounds in the crude drug. High-performance thin-layer chromatography (HPTLC) fingerprinting of water-soluble phenolics and nonpolar tanshinones was performed separately and the authentication of Radix Salviae Miltiorrhizae was achieved by comparing the fingerprints of the samples with those of the reference crude drug and by comparing the Rf values of the bands in TLC fingerprints with those of reference compounds. HPLC fingerprints were obtained by simultaneous separation of phenolics and diterpenoids in Radix Salviae Miltiorrhizae. The HPLC fingerprints of seven batches of samples from different regions of China showed similar chromatographic patterns, and seven peaks were selected as characteristic peaks. The relative retention time of these characteristic peaks in the HPLC fingerprints was established as an important parameter for the identification of this herbal medicine. The pharmacologically active marker compounds salvianolic acid B, rosmarinic acid, and tanshinone IIA in herbal medicine were quantitatively determined using reverse-phase HPLC techniques. The HPLC quantitation methods of the three marker compounds were validated and the measurement uncertainty, which is important for setting the proposed content limit of the marker compounds in herbal medicine, were further evaluated.

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We attempted to make the rapidly dissolving tablet (Tab) containing solid dispersion particles (SD) with indomethacin (IMC) and porous silica (Sylysia350) as carrier prepared by using spray-drying technique. Rapidly dissolving tablet was formulated with mannitol as a diluent and low substituted hydroxypropylcellulose (L-HPC) or partly pre-gelatinized starch (PCS) as a disintegrant. The percent dissolved from Tab (SD) was higher than that of tablet containing physical mixture (PM) at 20 min. Nearly 100% of drug in Tab (SD) was dissolved within 60 min, while the drug dissolution of Tab (PM) was not completed at the same time period. In addition, the tensile strength of Tab (SD) was much higher than that of Tab (PM). Adding L-HPC in Tab (SD) (Tab (SD-L-HPC)), the percent dissolved from Tab (SD-L-HPC) at 5 min became much higher than that from Tab (SD). The dissolution profile of IMC from Tab (SD-L-HPC) was almost the same irrespective of the compression pressure, while the tensile strength of tablet increased with increasing the compression pressure. In comparing the compaction property of these tablets by observing the ratio of residual die wall pressure (RDP) to maximum die wall pressure (MDP) (RDP/MDP), it was found that addition of L-HPC in the tablet formulation improved compactibility. In case that PCS was formulated as disintegrant, Tab (SD-PCS), similar improvement in the dissolution profile and tensile strength was observed, though the dissolution rate of IMC from Tab (SD-PCS) was slightly lower than that from Tab (SD-L-HPC) irrespective of the compression pressure.

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A series of bulky 2-substituted benzimidazoles was designed in order to find new leads for several biological targets. Formation by cyclodehydration from their monoacylated counterparts was shown to be strongly dependent upon the nature of the acyl group. In the case of a dicyclohexylmethyl group, cyclization was only observed in a p-toluenesulfonic acid/toluene mixture from the symmetrical diacylated precursor. Analysis of the mechanism was begun starting from mixed diacylated derivatives.

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FK888 (NK1 antagonist) is a candidate drug for migraine and selected as a model of amorphous drug. FK888 was micronized to develop as dry powder inhalers (DPIs) taking into consideration of its water insoluble property. The glass transition temperature (Tg) and fragility (m) were 90 °C and 118, respectively, and it was categorized as a fragile glass based on Angell's concept. FK888 was structually relaxed by aging below Tg, then the effect of aging on their physical and aerosol properties were investigated. The investigation on the moisture sorption–desorption isotherms of FK888 indicated that aged FK888 adsorbed less amount of water than that of unaged FK888. This unique moisture sorption–desorption behavior of the aged sample is explained by structural relaxation accompanying decrease of free volume and/or increase of density. As for the dissolution rate of unaged and aged FK888, they showed the similar value, suggesting that there would be no difference in bioavailability. In relation to the stability, FK888 DPIs prepared by unaged and aged FK888 were stored at 70 °C, and the respirable fraction of FK888 DPIs was evaluated by using multistage cascade impactor (USP apparatus 3). As a result, the respirable fraction of FK888 DPIs prepared by unaged sample was significantly decreased compared to the aged sample, suggesting that agglomeration may occur in the unaged sample during the storage. This phenomenon was supported by that the unaged sample showed a significant decrease in the surface area compared to that of the aged sample when stored at various conditions.

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Manidipine dihydrochloride or benidipine hydrochloride will change to hydrate form in part, when differential scanning calorimetric (DSC) measurement is carried out together with lactose monohydrate. This interaction was accelerated by compressing their mixture. It can be suggested that the interaction may cause by the disruption of crystal structure of lactose monohydrate due to compression to set free of water molecules. A new DSC peak at 170 °C, which was not observed in each component, appeared in DSC measurement of a mixture. This will be based on hydrate formed by the interaction, i.e., movement of water molecules. The profile of the plotting of the DSC peak area ratio before and after compression against the compression force changed by the molar ratio of lactose monohydrate in a mixture. In the case of low molar ratio of lactose monohydrate, profiles for manidipine dihydrochloride and benidipine hydrochloride differed from each other. This will be because manidipine dihydrochloride is stickier than benidipine hydrochloride. The profile for manidipine dihydrochloride became more gradual and showed lag compression force region when the amount of addition of the lubricant, magnesium stearate in a mixture increased. The endothermic peak area at 170 °C for manidipine dihydrochloride was larger than that for benidipine hydrochloride. It should be suggested that benidipine hydrochloride is easier to be transformed to its hydrate than manidipine dihydrochloride.

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A HPLC method is described in order to separate and identify 4 phenolic compounds including lithospermic acid B, 3,4-dihydroxyphenyllactic acid (danshensu), rosmarinic acid, and protocatechuic aldehyde as well as 3 lipophilic ones (tanshinone I, tanshinone II_A and cryptotanshinone) from the roots of Salvia miltiorrihiza or the herbal product containing S. miltiorrihiza available in Chinese or Japanese market. The influence of extractive conditions, such as method, solvents and time, on the 4 phenolic marker components in S. miltiorrihiza is well discussed. In order to investigate the stability of lithospermic acid B, the preparation samples of an injection and a granule were analyzed after being stored at 4 °C, 20 °C and 40 °C for up to six months.

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In the continuation of our investigation of the phytochemical constituents of Malagasy liverworts, a new cuparane-type sesquiterpenoid together with five known compounds was isolated from Bazzania decresens. Bazzania madagassa furnished a new cyclomyltaylane-type sesquiterpenoid and a new acoradienol. The structures of the isolated compounds were determined based on a combination of physical and spectroscopic evidence. The chemosystematics of the genus Bazzania as well as the biogenesis of cyclomyltaylane sesquiterpenoids in liverworts is discussed.

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Applicability of the Jouyban–Acree model for calculating absolute viscosity of binary liquid mixtures with respect to temperature and mixture composition is proposed. The correlation ability of the model is evaluated by employing viscosity data of 143 various aqueous and non-aqueous liquid mixtures at various temperatures collected from the literature. The results show that the model is able to correlate the data with an overall percentage deviation (PD) of 1.9±2.5%. In order to test the prediction capability of the model, three experimental viscosities from the highest and lowest temperatures along with the viscosities of neat liquids at all temperatures have been employed to train the model, then the viscosity values at other mixture compositions and temperatures were predicted and the overall PD obtained is 2.6±4.0%.

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We report the synthesis of optically active 2-aryl-2-fluoropropionic acids 2 as non-epimerizable mimics of 2-arylpropionic acids 1, a class of compounds which have been widely used as non-steroidal anti-inflammatory drugs (NSAIDs). This is a continuation of our research involving the design, synthesis, and evaluation of chiral fluorine-containing organic molecules as effective analogues of pharmacologically important compounds.

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Oxopropyl E-(pyrrolidine-2-ylidene)glycinamide (5c) and allyl E-(pyrrolidine-2-ylidene)glycinate (5d) were effectively synthesized from 2,3,5-tri-O-benzyl-4-O-tert-butyldimethylsilyl(TBDMS)-D-arabinal (7) using intramolecular 1,3-dipolar cyclic reaction of azide and olefin as a key reaction. These results proved this cyclic reaction should be applicable for the synthesis of various (pyrrolidine-2-ylidene)glycinate and glycinamide. In addition, the development of a synthetic route for the precursor of an unsaturated cyclic dehydro amino acid involved in azinomycins (carzinophilin) using relating glycinate, methyl E-(pyrrolidine-2-ylidene)glycinate (5a) was described.

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The isomerization kinetics of panipenem (INN: (+)-(5R,6S)-3-[(S)-1-(acetimidoylpyrrolidin-3-yl)thio]-6-[(R)-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, CAS No. 87726-17-8) in aqueous solution were investigated. An equilibrium between the Z-form and E-form was observed, and it was found that the isomerization rates were affected by the pH of the solution. Under acidic conditions, the isomerization rates were small. However, the isomerization rates were increased with the pH value. This phenomenon resulted from the extent of proton dissociation from the acetimidoyl group.

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A synthesis of optically active vomifoliol stereoisomers 1—4 and their glucosides, roseoside stereoisomers 5—8, was accomplished via α-acetylenic alcohol 11a or 11b effectively prepared by an asymmetric transfer hydrogenation of α,β-acetylenic ketone 10. Simultaneous separation of these stereoisomers by HPLC was also perfomed.

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We describe a facile efficient, and preparative approach for monohydroxyflavanone syntheses. Using this protocol, a hydroxyl is regio-selectively introduced at one carbon of a flavanone A- or B-ring per synthesis. The seven possible isomers were each synthesized from the corresponding monomethoxymethoxylated 2′-hydroxychalcones in acidic solution. These monohydroxyflavanones were characterized using a gas chromatography-mass spectrometry (GC-MS) system that incorporated a DB-5 capillary column. Ours is the first report of a preparative synthetic method during which a single hydroxyl can be selectively added to a flavanone A- or B-ring at any position. We are also the first to develop a procedure that separates the seven isomers by GC and characterizes the mass spectra of the isomers. Both the synthetic method and the GC-MS conditions may become important tools during future flavanone metabolism and oxidation studies.

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Enantioselective synthesis of the poison-frog alkaloids 237D, 207A, and two congeners of 235B′ has been achieved. The absolute stereochemistry of 237D was determined to be 5S, 8S, 9R by the present synthesis.

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Antimutagenic activity-guided fractionation of an extract prepared from the thorns of Gleditsia sinensis LAM. led to the isolation of one triterpenoid and four steroids, which were identified as D:C-friedours-7-en-3-one (1), stigmast-4-ene-3,6-dione (2), stigmastane-3,6-dione (3), stigmasterol (4), and β-sitosterol (5). Triterpenoid 1 was found for the first time in a natural source and the steroids 2—5 were first isolated from this plant. Stigmasterol was the most active antimutagen, showing 51.2% and 64.2% reduction of the induction factor against the mutagens MNNG and NQO, respectively, in the SOS chromotest. Some NMR data of the steroids 2 and 3 obtained have to be revised.

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Enzymatic resolution of six (±)-5-acetoxy-4-aryl-(2E)-pentenoate derivatives, compounds 9, 11, 13, 15, 17, and 19 bearing a different aromatic substitution pattern, using lipase OF-360 from Candida rugosa was carried out. The absolute configurations of all hydrolyzed products and all unchanged acetates were found to be S and R, respectively. Moreover, the enantiomeric excess of the enzymatic resolution products from 9, 11, and 13 with the ortho-methoxyl group in the aromatic ring was higher than that of the substrates with no methoxyl group at the ortho-position in the aromatic ring.

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Haloxylines A (1) and B (2), new piperidine alkaloids, have been isolated from the chloroform soluble fraction of Haloxylon salicornicum and their structures elucidated by spectroscopic techniques including 2D-NMR. Both the compounds displayed antifungal and cholinesterase enzymes inhibitory potentials.

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The simultaneous separation and determination of major anthraquinones (emodin, chrysophanol, rhein and their glucosides, aloe-emodin, sennoside A, and sennoside B) of Rhei Rhizoma were achieved by cyclodextrin modified capillary zone electrophoresis. The running electrolyte used in this method was 0.005 M α-cyclodextrin in 0.03 M borate buffer (pH 10.0) containing 20% acetonitrile, with an applied voltage of 20 kV.

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The reactions of benzo[h]quinoline N-oxide with methylsulfinyl carbanion and deuterated methylsulfinyl carbanion, respectively, were studied theoretically. Differences in yield between these reactions were explained using ab initio molecular orbital methods by considering the zero-point energy correction and the barrier penetration effect. In these reactions, two transition states affected the total reaction rate. The hydrogen- or deuterium-transfer step played a significant role, accounting for the difference in reaction rates.

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Two new acetophenone diglycosides, erythroxylosides A and B, were isolated from the aerial portion of Erythroxylum cambodianum together with (+)-catechin, (−)-epicatechin, quercetin 3-O-rutinoside, (3S,5R,6R,7E,9S-megastigman-7-ene-3,5,6,9-tetrol 3-O-β-D-glucopyranoside and citroside A. The structural elucidations were based on analyses of chemical and spectroscopic data.

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A new cyclodipeptide named as cordycedipeptide A, a new natural compound and two known compound were isolated from the culture liquid of Cordyceps sinensis (BERK.) SACC. Their structures were elucidated as 3-acetamino-6-isobutyl-2,5-dioxopiperazine (1), 3-isopropyl-6-isobutyl-2,5-dioxopiperazine (2) and 3,6-di(4-hydroxy)benzyl-2,5-dioxopiperazine (3) by 1D and 2D-NMR techniques. The cytotoxic assay showed compound 1 had the cytotoxic activities to L-929, A375, and Hela.

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A new pregnane glycoside has been isolated from the overripe fruits of Cherry tomato (Mini tomato), Lycopersicon esculentum var. cerasiforme (DUNAL) ALEF. The structure was determined to be 3-O-β-lycotetraosyl 3β-hydroxy-5α-pregn-16-en-20-one on the basis of spectroscopic analysis. The seasonal variation of the tomato saponin is discussed.

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Treatment of formylalkenoates 1 and 7 with 2,2′-azobis(2-methylpropanenitrile) (AIBN) in the presence of dioxygen gave oxygenated carboxylic acids 5, 6, 8, 9 instead of acyl radical cyclization products, through preferential reaction of the corresponding acyl radicals with dioxygen rather than intramolecular attack to an enoate moiety. The reaction of 1 with AIBN in the absence of dioxygen recovered starting 1 in 98% yield.

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Stereoselective synthesis of methyl (Z)-(4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene)acetate (1a) is described. Z-selectivity of the Horner–Wadsworth–Emmons (HWE) reaction was obtained based on an investigation of the reaction conditions for introduction of a methylidene group onto the 5-position of benzazepine.

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Fourteen flavonol glycosides including two new compounds were isolated from the leaves of two Diospyros plants (D. cathayensis and D. rhombifolia). The structures of isolated compounds were determined by spectroscopic analysis. The scavenging activity of 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical of the isolated compounds was also investigated.

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Two new bisindole alkaloids, named cinereapyrrole A (1) and B (2), were isolated from wild fruit bodies of Arcyria cinerea and three new bisindole alkaloids (3—5) were isolated from wild fruit bodies of Lycogala epidendrum. Seven known bisindoles (6—12) were concomitantly obtained from them. The structures of the new compounds were elucidated by spectral data. Among these bisindole alkaloids, compound 12 showed cytotoxicity against cultured tumor cell lines.

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