HETEROCYCLES

■ Contributions of Professor Masatomo Hamana in Heterocyclic Chemistry –Research Life of a Scientist in Heteroaromatic N-Oxide Chemistry —

Hiroshi Yamanaka*

*Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan

■ Asymmetric Synthesis of Piperidine Alkaloids Utilizing Diastereoselective Reaction of 1,3-Oxazolidine with Grignard Reagents

Kimio Higashiyama,* Keiji Nakahata, and Hiroshi Takahashi

*Faculty of Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan

Abstract

A facile method of synthesizing enantiomerically pure piperidine alkaloids, (R)-(-)-coniine and (2R,6S)-(-)-dihydropinidine, has been explored by employing the highly diastereoselective reaction of a 1,3-oxazolidine with Grignard reagents.

■ Synthesis of 5-Arylthio-3-Methyl-L-histidine, a Model for the Starfish Alkaloid Imbricante

Massashi Ohba, Takafumi Mukaihara, and Tozo Fujii*

*Faculty of Pharmaceutical Scicences, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan

Abstract

Syntheses of 3-methyl-5-phenylthio-L-histidine (8a) and 3-methyl-5-(1-naphthy1)thio-L-histidine (8b), selected as models for the asteroid alkaloid imbricatine (7), have now become feasible through a 10-step route starting from 4(5)-bromoimidazole (9). The key steps involve replacement of the 4-bromo group by an arylthio group in the aldehyde (14) and construction of the L-alanine moiety in the chlorides (17a,b) by the “bis-lactim ether” method.

■ A Synthetic Model Approach to the Sugar Moiety of Bleomycin

Masami Otsuka,* Toshiyuiki Nishio, Tetsuya Oshitari, Takashi Owa, Yukio Sugiura, Kenji Maeda, Masaji Ohno, and Susumu Kobayashi*

*Faculty of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113, Japan

Abstract

In order to investigate the role of the sugar moiety of antitumor antibiotic bleomycin, glycosylation of erythro-β-hydroxy-L-histidine derivative is examined and several glycosylated model compounds are prepared by the chloroacetimidate method. These models show excellent dioxygen activating capability.

■ Spin-Spin Coupling between Fluorine and Aromatic Protons of 3-Fluoroquinoline: Dependence on the Electronic Structure of the Ring Nitrogen

Ken-ichi Saeki, Kohfuku Kohda, Yutaka Kawazoe,* and Yohko Sakamoto

*Faculty of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan

Abstract

The spin-spin coupling constant, J 2H- 3F , of 3-fluoroquinoline was strongly dependent on the electronic structure of the ring nitrogen. J 2H-3F measured in CDCl₃ was almost null and increased as the acidity of solvent increased, reaching 2.8 Hz in 10% D₂SO₄. The J values of its methiodide and N-oxide were 3.1-3.3 and 3.8-4.6, respectively, which were not appreciably dependent on the acidity of the solvent for measurement.

■ Regioselective Allylation to a Tetrahydroisoquinoline

Hiroshi Hara, Akiko Seto, and Osamu Hoshino*

*Faculty of Pharmaceutical Sciences, Science University of Tokyo, 12, Ichigaya Funagawara-machi, Shinjuku-ku, Tokyo 162-0826, Japan

Abstract

The p-quinol acetate (1a) reacted with allyltrimethylsilane in dichlorcomethane in the presence of acid (BF₃·Et₂O or CF₃COOH) to give 8-allylcorypalline (3), while in acetonitrile to give 4-allylcorypalline (7), regioselectively. Plausible pathway on formation of 3 and 7 is described.

■ A Synthesis of 5-Silacyclotriveratrylenes

Hiroshi Hara, Hiroya Satoh, and Osamu Hoshino*

*Faculty of Pharmaceutical Sciences, Science University of Tokyo, 12, Ichigaya Funagawara-machi, Shinjuku-ku, Tokyo 162-0826, Japan

Abstract

The dilithio compound (4), derived from 4,5-bis(6-bromoveratryl)veratrol(3), reacted with dichlorodimethylsilane to give 5,5-dimethyl-5-silacyclotriveratrylene (2a). Similarly, several 5-silacyclotriveratrylenes (2b, 2c, and 2d) and a methylenedioxy analogue (6) were prepared. On the basis of ¹H-nmr spectra flexible conformation of the sila-heterocyclic system was elucidated.

■ Structure and Redox Reactions of Tricyclic Pyridinium N-Imines

Yoshiro Yamashita,* Shoji Tanaka, and Masaaki Tomura

*Institute for Molecular Science, Nishi-Gonaka 38, Myodaiji, Okazaki 444-8585, Japan

Abstract

X-Ray structural analysis of tricyclic pyridinium N -imine (1a), which is a novel N-alkylated pyridinium N-imine, revealed characteristics of the structure. Studies on the redox reactions demonstrated that pyridinium N -imines (1a-c) and quinolinium N -imine (2) are electron donors and oxidized with nitrosonium tetrafluoroborate.

■ Synthesis of Trifluoromethylated Tetrahydropyrans from Ene Reaction Products of Trifluoromethyl Ketones: Synthesis of Fluorine Analogs of a Sesquiterpene

Takabumi Nagai, Hiroshi Ohtsuka, Mayumi Koyama, Akira Ando, Takuichi Miki, and Itsumaro Kumadaki*

*Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho, Hirakata-shi, Osaka 573-0101, Japan

Abstract

As the extension of the ene reaction of trifluoromethyl ketones, α-trifluoromethylated tetrahydropyrans, including fluorine analogs of sesquiterpenes, were synthesized from trifluoromethylated homoallyl alcohols, the products of the ene reaction.

■ On the Synthesis of N-Substituted 5-Oxoperhydro-1,4-oxazepines from N-Substitued 1,2-Aminoethanols. A Dichotomy of Reaction Pathway

Benito Alcaide, M. Dolores Gracia-Gravalos, Berta López, Joaquín Plumet,* and Alberto del Valle

*Universidad Complutense de Madridas, Facultad de Química, Departamento de Química Orgánica, Ciudad Universitaria, E-28040 Madrid, Spain

Abstract

The reaction of N -substituted N-(1,2-diphenyl-2-hydroxiethyl)-β-chloropropionamides with NaH/DME affords cyclization to the 5-oxoperhydro-l,4-oxazepines or alcoholysis of the amide moiety depending on the nature of the substituent attached to the nitrogen atom. Some of the compounds synthesized show significant antitumour activity.

■ Enantiocontrolled Synthesis of the C_9-27 Segment of Milbemycin K from (R)- and (S)-Epichlorohydrins

Seiichi Takano,* Yoshinori Sekiguchi, and Kunio Ogasawara

*Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan

Abstract

The C_9-27 segment (11) of milbemycin K (10) has been synthesized using two molar equivalents of ( R )-epichlorohydrin [(R )-1] and one molar equivalent of (S)-epichlorohydrin [(S)-1] as chiral building blocks.

■ Chelation Controlled Aldol Reaction of Tetronic Acid Dianion with Ketones

Toshio Honda,* Hirotsune Kondoh, Akihiko Okuyama, Tomohisa Hayakawa, Masayoshi Tubuki, and Hiromassa Nagase

*Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan

Abstract

The chelation effect in the aldol reaction of dianion of tetronic acid with ketones was investigated to give the erythro adduct, predominantly, via the six-membered chelation transition state. The carbon-carbon bond formation occurred at the 5-position siteselectively in this reaction.

■ Total Synthesis of (+)-Menthofuran

Kozo Shishido,* Takeshi Takata, Koji Umimoto, and Masayuki Shibuya

*Faculty of Pharmaceutical Sciences, University of Tokushima, Sho-machi, Tokushima 770-8505, Japan

Abstract

Total synthesis of optically active menthofuran, a perfumy monoterpene, has been accomplished employing the intramolecular [3+2] cycloaddition-based methodology for the construction of fused furans.

■ A Simple Synthesis of a Phytoalexin, Methoxybrassinin

Masanori Somei,* Kensuke Kobayashi, Kazuhisa Shimizu, and Toshiya Kawasaki

*Faculty of Pharmaceutical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan

Abstract

A simple and an alternative multi-gram scale synthetic method for methoxybrassinin is developed starting from indole-3-carboxaldehyde.

■ Preparation od Cyclic α-Hydrazino Acids through N-Acylhydrazonium Intermediates

Floris P. J. T. Rutjes, Jan H. Udding, Henk Hiemstra,* and W. Nico Speckamp*

*Organic Chemistry Department, University of Amsterdam, Nieuwe Achtergracht 129 1018 WS Amsterdam, The Netherland

Abstract

An efficient synthesis of bicyclic hydrazine derivatives (5a) and (5b) through the intermediacy of exocyclic hydrazonium ions (4a) and (4b) is described.

■ Synthesis of 1-Fluoro-1-demethylmesoporphyrin-IX

Akihiro Suzuki, Hiroo Toi, Yasuhiro Aoyama, and Hisanobu Ogoshi*

*Department of Synthetic Chemistry, Kyoto University, Yoshida, Sakyou-ku, Kyoto 606-8501, Japan

Abstract

Total syntheses of 1-fluoro-1-demethylmesoporphyrin-IX and its metal complexes are described. The iron(III) complex forms stable reconstituted myoglobin. Paramagnetic ¹⁹F-nmr spectra of metalloporphyrins were measured for the high and low spin states of the iron(III) complexes.

■ Anionic Hetero[3,3]rearrangement. N-Acyl-N'-enylhydrazines to Pyrrolidinones

Yasuyuki Endo* and Koichi Shudo

*Faculty of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113, Japan

Abstract

N -Acyl-N ’-enylhydrazines rearrange upon treatment with base to afford
5-amino-2-pyrrolidinones. The rearrangement can be rationalized in terms of
initial stereospecific [3,3]sigmatropic shifts of the enolates followed by
intramolecular addition of the nitrogen atom of the amide group to the imino
group.

■ Diastereoselective Cyclization of ω-Formylated Allysilanes into Bicyclic α-Methylene-γ-butyrolactones; a Facile Synthesis of p-Menthanolides

Kiyoshi Nishitani, Hiroshi Fukuda, and Koji Yamakawa*

*Faculty of Pharmaceutical Sciences, Science University of Tokyo, 12, Ichigaya Funagawara-machi, Shinjuku-ku, Tokyo 162-0826, Japan

Abstract

Intramolecular cyclization of ω-formylated allylsilanes, ethyl (Z)- and
(E)-2-(trimethylsilyl)methyl-6(R)-methyl-7-hept-2-enoates (5a and 5b), was effected by BF₃·etherate. giving cis (1S,2S,5R)- and trans (1R,2S,5R)-hydroxy esters (6 and 7) in complete diastereoselectivities. Treatment of the allylsilanes (5a and 5b) with Ticl₄ predominantly gave the cis (1S,2S,5R)-isomer in excellent yields. These hydroxy esters (6 and 7) were easily converted into α-methylene-γ-butyrolactones, cis - and trans -p -menthanolides (II and III).

■ Structures of Sterically Encumbered 1,9-Bis(arylthio)dibenzothiophenes and Detection of Their Dithia Dications in Concentrated Sulfuric Acid by ¹H-NMR

Takeshi Kimura, Yoji Horie, Satoshi Ogawa, Hisashi Fijihara, Fijiko Iwasaki, and Naomichi Furukawa*

*Department of Chemistry, University of Tsukuba, 1-1-1 Ten-nodai, Tsukuba-shi, Ibaraki, 305-8571, Japan

Abstract

1,9-Bis(arylthio)dibenzothiophenes (1) and their monooxides (2) were prepared and the structures of the phenyl derivatives (1a) and (2a) were determined by X-ray crystallographic analysis. The dithia dications (3) were generated on dissolution of compounds (1) and (2) in concentrated sulfuric acid-d₂ and their structures were characterized by ¹H-nmr spectroscopy.

■ Use of 1,3-Dioxin-4-ones and Their Related Compounds in Synthesis. Part 35. Synthesis of Optically Pure Fluoromalonamic Acids by Means of Asymmetric Fluorination of Chiral 1,3-Oxazine-4,6-diones

Masayuki Sato,* Noritaka Kitazawa, and Chikara Kaneko

*Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan

Abstract

Fluorination of chiral 5-substituted 1,3-oxazine-4,6-dione derivatives proceeded stereoselectively to give the 5-fluorooxazinediones, which were readily transformed to optically pure fluoromalonamic acids.

■ Rections of Hexachlorocyclotriphosphazene with N-Methyl-1,3-diaminopropane: Isolation of Spirocyclic and not Intermolecular Bridge Products.

Vadapalli Chandrasekhar,* Madaligar Gopala Krishnarao Muralidhara, and Narredi Sivasanakara Reddy

*Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India

Abstract

The reactions of hexachlorocyclotriphosphazene with N -methyl-1,3-diaminopropane are discussed. The structures of the products have been established by spectroscopic methods. The products are formed exclusively via a spirocyclic pathway.

■ Synthesis of Iridolactones Isolated from Silver vine

Masaharu Kigawa, Masahid Tanaka, Hiroshi Mitsuhashi, and Takeshi Wakamatsu*

*Tsumura Reserach Institute for Biology and Chemistry (TRIBIC), 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan

Abstract

The naturally occurring iridolactones, nepetalactone, isodihydronepetalactone, and iridomyrmecin are synthesized in optically active forms starting from natural glycoside geniposide. The stereogenic centers were introduced with highly stereoselective hydrogenations.

■ Synthesis of N_a-Methoxyindole and N_a-Methoxyoxindole Alkaloids Having Yohimbine Skeleton

Hiromitsu Takayama, Norio Seki, Mariko Kitajima, Norio Aimi, Hiroko Seki, and Shin-ichiro Sakai*

*Faculty of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan

Abstract

Indoloquinolizidine (1) and yohimbine (7) were converted to the corresponding Na-methoxyindoles and Na-methoxyoxindoles by the oxidation of the dihydroindole derivatives with H₂O₂ and sodium tungstate.

■ A Tandem Cope-Claisen Rearrangement Reaction of meso-3,3'-Diphenylleucoisoindigos

Tetsuo Suyama, Takeshi Kato, Yutaka Morita,* and Hiroshi Miyamae

*Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan

Abstract

A unique and new rearrangement reaction of meso - 3,3 ’-diphenylleucoisoindigos was examined. Structures of the products were determined as 3,6’-biindolinones by X-ray analyses. The formal reaction mechanism was supposed to be a tandem Cope-Claisen type rearrangement.

■ New Condensing Reagents: Thiophosphorus Compounds Activated by 2-Oxazolone and 2-Benzoxazolinone Heterocycles

Teruyuki Otsubo, Chiyoko Matsukawa, Tadao Ishizuka, and Takehisa Kunieda*

*Faculty of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-hon-machi, Kumamoto 862-0973, Japan

Abstract

The thiophosphorus compounds (3-6 ) activated by 2-oxazolone and 2-benzoxazolinone heterocycles, which have the advantages of high solubility in organic solvents and good preservability, serve well as versatile condensing reagents for one-step formation of amides including β-lactams, esters and thioesters from carboxylic acids.

■ Synthesis of Sulfonamido Oligo-N-methylpyrrolecarboxamide Derivatives and Their Photochemical DNA Cleaving Activities

Toyomi Matsumoto, Yasuhiro Sakai, Kouhei Toyooka, and Masayuki Shibuya*

*Faculty of Pharmaceutical Sciences, University of Tokushima, Sho-machi 1, Tokushima 770-8505, Japan

Abstract

Synthesis of various sulfonamido oligo-N -methylpyrrolecarboxamide derivatives and their DNA cleaving activities under uv-A irradiation were described.

■ A New Approach to 5-Arylpyrrolidin-2-ones via 5-endo-Trig Radical Cyclization of α-Halo- or α-Thio-substituted N-(1-Arylethenyl)acetamides

Tatsunori Sato, Naomi Machigashira, Hiroyuki Iahibashi, and Masazumi Ikeda*

*Kyoto Pharmaceutical University, Misasagi-Shichonocho, Yamashina, Kyorto 607-8414, Japan

Abstract

N-(1-Phenylethenyl)carbamoylmethyl radicals generated by tributyltin hydride-mediated cleavage of carbon-halogen or carbon-sulfur bond underwent smooth cyclization in a “disfavored” 5-endo-trig manner to give 5-phenylpyrrolidin-2-one. This method was applied to the synthesis of (±)-cotinine.

■ Synthesis of (6S,8R)-6-(1'-Hydroxyethyl)carbopenem, a Thienamycin Type

Tomohisa Ohta, Sojiro shiokawa, Eiichiro Iwashita, Nobuaki Sato, Kuniya Sakurai, Takashi Ineyama, Hiroyuki Izawa, Kunisuke Izawa, and Shigeo Nozoe*

*Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan

Abstract

Title carbapenem (1) having thienamycin-type of side chain at C-6 was synthesized from L-glutamic acid. Chirospecific oxymercuration of 6-vinylcarbapenam (12a) successfully induced 8R -hydroxyl.

■ Synthesis of 7-Substituted Indolo[3,2-b]quinoline Derivatives

Ming-rong Chang, Yasuo Takeuchi, Kuniko Hashigaki, and Masatoshi Yamato*

*Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Okayama 700-8530, Japan

Abstract

Indolo[3,2-b]quinoline derivatives (7b-j) having the substituent, such as a nitro, amino, methyl, halogen, methoxy, or hydroxy group were prepared by three methods.

■ Short-step Synthesis of Rutecarpine and Tryptanthrin via Intramoleculer Aza-wittig Reaction

Shoji Eguchi,* Hisato Takeuchi, and Yuji Matsushita

*Institute of Applied Organic Chemistry, Faculty of Engineering, Nagoya University, Chikusa, Nagoya, Aichi 464-8601, Japan

Abstract

A convenient short-step synthesis of rutecarpine and tryptanthrin as quinazoline alkaloids containing indole skeleton via intramolecular aza-Wittig reaction was described.