HETEROCYCLES

■ Contents

■ New Strategy to Antiviral Agents from Peptide Nucleic Acid Derivatives

Tetsuo Yamasaki,* Mohamed Abdel-Aziz, Naotoshi Kiyota, Tokumi Maruyama, and Masami Otsuka

*School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka City, Miyazaki 882-8508, Japan

Abstract

New strategy to develop antiviral agents against HIV and herpes virus from the derivatization of peptide nucleic acid monomers has been described.

■ Useful Synthesis of the Longer Array Oxazole Rings for Telomestatin

Nobuaki Endoh, Katumasa Tsuboi, Riyong Kim, Yasuchika Yonezawa, and Chung-gi Shin*

*Laboratory of Organic Chemistry, Faculty of Engineering, Kanagawa University, 3-27-1 Rokkakubashi, Kanagawa-ku, Yokohama 221-8686, Japan

Abstract

The convenient syntheses of the precursors of the constituting Fragments A, B, A-B, and its macrocyclic compounds for telomestatin, which exhibits strong antitumor activity, were first achieved.

■ Preparation of 6-Phenyl- and 8-Phenyl Tetrahydro-isoquinolines from Boldine

Wei-Jan Huang, Chung-Hsiung Chen, and Shoei-Sheng Lee*

*School of Pharmacy, College of Medicine, National Taiwan University, 1 Jen-Ai Rd. Sec. 1, Taipei, 100, Taiwan, R.O.C.

Abstract

Four 6-phenyl- and 8-phenyltetrahydroisoquinolines were prepared by structural modifications of boldine nucleus. These involved four major reaction steps, including solvolysis of 2-hydroxyaporphine, ozonolysis of the C-9,10 double bond of phenanthrene nucleus leading to the key intermediate, and final Pictet-Spengler cyclization to respective target products.

■ Nucleophilic Substitution Reaction of N-2-(1-Hydroxyindol-3-yl)ethylindole-3-acetamide and -1-hydroxyindole-3-acetamide

Yu-ya Nakai, Aya Goto, Fumio Yamada, and Masanori Somei*

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

Abstract

Syntheses of N-2-(1-hydroxyindol-3-yl)ethyl-1-hydroxyindole-3-acetamide (3a) and -indole-3-acetamide (4a) are reported. They undergo nucleophilic substitution reaction at the 1-position upon reaction with indole in 85% formic acid to give new type compounds, N-2-[1-(indol-3-yl)indol-3-yl]ethylindole-3-acetamide (13), N-2-(indol-3-yl)ethyl- (14), and N-2-[1-(indol-3-yl)indol-3-yl]ethyl-1-(indol-3-yl)indole-3-acetamide (15).

■ A Facile and Practical Procedure for the Stereoselective Synthesis of (Z)-3-Quinuclidinylideneacetic Acid Derivative

Tsukasa Ishihara,* Shuichi Sakamoto, Shin-ichi Tsukamoto, and Isao Yanagisawa

*Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan

Abstract

A study of the isomerization of methyl (E)-3-quinuclidinylideneacetate derivative to the corresponding Z-isomer is reported. Theoretical calculations, performed using the MM3 molecular mechanics method, are in agreement with the experimental results. A facile and practical procedure for the stereoselective synthesis of methyl (Z)-3-quinuclidinylideneacetate derivative, via the Horner-Wadsworth-Emmons reaction with sodium methoxide in methanol, is also described.

■ Synthesis of Substituted Dibenzoxazepines and Dibenzthiazepine Using of 4-Bromo-5-nitrophthalonitrile

Igor’ G. Abramov,* Alexey V. Smirnov, Levan S. Kalandadze, Vladimir N. Sakharov, and Vladimir V. Plakhtinskii

*Yaroslavl State Technical University, 150023, Yaroslavl, Moscowsky Prospekt 88, Russia

Abstract

Proposed a method of synthesis of new cyano containing compounds of oxazepine and thiazepine series based on activated aromatic nucleophilic substitution reaction of bromine atom and nitro group in 4-bromo-5-nitrophthalonitrile by various bifunctional O-, N-, S-nucleophiles.

■ Photochemistry of 2-Indolyl Aryl Ethers: An Unexpected Rearrangement Leading to C-C Bond Formation

Ken S. Feldman* and Daniela Boneva Vidulova

*Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, U.S.A.

Abstract

Two types of 2-(p-tolyloxy)indole were prepared and their reactivity was studied under photochemical conditions. The expected electrocyclization was not observed. Instead, unprecedented rearrangement products were obtained. The reaction outcome was found to depend on the viscosity of the media.

■ Reductive Cleavage of Fused Isoxazoles with Chlorotrimethylsilane/Sodium Iodide: A Convenient Route to 3,4-Disubstituted Isoxazoles

Hyung Jin Kim,* Kyung Ho Choi, and Kwang-Jin Hwang

*Department of Applied Chemistry, Chonnam National Unviersity, Kwangju, 500-757, Korea

Abstract

The reaction of 7-aryl-4,5-dihydro-7H-pyrano- and 6-aryl-4H,6H-furo[3,4-c]isoxazoles with a combination of TMSCl/NaI afforded reductively ring cleaved 3,4-disubstituted isoxazoles (3, 4, 6 and 7). TMSCl/NaI (5/10 equivalents) mediated reductive cleavage of 3,6-disubstituted 4H,6H-furo[3,4-c]isoxazole (5) efficiently provided the key intermediates (6) and (7) leading to new fused isoxazoles, 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine (8,9) via further synthetic modification.

■ Phenolic Glycosides from Rhizomes of Smilax glabra

Jiuzhi Yuan, Wei Li, Kazuo Koike, Yingjie Chen, and Tamotsu Nikaido*

*Faculty of Pharmaceutical Sciences, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan

Abstract

A new lignan glycoside, (+)-syringaresinol 4-O-β-D-glucopyranosyl- (1→6) -β-D-glucopyranoside (1), together with twelve known compounds, were isolated from the rhizomes of Smilax glabra. The structure was established on the basis of chemical and spectroscopic methods.

■ A New 16N-Carboxyethyl Derivative of 3,12-Dihydroroquefortin

Anatoly G. Kozlovsky, Valentina P. Zhelifonova, Tatiyana V. Antipova, Vladimir M. Adanin, Svetlana M. Ozerskaya, Nataliya E. Ivanushkina, Friedrich A. Gollmick, and Udo Gräfe*

*Hans-Knölle-Institute for Natural Products Research, Beutenbergstrasse 11, D-07745 Jena, Germany

Abstract

New 16N-carboxyethyl derivative (2) of 3,12-dihydroroquefortin (1) was isolated from the fermentation broth of Penicillium aureovirens VKM FW-766. Structure of 2 was settled on the basis of MS spectrometry, 1D and 2D NMR spectroscopy.

■ Chemical Constituents of the Stem of Sargentodoxa cuneata

Amooru G. Damu, Ping-Chung Kuo, Li-Shian Shi, Chang-Qi Hu, and Tian-Shung Wu*

*Department of Chemistry, Natioanl Cheng Kung University, Tainan 701, Taiwan, R.O.C.

Abstract

A new phenylpropanoid glycoside, sargentol (1), was isolated and characterized from the traditional Chinese crude drug “Daxueteng”, the stem of Sargentodoxa cuneata, together with twenty seven known compounds. The structures of the isolated compounds were elucidated by means of various NMR techniques and MS spectral analysis.

■ Synthesis and Crystallographic Studies of New Acridinic Esters and Amides: An Efficient Synthetic Route to 4-Methyl Functionalized Acridines

Julien Chiron* and Jean-Pierre Galy

*UMR 6009, Laboratoire de Valorisation de la Chimie Fine, case 552, Facluté des Sciences et Techniques de Saint Jérôme, Avenue l'Escardille Normandie Niemen, 13397 Marseille Cedex 20, France

Abstract

In order to open a new way in antitumor drugs research, an efficient synthetic route to mono functional 4-substitued acridine derivatives has been developed on the basis of direct electrophilic substitution of acridine. This method leads to a wide range of simple acridinic patterns that can be linked to various side chains. We present here the synthesis of two new families of acridine ester and amide derivatives, obtained from acridinic alcohol and amine respectively, with high yields. Some crystallographic aspects of one representative compound of each family are discussed.

■ Thermal Rearrangement of Phenyl-substituted Ketene Ethylene Acetals

Mitsunori Oda,* Kazuo Morimoto, Nguyen Chung Thanh, Reina Ohta, and Shigeyasu Kuroda

*Department of Applied Chemistry, Faculty of Engineering, Toyama University, Gofuku 3190, Toyama 930-8555, Japan

Abstract

Thermal rearrangement of mono-, di-, and triphenyl-substituted ketene ethylene acetals was studied. Pyrolysis of all of these acetals provided phenyl-substituted tetrahydro-2-furanones as a major product. The more phenyl groups substitute on the ketene acetal skeleton, the lower reaction temperature was required for the rearrangement. In the cases of the diphenylketene acetals at high temperatures, fragmentation products, such as fluorene and benzophenone, probably derived from dipheylcarbene via diphenylketene, were observed.

■ Isolation and Identification of an Unusual Impurity in an Intermediate of Rimadyl^® (Carprofen)

John L. Tucker,* Keith M. DeVries, Philip D. Hammen, Peter R. Rose, Brian K. Raymer, and Diane Rescek

*Chemical Research & Development and the E.M.S. Department, Pfizer Global Research and Development, Groton, CT 06340, U.S.A.

Abstract

The isolation and identification of an unknown process related impurity in a key intermediate of Rimadyl^® (carprofen) is described. The structure of the unknown was evaluated by NMR spectral analysis and eventually confirmed by single crystal X-Ray. A re-slurry in warm acetic acid was found to reduce the level of the unknown to an acceptable level.

■ Synthesis of Benzo[1,2-b:5,4-b’]dithiophene-4,8-dione Derivatives

Kazuhiro Kobayashi,* Toshikazu Ogata, Kazuna Miyamoto, Osamu Morikawa, and Hisatoshi Konishi

*Department of Materials Science, Faculty of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan

Abstract

4,7-Dioxo-4,7-dihydrobenzo[b]thiophene-2-carboxylates (1) underwent regioselective acylation at the 5-position with a range of aldehydes under irradiation to give the corresponding 5-acyl-4,7-dihydroxybenzo[b]thiophene-2 carboxylates (2), which were then oxidized with Ag₂O to afford 5-acyl-4,7-dioxo 4,7-dihydrobenzo[b]thiophene-2-carboxylates (3). These acylated benzothiophenquinone derivatives were transformed in one-pot to 4,8-dioxo-4,8 dihydrobenzo[1,2-b:5,4-b’]dithiophene-2,6-dicarboxylates (5) by treatment with mercaptoacetates, followed by 1-trimethylsilylimidazole-mediated cyclization and cerium(IV) ammonium nitrate (CAN) oxidation.

■ A-Type Proanthocyanidins from the Bark of Parameria laevigata

Kohei Kamiya, Akiko Ohno, Yukiko Horii, Hanani Endang, Mansur Umar, and Toshiko Satake*

*Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Nishi-ku, Kobe 651-2180, Japan

Abstract

Parameritannin A-3, a new tetrameric A-type proanthocyanidin, along with the cinnamtannin B-2, pavetannin C-1 and cinnamtannin D-1 have been isolated from the bark of Parameria laevigata. Complete assignments by spectroscopic analysis established their structures as epicatechin - (2β→O→7, 4β→6) - epicatechin - (2β→O→7, 4β→8) - epicatechin - (4β→8) - epicatechin, epicatechin-(4β→8)-epicatechin-(2β→O→7, 4β→8)-epicatechin-(4β→8)-epicatechin, epicatechin-(4β→6)-epicatechin-(2β→O→7, 4β→8)-epicatechin-(4β→8)-epicatechin, epicatechin-(2β→O→7, 4β→8)-epicatechin-(4β→8)-catechin, respectively.

■ Diospolysaponin A, a New Polyoxygenated Spirostanol Saponin from the Tubers of Dioscorea polygonoides

Jaime Niño Osorio, Oscar M. Mosquera Martinez, Yaned M. Correa Navarro, Yoshihiro Mimaki,* Hiroshi Sakagami, and Yutaka Sashida

*Laboratory of Medicinal Plant Science, School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan

Abstract

Chemical investigation of the tubers of Dioscorea polygonoides has resulted in the isolation of a novel polyoxygenated spirostanol saponin, named diospolysaponin A (1), along with a known spirostanol saponin (2). The structure of 1 was determined on the basis of spectroscopic analysis and by enzymatic hydrolysis followed by chromatographic and spectroscopic studies to be (23S,25R)-12α,14α,17α,23-tetrahydroxyspirost-5-en-3β-yl O-α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranoside. The cytotoxic activity of 1 and 2 and their aglycons against HSC-2 cells is briefly presented.