HETEROCYCLES

■ Contents

■ BIBLIOGRAPHICAL DATA

Bernhard Witkop*

*National Institute of Health, 9000 Rockville Pike, Bethesda, MD 20892-0815, U.S.A.

■ Preface

Yuichi Kanaoka

*Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan

■ A Chemist in a Biomedical Institute

Bernhard Witkop

*Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestve and Kidney Diseases, National Institute of Health, Bethesda, MD 20892-0820, U.S.A.

■ From the "Ordeal Bean" (Physostigma venenosum) to the Ordeal of Alzheimer's Disease ----- Some of the Legacy of Percy Lavon Julian (1899 - 1975)

Bernhard Witkop

*NIH Accounts Payable, DFM, Building 31, Room B1B39, National Institute of Health, 31 Center Drive, MSC 2045, Bethesda, Maryland 20892-2045, U.S.A.

Abstract

The Calabar bean, Physostigma venenosum, contains an alkaloid, physostigmine, which has therapeutic effects in glaucoma, pathological muscle fatigue and presenile dementia (Alzheimer’s Disease), either as such or as suitable derivatives, all synthetically accessible by improvements of Percy Julian’s first total synthesis in 1935.

■ MCR IX: A New and Easy Way for the Preparation of Piperazine-2-keto-3-carboxamides

Alexander v. Zychlinski and Ivar Ugi*

*Institut für Organische Chemie und Biochemie , Technische Universität München, Lichtenbergstr. 4, D-85747 Garching, Germany

Abstract

Piperazine-2-keto-3-carboxamides (5) are formed by an one-pot U-4CR (Ugi four component reaction) between ethylenediamine (1), glyoxylic acid-hemiacetal (2), a carboxylic acid (3) and an isocyanide (4).

■ An Enantio- and Diastereoselective Synthesis of (-)-Isoretronecanol and (+)-Trachelanthamidine from a meso Precursor

Hiroyuki Konno, Masayo Kishi, Kou Hiroya, and Kunio Ogasawara*

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

Abstract

Two diastereomeric pyrrolizidine alkaloids, (-)-isoretronecanol and (+)-trachelanthamidine, have been synthesized in an enantio- and diastereoselective manner starting from a meso precursor via a catalytic asymmetrization.

■ Studies on the Stereochemistry of Theonezolides A-C: Elucidation of the Relative Configurations of 1,3-Diol Moieties of the C-4Å`C-17 Fragment

Jun'ichi Kobayashi,* Makiko Yonezawa, Shinji Takeuchi, and Masami Ishibashi

*Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan

Abstract

Four model compounds having syn and anti 1,3-diol type moieties corresponding to C-8/C-10 and C-14/C-16 positions contained in the C-4Å`C-17 fragment of theonezolides A-C were prepared. Comparison of their spectral data suggested that the 1,3-diol at C-8/C-10 and the OH/OMe groups at C-14/C-16 positions of theonezolides A-C were both syn.

■ A Novel Synthesis of Thebaine from Codeine

Andrew Coop and Kenner C. Rice*

*Laboratory of Medicinal Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, Bldg 8, Rm B1-23, Bethesda, MD 20892-0815, U.S.A.

Abstract

Codeine was converted into thebaine through methylation of the enolate of codeinone.

■ Isolation, Partial Synthesis and Stereochemical Study of 10-Hydroxystrictosamide, a Constituent of Nauclea orientalis in Thailand

Hiromitsu Takayama,* Osamu Ohmori, Masayo Sakai, Michiko Funahashi, Mariko Kitajima, Dammrong Santiarworn, Boonsom Liawruangrath, and Norio Aimi

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

Abstract

From the Rubiaceous plant, Nauclea orientalis, in Thailand, seven non-alkaloidal and two glycosidic indole compounds were isolated. 10-Hydroxystrictosamide (5) and its pentaacetyl derivative (11) were prepared to determine the C3 stereochemistry.

■ Synthesis and Cytotoxicity of Various Structural Types of Novel Cyclopropapyrroloindole(CPI) Derivatives

Yasumichi Fukuda,* Hirosuke Furuta, Yoshie Kusama, Hiroyuki Ebisu, Yasuo Oomori, and Shiro Terashima*

*Central Research Laboratories, Kyorin Pharmaceutical Co. Ltd., Mitarai, Nogi, Tochigi 329-0114, Japan

Abstract

The various structural types of novel cyclopropapyrroloindole (CPI) derivatives (7Å`10) were synthesized and their cytotoxicity was evaluated. Among these derivatives, 3-methoxycarbonylCPI(3-MCCPI) derivatives (8a,b) and cyclopropapyrrolocarbazole (CPC) derivative (10a) were found to exhibit comparable cytotoxicity to U-73,975 (adozelesin) (1).

■ Acid-catalyzed Photorearrangement of 1,3-Dimethylcyclooctapyrimidine-2,4-dione into 10,12-Diazatricyclo[6.4.0.0^1,5]dodeca-3,7-diene-9,11-diones

Kazue Ohkura, Yukari Noguchi, and Koh-ichi Seki*

*Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan

Abstract

UV irradiation of 1,3-dimethylcyclooctapyrimidine-2,4-dione in the presence of a large excess of trifluoroacetic acid (>10 equiv. molar) at low temperature afforded 6-substituted 10,12-diaza-10,12-dimethyltricyclo[6.4.0.0^1,5]dodeca-3,7-diene-9,11-dione, which is regarded as a product through intramolecular photo-Diels-Alder reaction.

■ Synthesis of Unnatural Enantiomer of Nectrisine and Its Biological Activity

Naoto Kogoshi, Akira Takatsuki, Yong Jip Kim, and Takeshi Kitahara*

*Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan

Abstract

ent-Nectrisine (2), the unnatural enantiomer of nectrisine (1), a potent α-glucosidase inhibitor, was synthesized from D-glucose derivative. Biological assay showed that 2 had no significant bioactivity.

■ Allylation of N-Acyl Quaternary Salts of Azaaromatics with Allyltrimethylsilane in the Presence of Triflate Ion

Takashi Itoh, Michiko Miyazaki, Kazuhiro Nagata, and Akio Ohsawa*

*School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan

Abstract

Imidazoles and thiazoles were allowed to react with allyltrimethylsilane in the presence of chloroformate and triflate ion to give N-acyl 2-allyl adducts in good yields. The same reaction was also proceeded in the cases of pyridazines and phthalazine as substrates.

■ Intramolecular [2+2] Photocycloaddition of Fumaramic Acid Ester Derivatives. Syntheses of 2-(2,3-Dicarboxycyclobutyl)glycines

Hidekazu Tsujishima, Keiko Shimamoto, Yasushi Shigeri, Noboru Yumoto, and Yasufumi Ohfune*

*Department of Material Science, Graduate School of Science, Osaka City University, Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan

Abstract

Two isomers of new glutamate analogs, (2S,1’R,2’R,3’S)- and (2S,1’R,2’R,3’S)-2-(2,3-dicarboxycyclobutyl)glycines (1a) and (1b), are synthesized from the novel 3-azabicyclo[3.1.1]heptan-2-one intermediates (5a) and (5b), respectively, via an intramolecular photocycloaddition of α,β-unsaturated amide ester (3).

■ Cycloaddition Reactions of Oxaquadricyclane, Oxanorbornadiene, and Related Compounds with Cyclooctyne

Kiyoshi Matsumoto,* Hiroyuki Taketsuna, Yukio Ikemi, Akikazu Kakehi, Takane Uchida, and Shinichi Otani

*Graduate School of Human and Environmental Studies, Kyoto University, Kyoto 606-8501, Japan

Abstract

Dimethyl oxaquadricyclane-2,3-dicarboxylate (1) with cyclooctyne (CO) gave, via carbonyl ylide (3a), a mixture of the exo and endo 1:1 adducts (2a,2b) along with the novel 1:2 adduct (2c), whereas the carbocyclic analogs underwent [σ2s+σ2s+π2s]cycloaddition. The first examples of inverse electron demand homo-Diels-Alder reactions of oxa-, aza- and carbo-norbornadienes with CO were also described.

■ Reactivity of Rieke Manganese: Synthesis of Pyrrolidine and Piperidine Derivatives

Makoto Hojo, Junji Yoshizawa, Yoshihiro Funahashi, Ryo Okada, Shin-ya Nakamura, Jun-ichi Tateiwa, and Akira Hosomi*

*Department of Chemistry, University of Tsukuba, Tsukuba, Ibaraki, 305-8571, Japan

Abstract

Low-valent manganese generated by the reduction of manganese(II) chloride using lithium naphthalenide (Rieke manganese) promotes reactions of alkyl halides with electrophiles such as acyl chloride, aldehyde, and ketone to afford alkylation products. N-Haloalkyl-N-allyltosylamides are converted to pyrrolidine and piperidine derivatives in high yields. In the reactions of aromatic aldehyde and ketone, pinacol-type coupling products are produced.

■ On the Stereoselective Construction of the B and A Rings of Halichondrin B. A PM3 Study

Osamu Yonemitsu,* Tatsuya Yamazaki, and Jun-ichi Uenishi

*Department of Chemistry, Okayama University of Science, Okayama 700-0005, Japan

Abstract

PM3 calculations were carried out to study the origin of stereoselectivity in the intramolecular Michael reaction for a highly efficient constructuion of the B and A rings of halichondrin B.

■ Absolute Stereostructures of Spinacosides C and D with a Novel Acetal Type Substituent from Spinacia oleracea (Spinach) and Basella rubra (Indian Spinach)

Masayuki Yoshikawa,* Toshiyuki Murakami, Kazuhiro Hirano, Hisashi Matsuda, Johji Yamahara, Kazuhiro Ohtani, Ryoji Kasai, and Kazuo Yamasaki

*Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan

Abstract

Spinacosides C and D with a novel acetal-type substituent were isolated from the fresh aerial parts of Spinacia oleracea (Spinach) and Basella rubra (Indian spinach). Their absolute stereostructures were determined on the basis of physicochemical and chemical evidence, which included the conversion from the α-L-arabinopyranosyl moiety of a known saponin momordin I to the acetal-type substituent of spinacoside D.

■ Organic Reactions in Water: Indium Mediated Synthesis of α-Alkylidene-β-lactams

Muthusamy Jayaraman, Maria T. Batista, Maghar S. Manhas, and Ajay K. Bose*

*George Barasch Bioorganic Laboratory, Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ 07030, U. S. A.

Abstract

Indium mediated Barbier type addition of allyl bromides to azetidine-2,3-diones (1) in aqueous media provided two homoallylic alcohols (for example, 2 and 3) which on mesylation followed by elimination in the presence of DBU gave a mixture of E and Z isomers of α-alkylidene-β-lactams (4 and 5) in excellent yield. These highly substituted β-lactams are versatile synthons for a variety of structures.

■ Antimalarial Activities in vitro of Homoprotoberberine Derivatives. Design of Novel Antimalarials and Structure-Activity Relationship Analysis

Junji Miyata, Hiromi Nakashima, Hideo Nemoto, Hye-Sook Kim, Yusuke Wataya, and Masataka Ihara*

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

Abstract

Antimalarial activities in vitro of homoprotoberberine derivatives against Plasmodium falciparum were examined. It has shown that 9-hydroxy-2,3,10-trimethoxyhomoprotoberberine (10) was the most potent compound and the hydroxyl group at the C-9 position would play a significant role in exhibiting antimalarial activity and selective toxicity.

■ Construction of 3,4-Disubstituted Tetrahydrofuran Ring by Radical Cyclizaition. A Model Study for Kainoid Synthesis

Satoshi Itadani, Kimiko Hashimoto, and Haruhisa Shirahama*

*School of Science, Kwansei Gakuin University, Uegahara, Nishinomiya 662-8501, Japan

Abstract

Radical cyclization for construction of the 3,4-disubstituted tetrahydrofuran ring was attempted. The radical was produced through a chargetransfer complex under irradiation conditions.

■ Synthesis and Evaluation of Enantiomerically Pure Azinomycin-Lexitropsin Hybrid Molecules with DNA-cleaving Activity

Kozo Shishido,* Shigenori Haruna, Hiromi Iitsuka, and Masayuki Shibuya*

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

Abstract

Several enantiomerically enriched azinomycin-lexitropsin hybrid molecules, (1a-c), (2a-c), (3a-c) and (12), were synthesized and their DNA-cleaving activities were evaluated. Of these, the compound (3c) with natural configuration was proved to exhibit the strongest activity.

■ Cycloaddition of Lithium Ynolate to Imines: Synthesis of 3,4-Disubstituted β-Lactams

Mitsuru Shindo,* Soichiro Oya, Yusuke Sato, and Kozo Shishido

*Institute for Medicinal Resources, University of Tokushima, Sho-machi 1, Tokushima 770-8505, Japan

Abstract

Cycloaddition reaction of a lithium ynolate to N-sulfonylimines afforded 3,4-disubstituted β-lactams. The cis-products were synthesized in high diastereoselectivity via quenching of the intermediate, β-lactam enolates, with phenol.

■ Perhydroisoquinoline Synthesis: C(20)-Substituted Analogs of Yohimbine-Type Alkaloids

David J. Hart* and David A. Ellis

*Department of Chemistry, The Ohio State University, 100 W. 18th Ave., Columbus, Ohio 43210, U.S.A.

Abstract

Reaction of tryptamine with (±)-(1R*,5S*,8R*)-1-(methoxymethyl)-7-oxo-6-oxabicyclo[3.2.1]oct-2-ene-8-acetaldehyde (12) provides a new entry to pentacyclic derivatives of yohimbine-type alkaloids.

■ Photochemical Rearrangements of 1-Acetyl-1,2-dihydroquinoline-2-carbonitriles to the 3,1-Benzoxazines and Cycloprop[b]indoles

Masazumi Ikeda,* Saeko Matsugashita, Chika Yukawa, and Takayuki Yakura

*Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607, Japan

Abstract

Irradiation of 1-acetyl-1,2-dihydroquinoline-2-carbonitrile (1) in ether gave the 3,1-benzoxazine (3b), while the 4-methyl congener (2) in either ether or ethanol gave the 3,1-benzoxazine (4b) and the cycloprop[b]indole (7). A possible mechanism for the formation of these products is also discussed.

■ New Syntheses of Murrayafoline-A and Murrayaquinone-A via Fischer Indolization of 2-Sulfonyloxyphenylhydrazone (Fischer Indolization and Its Related Compounds. Part 29)

Yasuoki Murakami,* Hiroshi Yokoo, and Toshiko Watanabe

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

Abstract

Two carbazole alkaloids, murrayafoline-A (4a) and murrayaquinone-A (4b), were synthesized from 1,2,3,4-tetrahydro-8-methanesulfonyloxy-6-methylcarbazole (8) prepared in the application of Fischer indolization of 2-sulfonyloxyphenylhydrazone.

■ The Synthesis of Ethyl 2-(2-Cyano-2-ethoxycarbonylethenyl)amino-3-dimethylaminopropenoate. The Synthesis of Substituted Aminoazolo-, Aminoazinopyrimidinones and 2H-1-Benzopyran-2-ones

Lovro Selic, Simona Golic Grdadolnik, and Branko Stanovnik*

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

Abstract

Ethyl 2-(2-cyano-2-ethoxycarbonylethenyl)amino-3-dimethylaminopropenoate (3) was prepared in two steps from ethyl 2-cyano-3-ethoxypropenoate, and used as a reagent for the preparation of N-protected 3-amino-4H-pyrido[1,2-a]pyrimidin-4-ones (9a-c), 5H-thiazolo[3,2-a]pyrimidin-5-one (10), 4H-pyrido[1,2-a]pyridin-4-one (11), 2H-1-benzopyranones (12a,b), and their tetrahydro derivatives (13a,b). Free amino 4H-pyrido[1,2-a]pyrimidin-4-ones (14a-c), 5H-thiazolo[3,2-a]pyrimidin-5-one (15) and 4H-pyrido[1,2-a]pyridin-4-one (16), were prepared from 9-13 by removal of the 2-cyano-2-ethoxycarbonylethyl as N-protecting group by heating with hydrazine hydrate.

■ Novel Heterocycles: A Benzodithiolane S-Oxide and a Benzothiadiazinane S-Oxide

Alan R. Katritzky,* Zhongxing Zhang, Ming Qi, Nusrallah Jubran, and Louis M. Leichter

*Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, U.S.A.

Abstract

Synthetic methodology has been developed for the synthesis of novel heterocycles from 3,3-diaryl-3H-2,1-benzoxathiole 1-oxides (2). Cyclic sulfinates (2) were converted directly into 3,3-diaryl-1,2-benzodithiolane 1-oxide (3) and 4,4-diaryl-1,2,3-benzothiadiazinane 1-oxide (4) which represent a cyclic thiosulfinate and a cyclic sulfinyl hydrazide, respectively. 3,7-Bis(dimethylamino)-10-(p-dimethylaminobenzene)thiaxanthene 5,5-dioxide (8a) and 3-dimethylamino-10-(p-dimethylaminobenzene)thiaxanthene 5,5-dioxide (8b) were formed from the reaction of hydrazine and compound (2).

■ Samarium Iodide Promoted Coupling of N-Substituted Azetidin-3-ones. A Novel Route to Spiroannulated Heterocyclic Oxiranes

Alan P. Marchand,* Arokiasamy Devasagayaraj, and Simon G. Bott*

*Department of Chemistry, University of North Texas, Denton, Texas 76203, U.S.A.

Abstract

Samarium iodide promoted reductive coupling of N-ethoxycarbonylazetidine-3-one (1a), N-p-toluenesulfonylazetidine-3-one (1b), and N-benzhydrylazetidine-3-one (1c) each afforded the corresponding pinacol (2a-2c, respectively). Each pinacol was converted into the corresponding dimesylate (3a-3c, respectively). When heated in the presence of base, 3a and 3b each afforded the corresponding spirocyclic oxirane (4a and 4b, respectively). In contrast to the behavior of 3a and 3b,3c proved to be inert under these conditions. Structure 4b was established unequivocally via application of X-Ray crystallographic methods.