HETEROCYCLES

■ Preface

George R. Pettit

*Cancer Research Institute, Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287-2404

■ Biographical Data

James P. Kutney*

*Department of Chemistry, The University of British Columbia, 2036 Main Mall, Vancouver, B.C., V6T 1Z1, Canada

■ Publications

James P. Kutney*

*Department of Chemistry, The University of British Columbia, 2036 Main Mall, Vancouver, B.C., V6T 1Z1, Canada

■ A Regioselective Route to 2,3,4-Trisubstituted Furans

Ivan Efremov and Leo A. Paquette*

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

Abstract

Several potential routes to furans substituted with C-C bonds at the 2-, 3-, and 4-positions have been evaluated.

■ A New Route to (-)-Aphanorphine Using a Dioxabicyclo[3.2.1]octane Chiral Building Block

Adel S. ElAzab, Takahiko Taniguchi, and Kunio Ogasawara*

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

Abstract

A new stereocontrolled route to (-)-aphanorphine, isolated from the fresh-water blue-green algae Aphanizomenon flos-aquae has been developed by using a chiral building block having a dioxabicyclo[3.2.1]octane framework and originally designed for the construction of the aldohexose molecules.

■ Antiinflammatory Principles and Three New Labdane-Type Diterpenes, Hedychilactones A, B, and C, from the Rhizome of Hedychium coronarium Koeng

Hisashi Matsuda, Toshio Morikawa, Yasuko Sakamoto, Iwao Toguchida, and Masayuki Yoshikawa*

*Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan

Abstract

Three new labdane-type diterpenes named hedychilactones A, B, and C were isolated from the methanolic extract of the fresh rhizome of Hedychium coronarium KOENG. Their structures were elucidated on the basis of chemical and physicochemical evidence, which included the application of the allylic benzoate rule. The methanolic extract and diterpene constituents were found to inhibit the increase of vascular permeability induced by acetic acid in mice and nitric oxide production in lipopolysaccharide-activated mouse peritoneal macrophages.

■ Short Stereoselective Syntheses of (-)-Ajmalicine, (-)-3-Iso-ajmalicine and Their 5-Methoxycarbonyl Derivatives from Secologanin

Richard T. Brown,* Bukar E. N. Dauda, Simon B. Pratt, and Paul Richards

*Department of Chemistry, The University of Manchester, Oxford Road, Manchester, M13 9PL, U.K.

Abstract

Enzymatic hydrolysis of secologanin ethylene acetal at pH 5.0 resulted in stereoselective rearrangement of its aglucone to a dihydropyran aldehyde, which on reductive amination with tryptamine and cyclisation afforded 3-iso-ajmalicine, subsequently inverted to ajmalicine; analogous use of methyl S-tryptophanate gave 5S-methoxycarbonyl-3-iso-ajmalicine, whereas the R-enantiomer rather surprisingly yielded the ajmalicine derivative, whose anomalous CD spectrum has been rationalised.

■ [2π + 2σ] and [8π + 2σ] Types Cycloaddition Reactions of Aza-, Thio-, and Thiaza-azulen-2(1H)-one Derivatives with Naphtho[b]cyclopropene: Effects of Solvents and Ytterbium Complex

Katsuhiro Saito,* Naoko Ito, and Shinichi Ando

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

Abstract

Reactions of naphtho[b]cyclopropene with 1-aza- or 1-thiaazulene-2(1H )-one derivatives in chloroform under the presence of a catalytic amount of ytterbium complex afforded [2π + 2σ] type cycloaddition products. The analogous reactions of the cyclopropene with a 1-thia-3-azaazulene-2(1H )-one derivative gave an [8π + 2σ] type cycloadduct. These reactions were considered to proceed via ionic processes, in which the azulene-2(1H )-one derivatives played as 2π and 8π components, respectively. On the other hand, reactions of the cyclopropene with 1-azaazulene-2(1H )-one derivatives in benzene yielded the another type of [8π + 2σ] type cycloadducts via a concerted process.

■ 2-Pyridone Ring Formation through the Photoreaction of Arenecarbothioamides with Unsaturated Carboxylic Acids

Kazuaki Oda,* Rikiji Nakagami, Naozumi Nishizono, and Minoru Machida

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

Abstract

Irradiation of arenecarbothioamides with 2,4-hexadienoic acid in benzene gives 2-pyridone derivatives in moderate yields. The corresponding benzo-fused 2-pyridone derivative was also obtained by use of o-vinylbenzoic acid as dienoic acid equivalent.

■ Synthesis of Heterocycle-annulated Azulenequinone Derivatives

Hidetsugu Wakabayashi,* Seiichi Matsumaru, Teruo Kurihara, and Masafumi Yasunami

*Department of Chemistry, Faculty of Science, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan

Abstract

Treatment of 2-methoxyazulene (2) with 4.2 equiv. of bromine in aqueous THF at 0°C for 1 h afforded 3-bromo-2-methoxy-1,5- (1a) and -1,7-azulenequinone (1b) in a 16:1 ratio. Reaction of 1a with o-aminobenzenethiols gave 12H-azuleno[1,2-b]benzo[e][1,4]thiazine-7,11-dione derivatives (6a,b).

■ Short Step Syntheses of Indolo[2,3-a]carbazoles Carrying an Alkyl, Allyl, or a Glycosyl Group at the 11-Position and a Novel 6,7-Dihydro-13H-cyclopentano[mn]indolo[3,2-c]acridine Derivative

Masanori Somei,* Fumio Yamada, Jun Kato, Yoshiaki Suzuki, and Yoshinori Ueda

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

Abstract

Novel 1-alkyl-, 1-allyl-, and 1-β-glycosyl-2,2’-biindolyls are prepared. Their Diels-Alder reaction produced 11-alkyl-, 11-allyl-, and 11-β-glycosylindolo[2,3-a]carbazoles. Formation of a novel 6,7-dihydro-13H-cyclopentano[mn]indolo[3,2-c]acridine derivative is also reported.

■ Ring Closing Metathesis Reaction of Dienes with Acrylate Moiety Leading to 5- to 7-Membered Lactones and Cyclization to 14-Membered Rings

Katsuyuki Nakashima, Masashi Imoto, Takuo Miki, Takahiro Miyake, Norihiro Fujisaki, Shiori Fukunaga, Reiko Mizutani, Masakazu Sono, and Motoo Tori*

*Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima, 770-8514, Japan

Abstract

Dienes with acrylate moiety have been subjected to olefin metathesis reactions using (PCy₃)₂Cl₂Ru=CHPh (1) and (PCy₃)Cl₂[H₂imid(Mes)₂]Ru=CHPh (2). 5- to 7-Membered α,β-unsaturated lactones were obtained in good yields. Formation of 14-membered compounds was attempted using different substrates.

■ Synthesis and Biological Evaluation of Ketorolac Analogs

Francisco J. Lopez,* Mary-Frances Jett, Joseph M. Muchowski, Dov Nitzan, and Counde O'Yang

*Roche Bioscience, Neurobiology Unit, 3401 Hillview Avenue, Palo Alto, CA 94304, U.S.A.

Abstract

Ketorolac analogs were synthesized and biologically evaluated. For the preparation of the N-methylpyrrole Ro114-1907, and the furan Ro113-8905, a hydroxyethyl-assisted regioselective benzoylation gave intermediates (4) and (12), and subsequently a key copper-mediated ring closure gave entry to the required bicyclic compounds (7) and (15). Ro113-8905 and the thiophene Ro101-8244 significantly inhibited both the writhing response and edema formation in rat, but were less potent than Ketorolac.

■ Asymmetric Synthesis of Tetrahydroquinoline Derivative, a Building Block of Martinellines, via Intramolecular Allylic Amination Using 9-PBN

Yasumasa Hamada,* Iyo Kunimune, and Osamu Hara

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

Abstract

A tetrahydroquinoline derivative, a core structure of martinellines, was prepared through intramolecular allylic amination of the racemic precursor with a stereogenic center using 9-PBN and palladium. The reaction proceeded in a reagent-controlled manner based on the chiral phosphine to give two diastereomeric products with moderate enantioselectivities.

■ Three-Step Total Synthesis of Pyrroloquinazolinoquinoline Alkaloid, Luotonin A, by Intramolecular Hetero Diels-Alder Reaction

Masahiro Toyota,* Chiyo Komori, and Masataka Ihara*

*Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Sendai 980-8578, Japan

Abstract

Total synthesis of luotonin A (1) was accomplished, starting from 3-aminomethyl-2-bromoquinoline (4) in three steps via intramolecular hetero Diels-Alder reaction.

■ Formal Synthesis of FPA, a Kainoid Amino Acid, via Ketyl Radical Cyclization

Mitsuru Kamabe, Takayuki Miyazaki, Kimiko Hashimoto,* and Haruhisa Shirahama*

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

Abstract

The formal synthesis of FPA, a kainoid amino acid, was performed through the SmI₂ induced ketyl radical cyclization as the key step. The stereoselectivity was inverted in the presence or absence of the proton source.

■ Rearrangement Reaction of 2-Methyltetrahydropyrans Having a C1’-Mesyloxy Group on the C2-Side Chain with Zinc Acetate: Ring Expansion and Ring Opening Reactions

Yasuharu Sakamoto, Mina Koshizuka, Hiroyuki Koshino, and Tadashi Nakata*

*RIKEN(The Institute of Physical and Chemical Research), Wako, Saitama 351-0198, Japan

Abstract

Rearrangements of four possible stereoisomers of 6-tert-butyl-2-(1’-mesyloxy)ethyl-2-methyltetrahydropyran with Zn(OAc)₂ in aq. AcOH were investigated. Rearrangement-ring expansion and/or rearrangement-ring opening reactions took place depending on the stereostructure of the substrates.

■ Preparation of Enantiomers of 17-Epoxy Eicosapentaenoic Acids and Their 18-Hydroxy Derivatives

Tadahiro Kato,* Toshio Nakai, Rumiko Ishikawa, and Yukiko Iio

*Department of Chemistry, Faculty of Science, Science University of Tokyo, Kagurazaka 1-3, Shinjuku-ku, Tokyo 162-8601, Japan

Abstract

By the action of NBS in aq DME, dl-17-bromo-18-hydroxy EPA methyl ester 6 was prepared, which was effectively resolved by lipase PS and vinyl acetate in the presence of a thiacrown ether to give the resolved bromoacetate (7) and bromohydrin (8), each being transformed into the corresponding epoxide (3 and 4). The absolute configuration of 8 was established by the Kusumi-Moscher method. Both epoxides were treated with LDA to provide allyl alcohols (5a and b), accompanied with the formation of cyclopropyl derivatives (10a and b).

■ Practical Synthesis of Both Enantiomers of Vasopressin V₂ Receptor Antagonist OPC-41061 Using the Catalytic Asymmetric Hydrogenation

Hiroshi Yamashita,* Tadaaki Ohtani, Seiji Morita, Kenji Otsubo, Keizo Kan, Jun Matsubara, Kazuyoshi Kitano, Yoshikazu Kawano, Minoru Uchida, and Fujio Tabusa

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

Abstract

The optically active enantiomers of 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (OPC-41061, 1) were enantioselectively synthesized. The asymmetric transfer hydrogenation of the ketone (2), which is the precursor of 1, gave the corresponding secondary alcohols in good yield and excellent enantiomeric excess.

■ Intramolecular Addition of a Hydroxyl to an N-Acyliminium System. Application to the Synthesis of Isoindolo[2,1-a][3,1]benzoxazine and Isoindolo[1,2-c][2,4]benzoxazepine Derivatives

Pascal Pigeon, Jana Sikoraiova, Stefan Marchalin, and Bernard Decroix*

*Laboratoire de Chimie, Faculté des Sciences et Techniques, Université du Havre, 25, rue Philippe Lebon, BP 540, 76058 Le Havre Cedex, France

Abstract

The titled compounds were prepared by the reaction of hydroxylated lactam (3a-c) or (10) with p-toluenesulfonic acid in dichloromethane. The ratio of diastereomeric mixtures (4b/5b (2/1) or 4c/5c (2/1) or 11/12 (5/1) is discussed.

■ Synthesis of 10b(R)-Hydroxypancratistatin, 10b(S)-Hydroxy-1-epipancratistatin, 10b(S)-Hydroxy-1,2-diepipancratistatin and Related Isocarbostyrils

George R. Pettit,* Noeleen Melody, Delbert L. Herald, Jean M. Schmidt, Robin K. Pettit, and Jean-Charles Chapuis

*Cancer Research Institute, Department of Chemistry and Biochemistry, Arizona State University, Main Campus, P.O. Box 872404, Tempe, AZ 85287-2404, U.S.A.

Abstract

Narciclasine (2) was transformed by a series of reactions where Sharpless asymmetric hydroxylations served as the stereochemical controlling step to 10b(R)-hydroxypancratistatin (3), 10b(S)-hydroxy-1-epipancratistatin (13) and 10b(S)-hydroxy-1,2-diepipancratistatin (16). Synthesis of 10b(S)-hydroxy-1,2-diepipancratistatin (16) proceeded from α-triol (11) via cyclic sulfate (14) and inversion of C-2 with cesium benzoate followed by saponification and treatment with a catalytic amount of acid. Compared to pancratistatin (1), these structural modifications led to decreased cancer cell growth inhibition against a mini-panel of human cancer cell lines. Narciclasine (2) inhibited the pathogenic yeast Cryptococcus neoformans, and modifications (4, 14 and 15) inhibited growth of the pathogenic bacterium Neisseria gonorrhoeae.

■ Synthesis of C₂ Symmetric 2,2’-Bipyridyl Imidazolidinone and Oxazaborolidine Derivatives

Robert S. Ward,* Denis Branciard, Rosemary A. Dignan, and Martyn C. Pritchard

*Chemistry Department, University of Wales Swansea, Singleton Park, Swansea SA2 8PP, U.K.

Abstract

4,4’-Bis(bromomethyl)-2,2’-bipyridine reacts with (4R,5R)-1-propanoyl-4,5-diphenylimidazolidinone to form a C₂ symmetric chiral bipyridine derivative. Similarly reaction of 4,4’-bis(bromomethyl)-2,2’-bipyridine with an amino alcohol prepared from L-tyrosine affords a C₂ symmetric diaminodiol. Treatment of the latter product with either borane or trimethylboroxine forms oxazaborolidines that have been used as catalysts in the asymmetric reduction of acetophenone. High enantiomeric excesses are obtained.

■ Synthesis and Some Reactions of Ethyl (2-Alkylimino-1,2-dihydro-1-azaazulen-1-yl)acetates

Noritaka Abe,* Yasutaka Fukumoto, Hiroyuki Fujii, and Akikazu Kakehi

*Department of Chemistry, Faculty of Science, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8512, Japan

Abstract

Ethyl (2-alkylimino-1,2-dihydro-1-azaazulen-1-yl)acetates (3) were synthesized from 2-alkylamino-1-ethoxycarbonylmethyl-1-azaazulenium salts, which were produced from 2-alkylamino-1-azaazulenes with ethyl bromoacetate. Reaction of 3 with acid anhydrides gave the mesoionic anhydro-3-acyl-1-alkyl-2-hydroxy-1,3a-diazacyclopent[a]azulenium hydroxide. Polar cycloaddition of 3 with methyl propiolate gave methyl 2-alkyl-1-oxo-1,2-dihydro-2,9b-diazaindeno[3,3a,4,5-bcd]azulene-8-carboxylate and 3-ethyl 5-methyl 2-alkylamino-2a-azabenz[cd]azulene-3,5-dicarboxylate.

■ Synthesis of (1→3)-C and Homo-(1→3)-C-linked Imino-disaccharides Starting from Levoglucosenone and Isolevoglucosenone

Christian Marquis, Francesca Cardona, Inmaculada Robina, Gaby Wurth, and Pierre Vogel*

*Section de Chimie de l‘Universié de Lausanne, BCH, CH-1015 Lausanne-Dorigny, Switzerland

Abstract

The reaction of 2,5-(benzyloxycarbonyl)imino-2,5-dideoxy-3,4-O-isopropylidene-L-ribose ((-)-15) with levoglucosenone (5) in the presence of Et₂AlI gave a 3,4-dideoxy-D-glycero-hex-3-enopyranos-2-ulose derivative ((-)-16) that was converted into the (1→3)-C-linked imino-disaccharide: methyl 3,4-dideoxy-3-[(1’S)-2’,5’-dideoxy-2’,5’-imino-D-ribitol-1’-C-yl)-α-D-lyxo-hexopyranoside ((+)-22). The addition of benzyl alcohol to isolevoglucosenone (3), followed by cross-aldol condensation with 3,6-[tert-butoxycarbonyl]imino-2,3,6-trideoxy-4,5-O-isopropylidene-L-arabino-hexose ((+)-30) generated, after water elimination, a single enone ((+)-31) that was converted into a homo-(1→3)-C-linked imino-disaccharide: 3-deoxy-3-(1’,2’,3’,6’-tetradeoxy-3’,6’-imino-L-arabino-hexitol-1’-C-yl)-β-D-galactofuranose (44).

■ High-Pressure Mediated Asymmetric Diels-Alder Reaction of Chiral Sulfinylacrylate Derivatives and Its Application to Chiral Synthesis of (-)-COTC and (-)-Gabosine C

Tamiko Takahashi,* Yoko Yamakoshi, Kazuya Okayama, Junko Yamada, Wei-Ying Ge, and Toru Koizumi

*Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan

Abstract

The asymmetric Diels-Alder reactions of chiral sulfinylacrylate derivatives (1 and 2) with dienes (3-12) were examined under high-pressure (1.2 GPa) conditions. The endo cycloadduct (13e) obtained from sulfinyl acrylate (1) and 2-methoxyfuran (5) was converted to (-)-COTC (25) and (-)-gabosine C (26).

■ Total Synthesis of Magnolamide

Ying Dong and Philip W. Le Quesne*

*Department of Chemistry and Barnett Institute, Northeastern University, Boston, MA 02115-5096, U.S.A.

Abstract

The first total synthesis of magnolamide, a new alkaloid from Magnolia coco, has been achieved using the titanium (IV) isopropoxide-mediated Paal-Knorr synthesis of the core pyrrole system.

■ Enzyme-catalyzed Dediastereomerization of Dibenzylbutanolides by Plant Cell Cultures

Masumi Takemoto,* Yuki Matsuoka, Kiyoshi Tanaka, Kazuo Achiwa, Nikolay Stoynov, and James Peter Kutney*

*School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan

Abstract

We have been developed a novel biocatalytic dediastereomerization method, i. e., reactions allowing the transformation of two diastereomers into one diastereomer in quantitative yield. When a mixture of two diastereomers (4R*-5) and (4S*-5) (1:1 ratio) was subjected to Catharanthus roseus cells in B5 medium, dediastereomerization took place to give a single diastereomer (4R*-5) in 80 % chemical yield with 100% diastereomeric excess and 0 % enantiomeric excess.

■ Synthesis of 9,11-Diazapentacyclo[6.4.0.0^1,3.0^2,5.0^4,8]dodecane-2,4-diones

Kazue Ohkura, Ken-ichi Nishijima, Yuji Kuge, and Koh-ichi Seki*

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

Abstract

UV-Irradiation of 5,6-dihydrocyclobutaquinazoline-2,4-dione derivatives (1c-g) furnished the corresponding 9,11-diazapentacyclo-[6.4.0.0^1,3.0^2,5.0^4,8]dodecane-10,12-diones (2c-g) in fair yields, whereas photoreaction of cyclobutaquinazoline-2,4-dione (1h) produced quinazoline-2,4-dione (4) and cyclooctapyrimidine (5).

■ Biomimetic Syntheses of Neurotrophic Americanol A and Isoamericanol A by Horseradish Peroxidase (HRP) Catalyzed Oxidative Coupling

Hironobu Takahashi, Keiji Matsumoto, Masumi Ueda, Youko Miyake, and Yoshiyasu Fukuyama*

*Institute of Pharmacognosy, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Nishihamabouji, Yamashiro-cho, Tokushima 770-8514, Japan

Abstract

Horseradish peroxidase (HRP) catalyzed oxidative coupling of caffeic acid has yielded novel dimeric compounds (8) and (9) having a 1,4-benzodioxane ring, which have been in turn converted to americanol A (1) and isoamericanol A (2) in a few steps respectively. Additionally, HRP has coupled with 3,4-dihydroxycinnamyl alcohol giving rise directly 1 and 2 in high yield.

■ Synthesis of the Bicyclic Secondary Amines via Dimethylaminomethylene Ketones from 3-Pyrrolidone and 4-Piperidone

Hideto Fukui,* Kiyoshi Inoguchi, and Jun Nakano

*Central Research Institute, Kaken Pharmaceutical Co., Ltd., Shinomiya, Minamikawara-cho, Yamashina-ku, Kyoto 607-8042, Japan

Abstract

The reaction of N-protected 3-pyrrolidone and 4-piperidone with N,N-dimethylformamide dimethyl acetal gave the dimethylaminomethylene ketones, which reacted with several types of hydrazines, amidines, and guanidine to afford the secondary amines having fused ring system.