HETEROCYCLES

■ Contents

■ FIFTIETH VOLUME OF HETEROCYCLES: PREFACE

Alan R. Katritzky

*Center for Drug Discovery, College of Pharmacy, University of Florida, Gainesville, Florida 32611-7200, U.S.A.

■ PREFACE

Koji Nakanishi

*Department of Chemistry, Columbia University, 3000 Broadway, Mail Code 3114, New York, New York 10027, U.S.A.

■ PREFACE for the Special 50th Volume of Heterocycles

Edward C. Taylor

*Department of Chemistry, Princeton University , Princeton, New Jersey 08544, U.S.A.

■ PREFACE: IS HETEROCYCLIC CHEMISTRY BORING?

Rolf Huisgen

*Institut für Organische Chemie, Universität München, Karlstrasse 23, D-80333 München, Germany

■ Editor’s Remark

Keiichiro Fukumoto

*The Japan Institute of Heterocyclic Chemistry, 1-7-17, Motoakasaka, Minato-ku, Tokyo 107-0051, Japan

■ An Enantiocontrolled Total Synthesis of (-)-Xanthorrhizol

Kenji Sato, Toshikazu Bando, Mitsuru Shindo, and Kozo Shishido*

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

Abstract

An efficient and enantiocontrolled total synthesis of natural (-)-xanthorrhizol (3) has been accomplished by employing the lipase-mediated asymmetric acetylation of the σ symmetrical prochiral 2-ary-1,3-propanediol (7) leading to the formation of the opically enriched monoacetate (6) as the key step.

■ An Efficient Synthesis of a Metabolite of Vasopressin V2 Receptor Antagonist, OPC-31260, by Metalloporphyrin-catalyzed Demethylation

Yoshikazu Kawano, Kenji Otsubo,* Jun Matsubara, Kazuyoshi Kitano, Tadaaki Ohtani, Seiji Morita, and Minoru Uchida

*Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Kagasuno 463-10, Kawauchi-cho, Tokushima 771-0192, Japan

Abstract

A secondary amine (3) as a metabolite of the vasopressin V2 receptor antagonist, OPC-31260 (1), was efficiently prepared through selective demethylation of the corresponding N,N-dimethylalkylamine N-oxide (2) with meso-(tetraphenylporphinato)iron(III) chloride [Fe( TPP)]Cl, where tetrazole as an additive played a crucial role in the achievement of high chemical yields.

■ Stereoselective Synthesis of Methylene Phosphonate Analogues of Thymidine 3'-Phosphate and 2'-Deoxyuridine 3'-Phosphate via Intramolecular N-Glycosylation Reaction of Thioglycosides

Tsutomu Yokomatsu, Takanori Shimizu, Tomoyuki Sada, and Shiroshi Shibuya*

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

Abstract

Methylene phosphonate analogues of thymidine 3’-phosphate and 2’-deoxyuridine 3’-phosphate were prepared in a stereocontrolled manner through intramolecular N-glycosylation of phenyl 2,3-dideoxy-3-diethylphosphonomeyhyl-5-O-(2-pyrimidinyl)-1-thioglycosides, followed by acid hydrolysis.

■ Synthesis of meso- and dl-2,2'-Methylenebis[tetrahydro-2-furanmethanol]. Potential Building Blocks for the Construction of Ionophores Housing Spirotetrahydrofuranyl Motifs

Leo A. Paquette,* Brian A. Stearns, Pamela A. Mooney, and Jinsung Tae

*Evans Chemical Laboratories, The Ohio State University, 120 W. 18th Avenue, Columbus, Ohio 43210, U.S.A.

Abstract

A seven-step route to diols (1) and (2) is described, along with a pathway for achieving incorporation of the aliphatic chain of 2 into a cyclohexane core.

■ A Synthesis of (±)-Ipalbidine Using Sulfur-controlled 6-Exo Selective Radical Cyclization of α-Phenylthio Amide

Masazumi Ikeda,* Jiro Shikaura, Noriko Maekawa, Kaori Daibuzono, Hirotaka Teranishi, Yoshiko Teraoka, Norio Oda, and Hiroyuki Ishibashi*

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

Abstract

A synthesis of (±)-ipalbidine (1) has been achieved using Bu3SnH-mediated 6-exo selective radical cyclization of 2-[3-(phenylthio)prop-2-enyl]-N-[α-(p-methoxyphenyl)-α-(phenylthio)acetyl]pyrrolidine (15) as a key step.

■ Asymmetric Synthesis of Rhopaloic Acid A Analogues and Their Biological Properties

Hiroko Nishitani, Asami Sasaoka, Munetaka Tokumasu, and Katsuo Ohkata*

*Department of Chemistry, Faculty of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-hiroshima, Hiroshima 739-8526, Japan

Abstract

Some of rhopaloic acid A analogues were synthesized and their bioactivity was investigated on the basis of the inhibition of gastrulation of sea urchin embryos.

■ Direct and Simple Conversion of Codeine to Thebainone-A and Dihydrothebainone

Andrew Coop and Kenner C. Rice*

*Building 8, Room B1-23, Laboratory of Medicinal Chemistry, National Institutes of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0815, U.S.A.

Abstract

Codeine can be rearranged directly to thebainone-A in 74% yield by treatment with BuLi. Hydrogenation of the crude material followed by crystallization as the hydrochloride salt leads to dihydrothebainone in 78% yield.

■ Synthesis and Chemiluminescence of 10-Hydroxy- and 10-Aminopyridazino[4,5-b]quinoline-1,4(2H,3H)-diones

Yoshinori Tominaga,* Noriko Yoshioka, Seigo Kataoka, Yasuhiro Shigemitsu, Takashi Hirota, and Kenji Sasaki

*Faculty of Pharmaceutical Sciences, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

Substituted anilines reacted with methyl1-methyl-4-methylthio-2,5-dioxo-3-pyrroline-3-carboxylate (1) in refluxing methanol to give the corresponding methyl 1-methyl-2,5-dioxo-4-phenylamino-3-pyrroline-3-carboxylates (3a-e) which were converted in good yields to 2-methylpyrrolo[3,4-b]quinoline derivatives (4a-e) by heating in diphenyl ether. Reaction of 4a-e with hydrazine hydrate gave 10-hydroxypyridazino[4,5-b]quinoline-1,4(2H,3H)-diones (5a-e) in good yields. The desired 10-aminopyridazino[4,5-b]quinoline-1,4(2H,3H)-diones (8a-e) were obtained by the chlorination of 4a-e with phosphorus oxychloride followed by ammonolysis with 28% ammonium hydroxide in good yields. Compounds (5) and (8) were found to be efficiently chemiluminescent in a similarly to luminol in the presence of H₂O₂ and horseradish peroxidase in a solution of a phosphate buffer pH 8.0.

■ Xanthone Receptors for Carboxylic Acids and Carboxylates

Mercedes Martín, Marta Almaraz, José V. Hernández, Antonio Tejeda, M^a Cruz Caballero, and Joaquín R. Morán*

*Departamento de Química OrgÁnica, Universidad de Salamanca, Plaza de los Caídos, 37008 Salamanca, Spain

Abstract

Large association constants have been obtained in CDCl₃ for carboxylic acids and xanthone receptor linked to a guanidine. Protonation of the guanidine with carboxylic acids has been studied in DMSO. Association of the guanidine receptor and monochloroacetic acid may be in this highly competitive solvent.

■ Asymmetric Diels-Alder Reaction of Optically Active 3-(3,3,3-Trifluoropropenylsulfonyl)oxazolidine: Synthesis of (8R)-8-Trifluoromethyl-2-oxa-6-thia-5-azatricyclo[5.2.2.0^1,5]undecane-6,6-dioxide

Takashi Okano,* Tomoyuki Nagai, Shoji Eguchi, and Hiroshi Kimoto

*Department of Molecular Design and Engineering, Graduate School of Engineering, Nagoya University, Chikusa, Nagoya, Aichi 464-8601, Japan

Abstract

Asymmetric Diels-Alder reaction of optically active 3-(3,3,3-trifluoro-propenylsulfonyl)-1,3-oxazolidine (1) with several dienes gave adducts regio- and stereoselectively in 69-78% de. Acetalization of 2-methoxybutadiene adduct with catechol gave tricyclic sultam-oxazolidine (15), wich could be readily deprotonated and gave bridgehead sulfide (16).

■ Synthesis of Bicyclic Derivatives of 5a-Carba-sugars: 6-Hydroxyl Group Conformationally Restricted 5a-Carba-D-mannopyranose Derivatives

Seiichiro Ogawa,* Masatsugu Ohno, and Takashi Ohhira

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

Abstract

Some bicyclic derivatives of 5a-carba-α-and β-D-manno-pyranoses, whose 6-hydroxyl groups are conformationally restricted, have been synthesized in order to provide key components of the trisaccharide mimics designed as inhibitors or substrate analogues useful for elucidation of mechanism and action GlcNAcT-V.

■ Electrochemical Reduction Reactions of 1,3-Diazadihydroazulanone Derivatives: 1,3- and 1,5-Hydrogen Migration Reactions in Electrochemical Reductions

Takayasu Ido, Satoru Kondo, and Katsuhiro Saito*

*Department of Applied Chemistry, Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya 466-8555, Japan

Abstract

Electrochemical reduction potentials of 1,3-diphenyl-1,3-dizadihydroazulanone derivatives were constructed from two stage reductions, each of which was influenced by the substituent on the phenyl group at 3-position. Electrochemical reductions of the diazadihydroazulanone derivatives affored 1,3- and 1,5-hydrogen migration products, which isomerized each other under the reaction conditions. The reaction is considered to proceed via 1,3- or 1,5- hydrogen migrations through a radical anion intermediate by the reductions.

■ Novel Synthesis of Diazetidine-2,4-dione by Ring Expansion of Diaziridinone

Mitsuo Komatsu,* Satoshi Tamabuchi, Satoshi Minakata, and Yoshiki Ohshiro

*Department of Applied Chemistry, Faculty of Engineering, Osaka University, 2-1 Yamadaoka, Toyonaka, Osaka 560-0043, Japan

Abstract

Treatment of N,N’-di-tert-butyldiaziridinone with Ni(CO)₄ under an atmosphere of carbon monoxide caused a carbonylative ring expansion to give di-tert-butyldiazetidinedione in good yield. In the presence of diphenylketene under the conditions, azetidinedione derivative was obtained.

■ Synthesis of Functionalized Pyrrolidines from Mesoionic 4-Trifluoroacetyl-1,3-oxazolium-5-olates and Aminomalonate

Masami Kawase,* Hiroshi Miyamae, and Setsuo Saito

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

Abstract

Mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates (1) undergo tandem addition of aminomalonate to afford 3-amido-4-trifluoromethylpyrrolidin-2-ones (2) in moderate yields.

■ First Total Synthesis of the Pandanus Alkaloids, Pandamarilactam-3Y and -3X

Hiromitsu Takayama,* Toshiyuki Kuwajima, Mariko Kitajima, Maribel G. Nonato, and Norio Aimi*

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

Abstract

Total synthesis of two Pandanus alkaloids, pandamarilactam-3y and -3x, having a γ-alkylidenebutenolide moiety, was accomplis via aldol-type condensation / β-elimmination
expedient.

■ Electrocatalytic Oxidation of Benzyl Alcohol and 1-Phenethyl Alcohol by a Decahydroquinolinyl-N-oxyl Radical

Futoshi Kurashima, Yoshitomo Kashiwagi,* Chikara Kikuchi, Jun-ichi Anzai, and Tetsuo Osa

*Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, sendai 980-8578, Japan

Abstract

(±)-trans, cis-4-Benzoyloxy-2,2,8a-trimethyldecahydroquinolinyl-N-oxyl reveals a reversible redox peak whose oxidation potential is at + 0.55V vs. Ag/AgCl. The compound catalyzed the oxidation reactions of benzyl alcohol and 1-phenethyl alcohol to benzaldehyde and acetophenone, respectively, in satisfied current efficiency ( 74.4-80.6%) and selectivity (100%).

■ Stereospecificity in the Carbopalladations of Chiral Allenes Followed by Intramolecular Nucleophilic Substitution Reactions

Fumiko Kato, Yuko Hiratsuka, Toshinori Mitsui, Takashi Watanabe, and Kunio Hiroi*

*Department of Synthetic Organic Chemistry, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan

Abstract

2-Halophenyl derivatives bearing nucleophilic centers at the appropriate sites reacted with chiral allenes under palladium-catalyzed reaction conditions, via carbopalladation followed by intramolecular nuclephilic substitution, to give heterocycles or carbocycles by selecting nitrogen anions or carbanions as nuclephiles, respectively. The stereospecificity in these conversions of chiral allenes into cyclic compounds was determined HPLC analysis with chiral column, and the mechanistic pathway in this transformation is rationalized on the basis of the stereochemistry of the similar intermolecular reaction process which was already established by us.

■ (S)-Proline-derived Chiral Ligands Bearing Organosulfur or -selenenyl Groups as Coordinating Elements in Palladium-catalyzed Asymmetric Allylic Alkylations

Yoshio Suzuki, Ikuko Abe, and Kunio Hiroi*

*Department of Synthetic Organic Chemistry, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan

Abstract

(S)-Proline-derived chiral ligands bearing organosulfur or -selenenyl groups as coordinating elements were synthesized, and applied to palladium-catalyzed asymmetric allylic alkylations. These heteroatoms in the ligands played a prominent role for the stereocontrol of the conformation of the intermediary palladium complexes, and resulting for the presentation of the high asymmetric induction in the asymmetric alkylations. The mechanism of the asymmetric synthesis using these ligands is rationalized on the basis of stereochemical outcome observed.

■ 4'-Hydroxyphenylcarbamates of (3aS)-Eseroline and (3aS)-N(1)-Noreseroline: Potential Metabolites of the Alzheimer's Anticholinesterase Drug Phenserine

Qian-sheng Yu, Nigel H. Greig,* Harold W. Holloway, and Arnold Brossi

*Drug Design & Development, Laboratory of Cellular & Molecular Biology, Gerontology Research Center, LCMB/DDD/Room 4-B-02, National Institute on Aging, Intramural Program, 5600 Nathan Shock Drive, Baltimore, Maryland 21224-6825, U.S.A.

Abstract

4’-Hydroxyphenylcarbamates of (3aS)-eseroline (3) and (3aS)-N(1)-noreseroline (4), as predicted metabolites of phenserine (1), were synthesized. Biological evaluation showed that 3 and 4 possessed potent activities for inhibition of acetylcholinesterase and butyrylcholinesterase in vitro. In contrast the ontermediates, 4’-benzyloxyphenserine (8) and 4’-benzyloxy N(1)-benzylphenserine (12), demonstrated unusually potent and selective activities against butyrylcholinesterase.

■ Synthesis with Bis(o-mercapto)phenyl Sulfide: An Easy Access to Sulfurcontaining 16-Membered Heterocycles

Juzo Nakayama,* Sanae Tanaka, Yoshiaki Sugihara, and Akihiko Ishii

*Department of Chemistry, Faculty of Science, Saitama University, Saitama, Saitama 338-8570, Japan

Abstract

Condensations of bis(o-mercaptophenyl) sulfide (4) with paraformaldehyde or diiodomethane in moderately concentrated solutions gave 28-49% yield of a 1:1 condensation product, dibenzotrithiocin (5b), and 6-10% yield of a 2:2 condensation product (6b) with a 16-membered ring, whereas condensation of 4 with diiodomethane in a dilute solution gave 5b in 90% yield. Condensations of 4 with 1,1’-carbonyl- and 1,1’-thiocarbonyl-diimidazoles gave 2:2 condensation products (6c) and (6d) as the practically sole product in 79 and 57% yields, respectively, thus providing a convenient synthesis of 16-membered heterocycles containing 6 sulfur atoms in the ring.

■ A New Stereoselective Synthetic Strategy for β-Hydroxy-α-amino Acids of Vancomycin

Mukund K. Gurjar,* Shashwati Pal, and Debendra K. Mohapatra

*Organic Chemistry Division III, Indian Institute of Chemical Technology, Hyderabad 500 007, India

Abstract

The synthesis of syn and anti β-hydroxy-α-amino acids representing rings C and E of vancomycin has been achieved starting from (R)- and (S)- Garner’s aldehydes by a stereocontrolled Grignard arylation reaction.

■ A Novel Method for Introduction of Carbon Substituents into Pteridine

Shizuaki Murata,* Masato Kujime, Takashi Sugimoto, Katsuhiko Murakami, and Chihiro Seo

*Graduate School of Human Informatics, Nagoya University, Nagoya 464-8601, Japan

Abstract

A reaction of 1,3-dimethyl-6-trifluoromethanesulfonyloxylumazine with an anion of a 1,3-dicarbonyl compound such as diethyl malonate and 1,3-cyclohexanedione gives the corresponding 6-substituted lumazine.

■ Formation of 5-Methylene-1,3-dioxepanes by the Reaction of 2,2,2-Triphenyl-1,2λ⁵-oxaphospholanes with Paraformaldehyde

Kentaro Okuma,* Yuichiro Tanaka, Ichiro Shuzui, and Kosei Shioji

*Department of Chemistry, Faculty of Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan

Abstract

Reaction of 2,2,2-triphenyl-1,2λ⁵-oxaphospholanes with paraformaldehyde yielded novel 7-membered cyclic methylene acetals (5-methylene-1,3-dioxepanes) in goood yields. Phosphonium betaines reacted with paraformaldehyde to give new betaines, which further reacted with paraformaldehyde to afford olefins via Wittig reaction. The mechanism of this reaction was discussed.

■ Reactions of 3-Ethyl- and 3-Phenyl-1-azabicyclo[1.1.0]butanes with Tosyl Chloride and Tosyl Azide

Alan P. Marchand,* Sulejman Alihodzic, Romuald Bartnik,* and Grzegorz Mloston

*Department of Chemistry, University of North Texas, NT Station, P.O. Box 305070, Denton, TX 76203-5070, U.S.A.

Abstract

Reaction of 3-ethyl-1-azabicyclo [1.1.0]butane (4) with TsCl and with TsN₃ have been studied in aqueous THF solution and in the presence of a varirty of nucleophilic trapping agents. Thus, reaction of 4 with Tscl-Na₂CO₃ afforeded N-p-toluenesulfonyl-3-chloro-3-ethylazetidine (6,34%), N-(N’-p-toluenesulfonyl-3’-eth-yl-3’-azetidinyl)-3-chloro-3-ethylazetidine(7,3.4%), and N-p-toluenesulfonyl-3-ethyl-3-hydroxyazetidine (8,31%). Whene this reaction was repeated in the presence of a tenfold molar excess of NaCl, the predominant reaction products were TsN₃ (32%) and an inseparable mixture of 6 and N-p-toluene-sulfonyl-3-azido-3-ethylazetidine (9; product ratio 6:9 = 1:1 ). Finally, 4 reacted with TsN₃ under four different sets of reaction conditions. In every case, 9 was the major product isolated from these reactions ( 32-74%). Similar results were obtained for the corresponding reactions of 3-phenyl-1-azabicyclo[1.1.0]butane (1) with TsCl. All of the results reported herein are consistent with expectations based upon a mechanism that involves uncleophilic trapping of a putative tertiary carbocationic intermediate.