HETEROCYCLES
An International Journal for Reviews and Communications in Heterocyclic ChemistryWeb Edition ISSN: 1881-0942
Published online by The Japan Institute of Heterocyclic Chemistry
Regular Issue
Vol. 48, No. 11, 1998
Published online:
■ A Convenient Synthesis of 4,5-Bis(trifluoromethyl)-pyridazines
Yasuhiro Kamitori,* Masaru Hojo, and Tatsuya Yoshioka
*Department of Chemical Science andd Engineerring, Faculty of Engineering, Kobe University, Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
Abstract
Acid catalyzed selfcondensation of 3-hydrazono-1,1,1-trifluoroalkan-2-ones (2) prepared from 1,1,1-trifluoroalkan-2,3-diones (1) and 100% hydrazine hydrate afforded 4,5-bis(trifluoromethyl)pyridazines (3) in satisfactory yields.
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■ Synthesis of N-Arylrolipram Derivatives - Potent and Selective Phosphodiesterase-IV Inhibitors - by Copper Catalyzed Lactam-Aryl Halide Coupling
Esther Aebischer, Edmond Bacher, F. W. Joachim Demnitz,* Thomas H. Keller, Miriam Kurzmeyer, Marta L. Ortiz, Esteban Pombo-Villar, and Hans-Peter Weber
*Novartis Pharma AG, Preclinical Research, S.350/315, CH-4002 Basel, Switzerland
Abstract
The copper catalysed coupling of rolipram (1) with a wide variety of aryl halides (2) affords N-arylrolipram derivatives (3), potent and selective phosphodiesterase type-IV inhibitors.
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■ The Structures of Mono-L-aspartyl Chlorin e6 and Its Related Compounds
Shuichi Gomi,* Toshio Nishizuka, Osamu Ushiroda, Naoki Uchida, Hirotada Takahashi, and Shinjiro Sumi
*Pharmaceutical Research Center, Meji Seika Kaisha Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan
Abstract
Structures of the photosensitizer mono-L-aspartyl chlorin e6 (1) and its related compounds were examined by chemical studies and spectral means. It was clarified that L-aspartyl moiety of 1 was attached to acetic acid side chain of chlorin e6, therefore, the structure of 1 was established to be (2S,3S)-18-carboxy-20-[N-(S)-1,2-dicarboxyethyl]carbamoylmethyl-13-ethyl-3,7,12,17-tetramethyl-8-vinylchlorin-2-propanoic acid. The thermal degradation product was determined to be an 18-decarboxyl derivative of 1. In addition, 15N NMR as signment of 1 in DMSO-d6 solution was confirmed by 1H-15N HMQC and HMBC techniques. In comparison with 1H chemical shifts in D2O and DMSO-d6, in was deduced that 1 in water is not persent as a free molecule, but as a complex of two or more molecules.
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■ Improved Procedures for Direct Conversions of Natural 3β-Hydroxy-gibberellins to 3α-Hydroxy-and 3-Oxo-gibberellins
Hideharu Seto,* Shozo Fujioka, Yuji Kamiya, and Shigeo Yoshida
*The Institute of Physical and Chemical Research, Wako-shi, Saitama 351-0198, Japan
Abstract
Natural 3β-hydroxy-gibberellins, GA3 (gibberellic acid) (1), GA1 (2), and GA4 (3), were directly converted to 3α-hydroxy-gibberellins, 3-epi-GA3 (4), -GA1 (5) and -GA4 (6), by highly α-biased equilibration through retro- and realdol mechanism with potassium tert-butoxide in tert-butyl alcohol, and to 3-oxo-gibberellins, 3-oxo-GA95 (7), -GA20 (8) and -GA9 (9), by catalytic oxidation with tetrapropylammonium perruthenate.
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■ Synthesis of Trifluoromethylated Dihydro-1,4-oxathiin-3-carboxanilides through Polymer-bound Activated Ester
Hoh-Gyu Hahn,* Kee Hyuk Chang, Kee Dal Nam, Su Yeoul Bae, and Heduck Mah
*Organic Chemistry Laboratory, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul 136-791, Korea
Abstract
A synthesis of new trifluoromethylated dihydro-1,4-oxathiin-3-carboxanilids (2) through polymer-bound activated ester is described. Chlorination of ethyl γ,γ,γ-trifluoroacetoacetate (3) followed by treatment of 2-mercaptoethanol gave hydroxyxathianes isomers (cis-10 and trans-11). Replacement of hydroxy to chlorine and then dehydrochlorination afforded trifluoromethyl dihydro-1,4-oxathiin ester (7). The polymer-bound trifluoromethylated dihydro-1,4-oxathiin-3-carboxylic acid, 4-hydroxy-3-nitrobenzophenone ester (16) was prepared through the reaction of polystyrene-bound 4-hydroxy-3-nitrobenzophenone (14) with the trifluoromethylated dihydro-1,4-oxathiin-3-carbonyl chloride (15). Refluxing of 16 with anilines in acetonitrile gave the corresponding carboxanilide (2). The reaction rate depended on the nucleophilicity of nitrogen in aniline.
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■ Synthesis of (2R,3S)-3-Hydroxy-2-hydroxymethylpyrrolidine from (4S,5S)-3-Benzyl-4-formyl-5-vinyl-2-oxazolidinone
Andrew G. H. Wee,* Douglas D. McLeod, and Trent J. Rankin
*Department of Chemistry, University of Regina, Regina, Saskatchewan, S4S 0A2, Canada
Abstract
(4S,5S)-3-Benzyl-4-formyl-5-vinyl-2-oxazolidinone (2), readily prepared via the reductive elimination of the mannose-derived iodo phenyl sulfone (6b), is used in the synthesis of the alkaloid (2R,3S)-3-hydroxy-2-hydroxymethylpyrrolidine (1).
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■ Synthesis of Praziquantel via N-Acyliminium Ion Cyclization of Amido Acetals through Several Synthetic Routes
Joong Hyup Kim, Yong Sup Lee, and Choong Sup Kim*
*Division of Applied Science, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul 130-650, Korea
Abstract
Syntheses of praziquantel have been accomplished via an N-acyliminium ion by several routes including the tandem nucleophilic addition-cyclization sequence from amido acetal (8) or (10) and a stepwise cyclization of enamide (9) generated from the nucleophilic addition reaction of amido acetal (8) or (10).
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■ Stereocontrolled Synthesis of 1β-Aminoalkylcarbapenems and Tricyclic Carbapenems (Trinems)
Yasuyoshi Iso* and Yasuhiro Nishitani
*Shionogi & Co. Ltd., Discovery research Laboratories, Fukushima-ku, Osaka 553-0002, Japan
Abstract
The effective synthesis of 1β-aminoalkylcarbapenems and trinems are described and the antibacterial activities of new carbapenem derivatives prepared by this advantageous synthetic method are also reported.
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■ Unprecedented Reactivity of 5-Substituted 3-Hydroxy-1,2,3,4-tetrahydroquinoline-2,4-diones with Ethyl (Triphenylphosphoranylidene)acetate
Antonín Klásek,* Kamil Koristek, Jirí Polis, and Janez Kosmrlj*
*Faculty of Technology, Technical University of Brno, Nám. TGM 275, 762 72 Zlín, Czech Republic
Abstract
3,5,8-Trisubstituted 3-hydroxy-1,2,3,4-tetrahydroquinoline-2,4-diones (3) reacted with ethyl (triphenylphosphoranylidene)acetate (4) to yield several products. The major products, 4,7-disubstituted 1,3-dihydro-3-phenylacetoxy-2H-indol-2-ones (5) and (11), were formed via the molecular rearrangement of 3, catalyzed by the strongly basic Wittig reagent. The Wittig reaction at the lactam group of 3, resulting in 2-ethoxycarbonylmethylene derivatives, can be explained by the poor reactivity of the sterically hindered 4-oxo group. Under acid catalysis, the Wittig reaction proceeded at the hindered 4-oxo group as well. A series of minor products were also obtained through the Wittig reaction of 3. A reaction mechanism of the molecular rearrangement of substances (3) is proposed.
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■ Total Synthesis of (RS)- and (R)-3-Alkanoyl-5-hydroxymethyltetronic Acid Homologues, HIV-1 Protease Inhibitory Natural Products
Masayuki Yamashita, Hiromichi Murai, Asmita Mittra, Tomomichi Yoshioka, Ikuo Kawasaki, Mariko Gotoh, Tomoko Higashi, Rie Hatsuyama, and Shunsaku Ohta*
*Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan
Abstract
5-Acetoxymethyl-γ-butyrolactone-3-carboxylic acids [(RS)-4a and (S)-4a] were prepared as racemic form starting from dibenzyl allylmalonate (5b) and optically active S form starting from (4S)-4-[2,2-bis(benzyloxycarbonyl)ethyl]-2,2-dimethyl-1,3-dioxolane [(S)-6b], and the 3-position of (RS)-4a and (S)-4a was acylated to afford (RS)-3a, (S)-3a, and (S)-3b. Phenylselenenylation of (RS)-3a, (S)-3a, and (S)-3b followed by H2O2-oxidation and subsequent acidic hydrolysis afforded the HIV-1 protease inhibitory 3-alkanoyl-5-hydroxymethyltetronic acids [(RS)-1a, (R)-1a, and (R)-1d, respectively].
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■ A Novel Synthesis of C-Nucleosides Having Pyrrolo[1,2-f]pteridine, 6- and 8-Deazapyrrolo[1,2-f]pteridine Ring Systems from 6-Hydroxy-6-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2H-pyran-3(6H)-one
Natsu Nishimura, Yoshitada Hasegawa, Souhei Mizuno, Misa Yuasa, and Isamu Maeba*
*Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tenpaku, Nagoya 468-8503, Japan
Abstract
A versatile intermediate pyranulose glycoside (1) for C-nucleoside synthesis was treated with 4,5-diaminopyrimidine in AcOH to give 1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)pyrrolo[1,2-f]pteridine (2) in 58% yield. However, treatement of 1 with 4,5,6-triaminopyrimidine in TFA afforded the 4-aminopteridine (4) without formation of the pyrrolo[1,2-f]pteridine. Similar reaction of 2,3- and 3,4-diaminopyridines with 1 in AcOH led to formation of 8- and 6-deazapyrrolo[1,2-f]pteridines (5 and 6), respectively. Removal of the sugar protecting groups in 2, 5, and 6 with sodium carbonate gave the deprotected C-nucleosides (7, 8 and 9).
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■ Syntheses of Fluorine-containing 1,2-Dihydropyrimidines and Pyridines from β,β-Bis(trifluoroacetyl)vinylamine, Ketones and Ammonia
Etsuji Okada,* Tatsuhiko Kinomura, and Yukio Higashiyama
*Department of Chemical Science andd Engineerring, Faculty of Engineering, Kobe University, Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
Abstract
β,β-Bis(trifluoroacetyl)vinylamine (1) reacted easily with various ketones in the presence of aqueous ammonia under mild conditions to give trifluoroacetylated 4-trifluoromethyl-1,2-dihydropyrimidines (4), α-trifluoromethylpyridines (5), and γ-trifluoromethylpyridines (6) in moderate yields.
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■ 14,15-Disubstituted Marcfortine A Derivatives
Byung H. Lee* and Michael F. Clothier
*Animal Health Discovery Research, Pharmacia & Upjohn, Inc., 7000 Portage Road, Kalamozoo, MI 49001-0199, U.S.A.
Abstract
The novel 14,15-disubstituted marcfortine A derivatives (4 and 14) were synthesized starting with known derivatives (5 and 10). Assay of their anthelmintic activity disclosed some novel aspects of the structure-activity relationships for marcfortine A (1).
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■ Studies on Urothion. Determination of the Absolute Configuration of the Dephospho Form B Derived from Urothion
Atsushi Sakurai,* Yuji Hashimoto, Nobuhiro Kuboyama, and Yasuaki Okumura
*Department of Chemisttry, Faculty of Science, Shizuoka University, Ohya, Shizuoka 422-8529
Abstract
In order to determine the absolute configuration of urothion (4), the CD spectrum of the dephospho form B (3b) derived from 4 was compared with those of both enantiomers of the dephospho form B ((R)-3b and (S)-3b) which were prepared by asymmetric synthesis. R-Configuration was concluded for the secondary hydroxyl group on the side chain of 3b, as well as 4, which is the same configuration as that of molybdopterin (1). This supports the view that 4 might be a urinary metabolite of 1.
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■ Synthesis and Activity as a Glycosidase Inhibitor of 2,8-Dihydroxyindolizidines
Ho Seong Na, Jaehyuck Choi, Jaehoon Yu, Kye Jung Shin, Kyung Ho Yoo, Dong Jin Kim,* and Sang Woo Park*
*Medicinal Chemistry Research Center, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul 130-650, Korea
Abstract
The synthesis and enzyme assay of 2,8-dihydroxyindolizidines (5) were described. Four diastereomers of these were prepared from trans-4-hydroxy-L-proline (6) which is commercially available amino acid. Among synthetic compounds 5a1 and 5b2 showed medium potent inhibition to α-amyloglycosidase, while 5a2 displayed medium activity to α-glucosidase.
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■ Preparation of New 3-Hydroxyquinoline Alkaloid, Jineol and Its Ether Derivatives Using Directed ortho-Lithiation of Chloroquinoline as the Key Step
Yoshinobu Tagawa, Hiroyuki Yamashita, Manami Nomura, and Yoshinobu Goto*
*Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
Abstract
A new alkaloid, jineol (3,8-dihydroxyquinoline) was conveniently prepared employing directed ortho-lithiation of chloroquinoline for 3-position of quinoline ring. Moreover, the ether derivatives of jineol were obtained by the reaction of jineol with alkyl halide in the presence of KOH in DMSO in 26-96% yields.
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■ The Anomeric Effect of Monosaccharides and Their Derivatives. Insights from the New QVBMM Molecular Mechanics Force Field
Vernon G. S. Box
*Department of Chemistry, The City College of the City University of New York, Convent Avenue @ 138th Street, New York, NY 10031, U.S.A.
Abstract
The new force field, Quantized Valence Bonds’ Molecular Mechanics, QVBMM, was designed to embrace most of the concepts in Valence Shell Electron Pair Repulsion (VSEPR) theory and to uniquely integrate lone pairs into molecular mechanics. This force field is executed in the molecular modeling program STR3DI.EXE and is particularly useful in the molecular modeling studies of molecules that possess lone-pair-bearing heteroatoms. This force field was used to study the stereo-electronic effects found in the simple derivatives of tetrahydropyran, and hence to investigate the Anomeric Effect of monosaccharides.