HETEROCYCLES

■ Preface
In Honor of Professor Satoshi Omura on the Occation of His 70^th Birthday

Takeshi Kitahara

*Professor Emeritus, the University of Tokyo
Guest Professor, Kitasato University
Head, The Kitasato Institute
Professor, Teikyo Heisei University

■ Biographical Data

Satoshi Ōmura*

*Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan

■ Publications List

Satoshi Ōmura*

*Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan

■ 3,4,5,6-Tetrasubstituted 2-Pyridone Synthesis via Nucleophilic Addition of Active Methine Compounds to Dialkynyl Imines Directed to the Synthesis of (-)-A58365A

Iwao Hachiya, Shiho Fukushima, and Makoto Shimizu*

*Department of Chemistry for Materials, Mie University, Tsu, Mie 514-8507, Japan

Abstract

3,4,5,6-Tetrasubstituted-2-pyridone synthesis via nucleophilic addition of active methine compounds to dialkynyl imines directed to the synthesis of (-)-A58365A has been developed. The reaction of active methine compounds such as malonic esters or β-keto esters to dialkynyl imines provided 3,4,5,6-tetrasubstituted-2-pyridones in moderate to good yields.

■ Total Synthesis of (—)-Pramanicin

Shin-ya Aoki, Taro Tsukude, Yukari Miyazaki, Ken-ichi Takao, and Kin-ichi Tadano*

*Department of Applied Chemistry, Keio University, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan

Abstract

The total synthesis of natural (-)-pramanicin, a highly oxygenated γ-lactam-type antifungal agent, is described. The enantiospecific total synthesis of this natural product commenced with 5-deoxy-1,2-O-isopropylidene-α-D-xylofuranose as an enantiopure starting material.

■ Rapid ‘SAR’ via Click Chemistry: An Alkyne-Bearing Spiramycin is fused with Diverse Azides to Yield New Triazole-Antibacterial Candidates

Tomoyasu Hirose, Toshiaki Sunazuka, Yoshihiko Noguchi, Yukie Yamaguchi, Hideaki Hanaki, K. Barry Sharpless, and Satoshi Omura*

*Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642,

Abstract

The spiramycin analogue, 2’-acetyl-4’’’-de-N-methyl-4’’-O-t- butyldimethylsilylspiramycin I 3,18-(O-t-butyldimethylsilyl)acetal(1), was found to be an adequate antibacterial agent against MRSA strains. An acetylenic sidechain was attached to 1 producing the analog (8), with the core intact but displaying a tethered terminal alkyne, ready for reaction with 19 diverse azides. In the event, the copper-catalyzed Fokin-Huisgen triazole synthesis/coupling gave each of the nineteen new 4’’-O-acyl triazole derivatives of 1 in good to nearly quantitative isolated yields.

■ Synthesis of Tulipalin B and 1-O-Methyl-6-tuliposide B

Kengo Shigetomi, Takao Kishimoto, Kazuaki Shoji, and Makoto Ubukata*

*Division of Applied Bioscience, Research Faculty of Agriculture, Hokkaido University, Sapporo 060-8589,Japan

Abstract

Toward the total synthesis of 6-tuliposide B, facile synthesis of tulipalin B and 1-O-methyl-6-tuliposide B (Methyl 6-O-((S)-3’,4’-dihydroxy-2’- methylenebutanoyl)-β-D-glucopyranoside) has been achieved.

■ Stereoselective Synthesis of trans-3a-Aryloctahydroindoles Using Cyclization of N-Vinylic α-(Methylthio)acetamides

Miho Saito, Jun-ichi Matsuo, Masahiko Uchiyama, and Hiroyuki Ishibashi*

*Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa 920-1192, Japan

Abstract

Treatment of N-(2-arylcyclohex-1-enyl)-α-(methylthio)acetamide with NCS underwent cyclization to give 3a-arylhexahydroindol-2-one, which was stereoselectively converted into trans-3a-aryloctahydroindole.

■ Acridone Heterocycles as Fluorescent Sensors for Anions

M. Teresa Blázquez, Francisco M. Muñiz, Silvia Sáez, Luis M. Simón, Ángel Alonso, César Raposo, Anna Lithgow, Victoria Alcázar, and Joaquín R. Morán*

*Organic Chemistry Department, University of Salamanca, Plaza de los Caídos 1-5, Salamanca E-37008, Spain

Abstract

An acridone heterocycle with a suitable functionalization can be used as a fluorescent sensor for anions. Large differences in fluorescence efficiency are observed when chlorides are associated in the receptor cavity. Chlorides form two different complexes in chloroform, with 2:1 and 1:1 stoichiometries. The combined presence of receptor (1) and 18-crown-6 ether allows the extraction of aqueous α-amino acids to the chloroform phase. This extraction is very sensitive to temperature.

■ Direct Observation of ESR Spectra of Bicyclic Nine-Membered Enediynes at Ambient Temperature

Masahiro Hirama,* Kimio Akiyama,* Parthasarathi Das, Takashi Mita, Martin J. Lear, Kyo-ichiro Iida, Itaru Sato, Fumihiko Yoshimura, Toyonobu Usuki, and Shozo Tero-Kubota

*Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan

Abstract

The ESR spectra for synthetic bicyclo[7.3.0]epoxydodecadienediynes in solution at room temperature are steady. These spectra originate from the Masamune-Bergman cyclization of bicyclo[7.3.0]epoxydodecadienediynes to p-benzyne biradicals and the equilibrium between the two forms. Comparison of the ESR spectra of the unlabeled and ¹³C-labeled nine-membered enediynes indicated that the spectra are not directly due to the p-benzyne biradicals but rather to more stable secondary radical intermediates.

■ Convergent Synthesis of the CDEF Ring Fragment of Yessotoxin via α-Cyano Ethers

Tohru Oishi,* Miho Suzuki, Koji Watanabe, and Michio Murata

*Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan

Abstract

The synthesis of the CDEF ring fragment of yessotoxin, a marine ladder polyether, has been achieved. Union of three components, the C ring aldehyde, the F ring diol, and trimethylsilyl cyanide, was accomplished by treatment with Sc(OTf)₃ to afford the α-cyano ether both in stepwise and one-pot reactions. The DE ring system was constructed through a ring closing metathesis reaction and reductive etherification sequence.

■ 4-Aryl-2-quinolones via a Domino Heck Reaction / Cyclization Process

Roberta Bernini, Sandro Cacchi,* Giancarlo Fabrizi,* and Alessio Sferrazza

*Department of Studies of Chemistry and Technology of Biologically Active Substances, University “La Sapienza”, P. le A. Moro 5, 00185 Rome, Italy

Abstract

The reaction of methyl β-(o-acetamidophenyl)acrylates with aryl iodides in the presence of Pd(OAc)₂ and KOAc in DMF at 120 °C affords 4-aryl-2-quinolones in allowable to good yields.

■ Synthesis of Cyclic Polyglycerols

Takahiro Kawagishi, Kimio Yoshikawa, Makoto Ubukata, Masahiro Hamada, and Noriyuki Nakajima*

*Biotechnology Research Center, Toyama Prefectural University, Imizu, Toyama 939-0398, Japan

Abstract

Authentic standards of cyclic polyglycerol, with well-defined structures and degrees of polymerization from 3 to 6 cyclic oligomers, have been efficiently synthesized. The intramolecular cyclization conditions gave cyclic glycerols more effectively than intermolecular coupling conditions.

■ Oxidative Cyclization of Isodityrosine Tripeptides: Optimized Condition and Application of Electrochemically Generated Thallium(III) Ion

Takamasa Tanabe, Rika Obata, and Shigeru Nishiyama*

*Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku, Yokohama 223-8522, Japan

Abstract

Thallium(III) trinitrate oxidation of the tripeptide, which was a synthetic precursor of the 17-membered isodityrosine natural product, eurypamide, was investigated to give the desired cyclized compound in 96% yield at best. In addition, the thallium(III) species generated by electrochemical oxidation of thallium(I) successfully produced the target compounds.

■ Reaction of 2H-Cyclohepta[b]furan-2-ones with Pyridinium Salts of Trifluoromethanesulfonic Anhydride

Noboru Morita,* Tomohiro Matsuki, Masashi Nakashima, Taku Shoji, Kozo Toyota, Shigeru Kikuchi, and Shunji Ito

*Department of Chemistry, Graduate School of Science, Tohoku University, Sendai, 980-8578, Japan

Abstract

2H-Cyclohepta[b]furan-2-one (1) reacted with TPT, electrophilically to give 3-dihydropyridinyl-2H-cyclohepta[b]furan-2-one and subsequent treatment with sodium hydroxide in ethanol gave 3-(4-pyridinyl)-2H-cyclohepta[b]furan- 2-one in excellent yields. Furthermore, it reacted with methyl iodide give a corresponding pyridinium salt easily.

■ 5-Acyl-2H-pyran-2-ones in the Schmidt Reaction: Migration of the Pyran-2-one Ring

Franc Pozgan, Maja Krejan, Slovenko Polanc, and Marijan Kočevar*

*Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, SI-1000 Ljubljana, Slovenia

Abstract

The Schmidt reaction of the 5-acyl-2H-pyran-2-ones (1a—f) using NaN₃/H₂SO₄ was investigated. The reaction proceeded with complete regioselectivity in the 5-acetyl series to give the corresponding 5-acetylamino derivatives (2a—c) via pyran-2-one ring migration. In contrast, the reaction applied to the 5-benzoyl-2H-pyran-2-ones (1d—f) led to the formation of both regioisomers, (2d—f) and (3d—f). The latter resulted from the phenyl shift in this reaction and were obtained as minor products. The 3,5-diacylamino-2H-pyran-2-ones (2a) and (2d) were selectively debenzoylated at position 3.

■ Starter Unit Specificity of the Asukamycin “Upper” Chain Polyketide Synthase and the Branched-Chain Fatty Acid Synthase of Streptomyces nodosus subsp. asukaensis

Yiding Hu and Heinz G. Floss*

*Department of Chemistry, University of Washington, Seattle, WA 98195-1700, U.S.A.

Abstract

Asukamycin, a member of the manumycin family of antibiotics, obtained from Streptomyces nodosus subsp. asukaensis, contains two amide-linked polyketide chains, one of which, the “upper” chain, is initiated by cyclohexanecarboxylic acid as the starter unit. Analysis of the congeners of asukamycin present in the fermentation and of the fatty acid spectrum of the mycelial lipids revealed that the “upper” chain polyketide synthase (PKS) and the branched-chain fatty acid synthase (FAS) of S. nodosus ssp. asukaensis share qualitatively, although not quantitatively, the same starter unit selectivity for branched chain and alicyclic carboxylic acids. Feeding of various alicyclic carboxylic acids of different ring size resulted in the formation of new asukamycin analogs as well as changes in the fatty acid spectrum. Feeding of various alicyclic carboxylic acids also shut off the endogenous production of cyclohexanecarboxylic acid.

■ Exploring the Synthesis of Masked Phosphoramido 6-Vinylcytidine Derivatives as Building Blocks for Cross-Linking Oligonucleotides

Marco Radi, Raffaella Spinosa, Maria Cristina Parlato, Federico Corelli, and Maurizio Botta*

*Department of Medicinal Chemistry, University of Siena, Via Aldo Moro, 53100 Siena, Italy

Abstract

In the present work the synthesis of building blocks (2a,b), bearing a masked form of the reactive vinyl group bound to the C-6 position of a cytidine derivative, has been studied. The understanding of byproduct formation together with conformational considerations let us to plan a straightforward approach for the synthesis of the target compounds.

■ Reactions of 8-(Triphenylphosphoimino)quinoline with Aryl Aldehydes and Aryl Isocyanates: Formation of 2-Aryl-4H-imidazo[4,5,1-ij]quinolines and Related Systems

Kentaro Nagamatsu, Erina Akiyoshi, Hidenori Ito, Hiroyuki Fujii, Akikazu Kakehi, and Noritaka Abe*

*Department of Chemistry, Faculty of Science, Yamaguchi University, Yoshida, Yamaguchi 753-8512, Japan

Abstract

The reaction of 8-(triphenylphosphoimino)quinoline with aryl aldehydes gave 2-aryl-4H-imidazo[4,5,1-ij]quinolines. In the reaction, tandem aza-Wittig reaction and cyclization attended with hydride shift occurred. The reaction of 8-(triphenylphosphoimino)quinoline with aryl isocyanates gave 1,3-diaryl-1,2,3,9a-tetrahydro[1,3,5]triazolo[2’,3’:2,1;3’,4’-a]imidazo[4,5,1-ij]quinolin-2-ones (11) and 2-(arylamino)imidazo[4,5,1- ij]quinolin-4(4H)-ones (12). The structures of 11a (Ar = Ph) and 12a (Ar = Ph) were confirmed by X-Ray structure analyses.

■ Synthesis of New Pyrrolidine Derivatives as Inhibitors of α-Mannosidase and of the Growth of Human Glioblastoma Cells

Sylvain Favre, Hélène Fiaux, Catherine Schütz, Pierre Vogel, Lucienne Juillerat-Jeanneret,* and Sandrine Gerber-Lemaire*

*Laboratory of Glycochemistry and Asymmetric Synthesis, Ecole Polytechnique Fédérale de Lausanne (EPFL), Batochime (BCH), CH-1015 Lausanne, Switzerland

Abstract

New 2-benzylamino-3,4-dihydroxypyrrolidines bearing aromatic and aliphatic amido side chains have been prepared. The influence of the amido substituents on the inhibitory activity of these diamines toward 24 commercially available glycosidases was determined. The most potent and selective α-mannosidase inhibitor (6d) (N-[(2R)-2-({[(2R,3R,4S)-3,4-dihydroxypyrrolidin -2-yl]methyl} amino)-2-phenylethyl]-3-bromobenzamide) of these series was also the most potent inhibitor of the growth of human glioblastoma cells.

■ Novel Chiral Synthetic Path to Indolizidine and Quinolizidine Alkaloids by Means of a Samarium Diiodide-Promoted Reductive Carbon-Nitrogen Cleavage Reaction: Synthesis of (+)-(8R, 8aR)-Perhydro-8-indolizidinol and (—)-Deoxynupharidine

Miho Katoh, Hirotake Mizutani, and Toshio Honda*

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

Abstract

Novel chiral synthetic procedures for indolizidine and quinolizidine alkaloids were developed, where a samarium diiodide-promoted carbon-nitrogen bond cleavage reaction was employed as a key step. Application of the procedure led to the total synthesis of (+)-(8R, 8aR)-perhydro-8-indolizidinol and (-)-deoxynupharidine.

■ Syntheses of Ulocladol

Hitoshi Abe,* Tomoko Fukumoto, Keisuke Nishioka, Masatsugu Arai, Yasuo Takeuchi, and Takashi Harayama

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

Abstract

Several synthetic routes to produce ulocladol were established through a short-step transformation involving the selective demethylation or a lactone transformation process.

■ Three New Phlegmarine-Type Lycopodium Alkaloids, Lycoposerramines-X, -Y and -Z, Having a Nitrone Residue, from Lycopodium serratum

Kazuaki Katakawa, Mariko Kitajima, Kentaro Yamaguchi, and Hiromitsu Takayama*

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

Abstract

Three new phlegmarine-type Lycopodium alkaloids, lycoposerramines-X (2), -Y (3), and -Z (5), having a nitrone residue were isolated from the club moss Lycopodium serratum Thunb. The structures of these new alkaloids, together with the stereostructures of the related alkaloids, huperzines J (1) and K (4), were elucidated by spectroscopic analyses.

■ Further Structure-Activity Relationships of the Myxobacterial Antibiotics Cystothiazoles

Bangi A. Kundim, Jianhua Qi, Ryosuke Fudou, Shigeru Yamanaka, and Makoto Ojika*

*Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa-ku, Nagoya 464-8601, Japan

Abstract

Eight derivatives of the bithiazole-type myxobacterial antibiotic cystothiazole A were evaluated for antifungal activity against a phytopathogenic microorganism for a further structure-activity relationship. Two of them, an acetate and a fully conjugated non-chiral derivative, were new derivatives obtained by chemical derivatization of cystothiazole C. The results confirmed the importance of the bend conformation at C-4/C-5, the methyl ether at C-5, and the lipophilicity of the terminal alkyl group of the molecule.

■ Anthocyanins from the Rhizome of Raphanus sativus, and Change in the Composition during Maturation

Mihoko Mori, Shuji Nakagawa, Masayoshi Maeshima, Satoshi Niikura, and Kumi Yoshida*

*Graduate School of Information Science, Nagoya University, Chikusa, Nagoya 464-8601, Japan

Abstract

Four new acylated anthocyanins with three known pigments were isolated from the rhizome of the Chinese red radish (Raphanus sativus cv. Beijing hong xin), and their structures were determined. All of them possessed pelargonidin 3-sophoroside-5-glucoside as a common structure, and each was substituted with one to two aromatic acyl residues, with/without a malonyl residue and with/without a sugar residue. The major aromatic acyl moiety was feruloyl. Most of the pigments were malonylated. The cambium part was richer in polyacylated anthocyanins than the parenchyma part.

■ Chaxine A, an Osteoclast-Forming Suppressing Substance, from the Mushroom Agrocybe chaxingu

Hirokazu Kawagishi,* Takuto Akachi, Tetsuhiro Ogawa, Kikuko Masuda, Kohji Yamaguchi, Kazunaga Yazawa, and Mamoru Takahashi

*Graduate School of Science and Technology, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529, Japan

Abstract

A novel compound, chaxine A, (1), and a known one (2) were isolated from the mushroom Agrocybe chaxingu. These compounds suppressed the formation of osteoclast.

■ 1-Hydroxyyohimbine and Its Derivatives: New Potent α₂-Blockers for the Treatment of Erectile Dysfunction

Masanori Somei,* Koichi Noguchi, Katsumasa Yoshino, Koichiro Mori, Mamiko Asada, Fumio Yamada, Yoshio Tanaka, Koki Shigenobu, and Katsuo Koike

*Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192, Japan

Abstract

1-Hydroxyyohimbine and its various derivatives are prepared for the first time. These novel compounds are found to be potent α₂-blockers comparable to yohimbine itself.

■ A New Useful Conversion Method of Naltrexone to 14-Deoxynaltrexone

Yumiko Osa, Yoshihiro Ida, Yumiko Yano, Kimio Furuhata, and Hiroshi Nagase*

*School of Pharmaceutical Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan

Abstract

A novel synthetic method of 14-deoxynaltrexone (2), a μ-opioid receptor antagonist possessing a new message-structural part of opioid ligands, was established. Naltrexone methyl ether (5) was first converted to its acetal (24), followed by dehydration with thionyl chloride in pyridine to afford 8,14-dehydroderivative (26) of 24. The resulting unsaturated compound (26) was reduced with PtO₂ under hydrogen to give saturated compound (27), which was then acid-hydrolyzed to afford the desired 14-deoxynaltrexone (23) (3-O-methyl of 2) without degradation of the naltrexone skeleton. The total yield from naltrexone (1) to 23 was 86%. Finally, 23 was demethylated to give 14-deoxynaltrexone (2) in 85% yield. This method provides a useful reaction route to give various important intermediates as a message part to synthesize selective ligands for the opioid receptor subtypes.

■ Synthesis of Functionalized Phospholane Oxides and Phosphorinane Oxides from 1,4- and 1,5-Di-O-mesyloxy Compounds

Tadashi Hanaya,* Karsten Schürrle, and Hiroshi Yamamoto

*Department of Chemistry, Faculty of Science, Okayama University, Tsushima-naka, Okayama 700-8530, Japan

Abstract

Treatment of 1,4-di-O-mesyl-2,3-di-O-methyl-L-threitol (8b) with phenylphosphine in the presence of sodium hydride in DMSO, followed by the action of hydrogen peroxide, afforded 3,4-dimethoxy-1-phenylphospholane 1- oxide (7), while the same treatment of 1,5-di-O-mesyl-2,3,4-tri-O-methyl-meso- xylitol (11b) provided 2,3,4-trimethoxy-1-phenylphosphorinane 1-oxide (14).

■ Arabidopside F, a New Oxylipin from Arabidopsis thaliana

Haruyuki Nakajyo, Yosuke Hisamatsu, Mitsuhiro Sekiguchi, Nobuharu Goto, Koji Hasegawa, and Hideyuki Shigemori*

*Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba 305-8572, Japan

Abstract

A new oxylipin, arabidopside F (1) was isolated from the aerial parts of Arabidopsis thaliana, together with MGDG-O (2), arabidopsides A (3) and B (4). The structure of arabidopside F (1) was elucidated by spectroscopic data and chemical means. Arabidopside F (1) was a rare monogalactosyl diacylglyceride containing dinor-oxophytodienoic acid and 1 exhibited inhibitory effects on the growth of the root of cress (Lepidium sativum L.) seedlings at 5x10^-5 mol/L.