Synthesis of Pyrrolo [2,1-b] thiazolines Using N-(Trimethylsilylmethyl)-2- methylthiothiazolinium Trifluoromethanesulfonate

N-(Trimethylsilylmethyl)-2-methylthiothiazolinium trifluoromethanesulfonate(4), readily prepard from 2-methylthiothiazoline (2) and trimethylsilylmethyl trifluoromethenesulfonate (1), reacted with activated alkenes (5) and alkynes (6) in the presence of cesium fluoride in acetonitrile to give the corresponding 4, 5-dihydropyrrolo [2, 1-b] thiazoline and pyrrolo [2, 1-b] thiazoline derivatives. The 1, 3-dipolar cycloaddition reaction is one of the most important reaction to construct five-membered heterocycles. We have reported that tailor-made azomethine and thiocarbonyl ylids can be generated by the 1, 3-elimionation reaction of trimethylsilylmethyl- substituted ketene N,S- or S,S- acetals promoted by fluoride ion and react with dipolarophiles to give five-membered heterocycles. As an unpublished result, we have recognized that the reactuion of 3-trimethylsilylmethylamino-3-methylthio-2- cyanoacrylonitrile with dipolarophiles in the presence of a fluoride ion gives five-membered heterocycles but the reaction of 3-trimethylsilylmethylamino-2-cyanoacrylonitrile with dipolarophiles gives no cycloadducts. These facts have shown that the elimination of a methylthio group following cleavage of carbon-silicon bond is a useful tool for the generation of 1,3-dipolar. Here we descrive the reaction of N-(trimethylsilylmethyl)-2- methythiothiazolinium trifluoromethanesulfonate, which has a Me3SiCH2 -N=C-SMe system, with dipolarophiles gives 4,5-dihydropyrrolo [2,1 - b] thiazoline derivatives. Trimethysilylmethyl trifluoromethanesulfonate (1) is an interesting compound to the preparation of silicon-containing sulfonium, nitrogen and other ylids. Starting material 1 was prepared according to the literature. A solution of 2-methylthiothiazoline (2) in dichloromethane was treated with 1 and stirred at room temperature for over night. After the solvent was removed N- (trimethylsilymethyl)-2-methylthiothiazolinium trifluoromethanesulfonate (4) was afforded. The crude salt 4 was used in the next step without purification. A solution of 4, thus obtained, and dimethyl fumarate(6b) in the prsence of cesium fluoride in acetonitrile was stirred at room temperature for 24h. The usual work-up after treatment with aqueous ammonium chloride and separation by preparative t.l.c. gave dimethyl 4,5-dihydropyrrolo [2, 1-b] thiazoline -5, 6-dicarboxylate(7b), formal [3+2] cycloaddition product, in 53% yield. The cycloadditon behavior of an unsymmetrically substituted dipolarophile was studied to determine the regioselectivity of the reaction. The reaction of 4 and methyl acrylate (6a) under the similar conditions gave methyl 4,5-dihydop yrrolo [2,1-b] thiazoline-6-carboxylate (7a) in 57% yield, exclusively. When methyl cinnamate (6d) was used as a dipolarophile, cycloadduct 7d was obtained as a single pro duct. The representative results are listed in Table 1. N-(Trimethylsilylmethyl)-2- methylthiobenzothia-zolium trifluoromethenesulfonate (5) was also prepared and reacted with activated alkenes (6a-6d) to give the corresponding [3+2] cycloadducts (8a-8d) in a manner similar to that described for 7a. The reaction also shows complete regiospecificity in the cycloaddition with unsymmetrically substituted olefins. However the reactions of 4 and 5 with N-methylmaleimide was unsuccessful under the present reaction conditions. Salt 4 and 5 reacted with alkynes (9a and 9b) under the similar conditions to give [3+2] cycloaiddition products, pyrrolo [2, 1-b] thiazoline derivatives(10a and 10b) and pyrrolo [2, 1-b] benzothiazole derivatives (11a and 11b). (see Table 2) This work demonstrates a mild and simple procedure for the preparation of pyrrolo [2, 1-b] thiazoline and pyrrolo [2, 1-b] benzothiazole derivatives

Synthesis and Fluorescence of 2-pyrone Derivatives for Electroluminescence Devices(SPECIAL ISSUE CELEBRATING TEN YEARS OF ESTABLISHMENT OF FACULTY OF ENVIRONMENTAL STUDIES)

A convenient method of synthesizing 6-aryl- and 6-styryl-4-methylsulfanyl-2-oxo-2H-pyran derivatives through the reactions of various active methylene compounds with ketene dithioacetals and investigation of the fluorescence of the products in the solid state are described. The structure-activity relationships of various 2-pyrone derivatives and the effects of different aryl and styryl substituents on the aryl group were clarified. Materials which are strongly fluorescent in the primary colors (red, green, and blue) are the most important materials in the field of organic electroluminescence (EL). The 2-pyrone derivatives synthesized in this work emitted light at 447～620 nm in the solid state

Bisphenol A Incorporated into Eggs from Parent Fish Persists for Several Days

Chronological changes of bisphenol A (BPA) concentration were investigated for a week in mature medaka (Oryzias latipes) and spawned eggs (embryo) after exposing the fish to BPA at a concentration of 100 μg/l in water. The BPA concentrations in mature fish and spawned eggs increased beginning at the day after initial exposure, and reached an approximately constant level on the second day. On the other hand, the decrease in BPA concentration in the parent body was rapid after being placed back into pure water (average decrease was 87% on the first day, and 98% on the second day), while approximately 24% of the BPA in the spawned eggs from the parents remained after the fourth day in pure water. Thus, it was assumed that there is no system for BPA excretion from eggs. Another experiment was conducted, in which eggs spawned from a parent on the fourth day of exposure were raised in pure water. The BPA concentration in the eggs on the sixth day was approximately 29% lower when compared to that at spawning. Therefore, it was assumed that the embryo cannot conjugate BPA incorporated into the egg due to an underdeveloped metabolic or excretion mechanism

Hormonal activity of polycyclic musks evaluated by reporter gene assay.

Synthetic musk fragrance compounds, such as polycyclic musks (PCMs), are a group of chemicals used extensively as personal care products, and can be found in the environment and the human body. PCMs, such as 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexa-methylcyclopenta-gamma-2-benzopyran (HHCB) and 7-acetyl-1,1,3,4,4,6-hexamethyltetralin (AHTN), are known to have agonistic activities toward human estrogen receptor alpha (hERalpha) and hERbeta, and have antagonistic activity toward the human androgen receptor (hAR), as shown in several reporter gene assays. However, little is known about the interaction of PCMs with the human thyroid hormone receptor (hTR), and the hormonal effects of other PCMs except for HHCB and AHTN. In this study, we focus on the interactions of six PCMs, namely, HHCB, AHTN, 4-acetyl-1,1-dimethyl-6-tert-butyl-indan (ADBI), 6-acetyl-1,1,2,3,3,5-hexamethylindan (AHMI), 6,7-dihydro-1,1,2,3,3-pentamethyl-4(5H)-indanone (DPMI), and 5-acetyl-1,1,2,6-tetramethyl-3-isopropy-lindan (ATII) with hERalpha, hAR, and hTRbeta by in vitro reporter gene assay using Chinese hamster ovary cells. All the samples were found to be agonists toward hERalpha, whereas no agonistic activities of these PCMs for hAR and hTRbeta were observed. No antagonistic activities for hERalpha and hTRbeta were observed at the concentrations tested. However, several PCMs, namely, HHCB, AHTN, ATII, ADBI, and AHMI, showed dose-dependent antagonistic activities for hAR, and the IC50 values of these compounds were estimated to be 1.0 x 10(-7), 1.5 x 10(-7), 1.4 x 10(-7), 9.8 x 10(-6), and 1.4 x 10(-7) M, respectively. The results suggest that these PCMs interact with hERalpha and hAR but have no hormonal effect on hTRbeta. This is the first report on the agonistic and antagonistic activities of ATII, ADBI, AHMI, and DPMI for hERalpha and hAR as determined by in vitro reporter gene assay using stably transfected Chinese hamster ovary cells

Characterization of a Single Chain Fv Antibody that Reacts with Free Morphine

An immune phage library derived from mice, hyperimmunized with morphine-conjugated BSA, was used to isolate a single-chain Fv (scFv) clone, M86, with binding activity to morphine-conjugated thyroglobulin (morphine-C-Tg) but not to codeine-, cocaine-, or ketamine-conjugated Tg. Surface plasmon resonance analysis using a morphine-C-Tg-coupled CM5 sensor chip showed that the Kd value was 1.26 × 10−8 M. To analyze its binding activity to free morphine and related compounds, we performed a competitive ELISA with M86 and morphine-C-Tg in the absence or presence of varying doses of free morphine and related compounds. IC50 values for opium, morphine, codeine, and heroin were 257 ng/mL, 36.4, 7.3, and 7.4 nM, respectively. Ketamine and cocaine exhibited no competitive binding activity to M86. Thus, we established a phage library-derived scFv, M86, which recognized not only free morphine and codeine as opium components but also heroin. This characteristic of M86 may be useful for developing therapeutic reagents for opiate addiction and as a free morphine-specific antibody probe

In Vivo Evaluation of 4-Methyl-2, 4-bis(4-hydroxyphenyl) pent-1-ene (MBP), a Bisphenol A Metabolite, Using the Nematode Caenorhabditis elegans(SPECIAL ISSUE CELEBRATING TEN YEARS OF ESTABLISHMENT OF FACULTY OF ENVIRONMENTAL STUDIES)

In this study, we investigated the lethal and sublethal effects of 4-methyl-2 ,4-bis(4-hydroxyphenyl)-pent-l-ene (MBP), a bisphenol A (BPA) metabolite, using the nematode Caenorhabditis eleganas (C. elegans) grown on Nematode Growth Medium (NGM) 1.7% agar plates. The bioconcentration factor (BCF) was also determined. The 24 hr-median lethal concentration (24 hr-LC_) value of MBP was 0.49 mM (134 mg/1), and the acute toxicity of MBP against C. elegans was slightly stronger than that of BPA. In contrast to BPA, the sublethal toxicity of MBP in a multi-generation test, as determined by reproduction and fecundity, was slightly lower. The growth of animals, as determined by body lenth, was enhanced by 3-8% at 0.1 mM MBP, after 48-72 hr. The BCF value after exposure for 48 hr was determined to be approximately 19-105 as compared with the nominal concentration