HETEROCYCLES

■ Contents

■ Synthesis and Biological Evaluation of Water Soluble Taxoids Bearing Sugar Moieties

Tadakatsu Mandai,* Hiroshi Okumoto, Tetsuta Oshitari, Katsuyoshi Nakanishi, Katsuhiko Mikuni, Ko-ji Hara, Ko-zo Hara, Wakao Iwatani, Tetsuya Amano, Kosho Nakamura, and Yoshinori Tsuchiya

*Department of Chemical Technology, Kurashiki University of Science & the Arts, 2640 Nishinoura, Tsurajima-cho, Kurashiki 712-8505, Japan

Abstract

Synthesis and biological evaluation of a variety of water soluble taxoids with sugar moieties are described.

■ Photochemistry of Heterocyclic Cage Compound: Photoreaction of 2,7-Dihydro- azepine to Give 2,3-Dihydroazepine and Photoreaction of the 2,3-Dihydroazepine to Form 1,2-Dihydroaniline

Katsuhiro Saito* and Yoshitaka Emoto

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

Abstract

Photoirradiation of a heterocyclic cage compound, 2,7-dihydroazepine derivative with a low pressure mercury lamp afforded a 2,3-dihydroazepine derivative. This reaction was influenced by the solvent used. On the other hand, the analogous photoirradiation of the 2,3-dihydroazepine derivative gave a 1,2-dihydroaniline derivative. An presence of triplet sensitizer promoted the reaction.

■ Acid-catalyzed Cycloaromatization of Enediyne Model Compounds via Enyne-Allene Intermediates

Ichiro Suzuki, Akira Shigenaga, Hisao Nemoto, and Masayuki Shibuya*

*Faculty of Pharmaceutical Sciences, University of Tokushima, Sho-machi 1-78, Tokushima 770-8505, Japan

Abstract

The synthesis of enediyne models which produce dehydrotoluene diradicals preferentially under acidic conditions by means of intramolecular participation of the carboxylic acid is described. To diminish an ionic character of diradicals, an electron-withdrawing group was introduced into the radical-forming carbon of the substrate.

■ Carbon-13 Spin-Lattice Relaxation Time (T₁) for Assignment of Brominated Carbons

Takashi Ooi,* Kyoko Utsumi, and Takenori Kusumi

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

Abstract

T₁ values can be used to distinguish a brominated quaternary carbon for other quaternary carbons, because the former carbon shows the T₁ value which is generally much smaller than the values of the latter carbons.

■ Efficient Stereoselective Synthesis of (2S,3S,5R)-(+)-Preussin

Antoni Krasinski, Henryk Gruza, and Janusz Jurczak*

*Institute of Organic Chemistry, Polish Academy of Sciences, 01-224 Warsaw, Poland

Abstract

Allyltrimethylsilane reacted with N-carbobenzoxy-L-phenylalaninal to afford with high diastereoselectivity syn-adduct which was subsequently transformed into (2S,3S,5R)-(+)-preussin.

■ Diastereocontrol in the Reaction of (R)- 2,2-Dimethyl-4-acyl-1,3-dioxolanes with Alkylmetals: A Facile Entry to Enantiopure Terpenetriols

Hisashi Mikoshiba, Koichi Mikami, and Takeshi Nakai*

*Department of Applied Chemistry, Tokyo Institute of Technology, Meguro-ku, Tokyo 152-8552, Japan

Abstract

The reactions of the 4-acetyldioxolane with terpenoid Grignard reagents are shown to proceed predominantly through the α-chelation model to give the syn-triol derivatives in ~70% selectivity. A novel and efficient protocol to effect the stereoselective methylation onto the terpenoid-derived 4-acyldioxolanes has been developed which affords the desired anti-terpenetriols in high stereopurities.

■ Synthesis of α-(Trifluoromethyl)pyrrolidines by Cyclization of N-Tosyl-α-(trifluoromethyl)homoallylamine Derivatives

Itsumaro Kumadaki,* Shuichi Jonoshita, Kazuyuki Sato, Masaaki Omote, and Akira Ando

*Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan

Abstract

Treatment of N-tosyl-α-(trifluoromethyl)homoallylamines (4), obtained by the ene type reaction of N-(2,2,2-trifluoro-1-ethoxyethyl)tosylamide (3), with a protic acid afforded N-tosyl-α-(trifluoromethyl)pyrrolidine derivatives (5 and 6). For example, 4-phenyl-N-tosyl-1-(trifluoromethyl)-3-butenylamine (4a) gave cis- and trans-2-phenyl-N-tosyl-5-(trifluoromethyl)pyrrolidines (5a and 6a). Interestingly, 6a was a major product in a moderate reaction condition, while 5a was a major product in more drastic conditions. The mechanism of these reactions is speculated. Treatment of 4a with iodine in the presence of sodium hydrogencarbonate brought about iodocyclization to give 3-iodo-2- phenyl-5-(trifluoromethyl)-N-tosylpyrrolidines (7 and 8).

■ Facile Conversion of Trialkylsilyl Esters to Alkyl Esters Mediated by Tetrabutyl- ammonium Fluoride Trihydrate

Takashi Ooi, Hayato Sugimoto, and Keiji Maruoka*

*Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan

Abstract

Trialkylsilyl esters can be smoothly converted into the corresponding alkyl esters by treatment with tributylammonium fluoride trihydrate (TBAF•3H₂O) and alkyl halides in THF. This direct transformation was found applicable to the formation of lactones through intramolecular alkylations.

■ A Molecule Detection Sensor of Modified Cyclodextrin Based on Guest-responsive Intramolecular Fluorescence Quenching

Akio Yoshida, Toshinao Yamasaki, Taiyo Aoyagi, and Akihiko Ueno*

*Department of Bioengineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan

Abstract

A β-cyclodextrin derivative bearing both pyrene and p-nitrobenzene units exhibits remarkable guest-responsive fluorescence quenching and acts as a chemosensor for molecule detection.

■ Studies on Pyrimidine-annulated Heterocycles: Synthesis and Function of Novel 9-Substituted Cyclohepta[b]pyrimido[5,4-d]furan-8,10(9H)-diones

Tohru Takayasu, Yutaka Mizuta, and Makoto Nitta*

*Department of Chemistry, School of Science and Engineering, Materials Research Laboratory for Bioscience and Photonics, Waseda University, Shinjuku-ku, Tokyo 169-8555, Japan

Abstract

A new short synthesis of 9-substituted cyclohepta[b]pyrimido[5,4-d]furan-8,10(9H)-diones has been accomplished by the reaction of 3-methyl-, 3-butyl-, and 3-phenylbarbituric acids with 2-chlorotropone in an enolate-substitution process and subsequent dehydrative cyclization by using CF₃CO₂H. These novel compounds exhibited a strong function in oxidizing some alcohols under neutral and aerobic conditions to give an aldehyde or ketones in anÅ@autorecycling process, while they are hydrogenated to mixtures of 5,7-, 1,7-, andÅ@3,7-dihydrocyclohepta[b]pyrimido[5,4-d]furan-8,10(9H)-dione derivatives.

■ Synthesis of a Novel Artemisinin Analogue Having Potent Antimalarial Activity

Kiyosei Takasu,* Ruriko Katagiri, Yuko Tanaka, Masahiro Toyota, Hye-Sook Kim, Yusuke Wataya, and Masataka Ihara*

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

Abstract

An artemisinin analogue containing 1,2,4-trioxane structure was designed and synthesized. The compound exhibited significant and selective in vitro antimalarial activity

■ 1,3-Dipolar Cycloaddition of 1-Phenylpropa-1,2-diene with Pyridinium Dicyanomethylides: 1-Phenylpropa-1,2-diene as a Synthetic Equivalent of 1-Phenylpropyne

Kiyoshi Matsumoto,* Naoki Tanaka, Takane Uchida, Yukio Ikemi, Naoto Hayashi, Kinuyo Aoyama, and Akikazu Kakehi

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

Abstract

Pyridinium dicyanomethylides (1) underwent 1, 3-dipolar cycloaddition with 1-phenyl-propa-1,2-diene (2) to give a mixture of 3-cyano-2-methyl-1-phenylindolizines (4) and 3-cyano-1-methyl-2-phenylindolizines (5), accompanied by dehydrocyanation and 1, 3-sigmatropic hydrogen shift.

■ Chiral Ketone-catalyzed Asymmetric Epoxidation of Stilbene with Oxone®

Koichiro Matsumoto and Kiyoshi Tomioka*

*Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan

Abstract

Chiral 7-membered ketones bearing a 1,2-ethylenediamine backbone were synthesized and examined their catalytic behaviors in an asymmetric epoxidation of stilbene with Oxone®.

■ An Efficient and Expeditious Synthesis of a Novel 5H-Naphth[1',2':5,6][1,4]- oxazino[2,3-b]quinoxalin-5-one and Its Unique Inhibitory Activity against a Panel of Human Cancer Cell Lines

Fusae Miyata, Sadamu Yoshida, Takao Yamori, and Tadashi Katoh*

*Sagami Chemical Research Center, Nishi-Ohnuma, Sagamihara, Kanagawa 229-0012, Japan

Abstract

The title compound (1) was efficiently synthesized in two steps starting from 2,3-dichloroquinoxaline (2) and 1-amino-2-naphthol (3); the method involves cyclization of 2 with 3 and subsequent salcomine oxidation. The compound (1) showed unique inhibitory activity against a panel of human cancer cell lines.

■ Enantiocontrol in Tandem Allylic Sulfonium Ylide Generation and [2,3] Sigmatropic Rearrangement Catalyzed by Chiral Dirhodium(II) Complexes

Shinji Kitagaki, Yoshimasa Yanamoto, Hisae Okubo, Makoto Nakajima, and Shunichi Hashimoto*

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

Abstract

Tandem sulfonium ylide formation and [2,3] sigmatropic rearrangement sequence from allylic sulfides and diazoacetates has been effected by using dirhodium(II) tetrakis[3(S)-phthalimido-2-piperidinonate], Rh₂(S-PTPI)₄, as a chiral catalyst, displaying enantioselectivities of up to 58%. It has been demonstrated that the [2,3] sigmatropic rearrangement proceeds through chiral, nonracemic free sulfonium ylides dissociated from the dirhodium(II) complex.

■ Intramolecular Oxymercuration of 4-Hexen-1-ols: Kinetic vs. Thermodynamic Products Regulated by Mercuric Salts

Mugio Nishizawa,* Terumi Kashima, Masahiro Sakakibara, Akihito Wakabayashi, Kazuya Takahashi, Hiroko Takao, Hiroshi Imagawa, and Takumichi Sugihara*

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

Abstract

The rate and mode of intramolecular oxymercuration of 4-hexen-1-ol derivatives was greatly affected by mercuric salts. Mercuric acetate induced a slow reaction to give substituted tetrahydrofurans via 5-exo-trans cyclization. In contrast, 6-endo-trans cyclization proceeded exclusively by mercuric triflate with or without N,N,N’,N’-tetramethylurea.

■ Application of Phthalimidine Synthesis with Use of 1,2,3-1H-Benzotriazole and 2-Mercaptoethanol as Dual Synthetic Auxiliaries. 2. Effective Synthesis of Phthalimidines Possessing Bulky Group at 2-Position

Ichiro Takahashi,* Teruki Kawakami, Mako Kimino, Etsushi Hirano, Shigeki Kamimura, Takanori Tamura, Hidehiko Kitajima, Minoru Hatanaka, Hiroyuki Uchida, Akihiko Nomura, and Motohiro Tanaka

*Department of Applied Chemistry and Biotechnology, Faculty of Engineering, Fukui University, Bunkyo, Fukui 910-8507, Japan

Abstract

Potentially bioactive phthalimidines are prepared in fair to good isolated yields by the 1:1 condensation reaction of o-phthalaldehyde with a variety of sterically-hindered primary alkyl amines in the presence of 1,2,3-1H-benzotriazole and 2-mercaptoethanol as dual synthetic auxiliaries.

■ Structure of Sanggenon O, a Diels-Alder Type Adduct Derived from a Chalcone and a Dehydroprenylated Sanggenon-Type Flavanone from Morus cathayana

Ya-Qin Shi, Toshio Fukai, and Taro Nomura*

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

Abstract

The structure of sanggenon O, which was isolated from the Chinese crude drug “Sag-bai-pi” and the root bark of Chinese mulberry tree (Morus cathayana), was revised based on its spectral and chemical evidences. The compound is regarded as a Diels-Alder type adduct produced with a chalcone and a 6-dehydroprenylflavanone forming an ether linkage between the 2’- and 3-positions and its absolute configuration was 2S,3R,3”S,4”R,5”S.

■ New Synthetic Approach to Azuleno[1,2-c]pyrroles and Conversion to Benz[a]azulenes

Dao-Lin Wang and Kimiaki Imafuku*

*Department of Chemistry, Faculty of Science, Kumamoto University, Kurokami, Kumamoto 860-8555, Japan

Abstract

1-Acetyl-2-(bromomethyl)azulenes were obtained as new synthons directed to heterocycle-fused azulenes. 3-Methoxycarbonyl- and 3-cyano-substituted 1-acetyl-2-(bromomethyl)azulenes (3a,b) reacted with anilines (6a-d) in the presence of potassium carbonate to afford 9-substituted 2-aryl-3-methylazuleno[1,2-c]pyrrole (7aa-ad,ba-bd) in moderate to good yields. These azuleno[1,2-c]pyrroles (7aa-ad,ba-bd) were condensed with acetylenedicarboxylates to give 1-anilino-2,3-dialkoxycarbonyl-4-methylbenz[a]azulenes (8aa-ad,ba,bb,bd; 10aa-ad,ba-bd) and 2-aryl-1-(1,2-dialkoxycarbonylethenyl)-4-methylazuleno[1,2-c]pyrroles (9ab-ad,ba-bd; 11aa-ad,ba-bd) via cycloadducts.

■ Reaction of 2-Aminoazulenes with Aldehydes. One Pot Synthesis of Diazuleno[2,1-b:1,2-e]pyridines

Tetsuo Okujima, Tomomi Terazono, Shunji Ito,* Noboru Morita,* and Toyonobu Asao

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

Abstract

Diazuleno[2,1-b:1,2-e]pyridines (2a and 2b) were prepared in one pot by the reaction of 2-aminoazulene (1a) with paraformaldehyde or benzaldehyde in moderate yields. Bis(2-amino-3-ethoxycarbonyl-1-azulenyl)methane (8a) was formed by the reaction of ethyl 2-aminoazulene-1-carboxylate (1b) with 1/2 molar amount of paraformaldehyde. Treatment of 8a with paraformaldehyde at room temperature afforded three heterocyclic compounds (9, 10, and 11). When 2-acetylaminoazulenes (1c and 1d) were used for this reaction, bis(2-acetylamino-1-azuleny)methanes (8b and 8c) were exclusively formed.

■ An Efficient Preparation of 2H-Cyclohepta[b]furan-2-ones

Noboru Morita,* Masao Kudo, Ryuji Yokoyama, and Shunji Ito*

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

Abstract

2H-cyclohepta[b]furan-2-one (3) was prepared in high yield from a [2+2] cycloadduct between cycloheptatriene and dichloroketene by Baeyer-Villiger oxidation followed by dehydrochlorination. 3-Chloro- (8) and 6-chloro-2H-cyclohepta[b]furan-2-one (9) were obtained from the [2+2] cycloadduct by adding an epoxidation step to the above synthetic way in moderate yields.

■ Synthesis of 1,3-Thiazolidines from Aromatic Thioketones and N-Benzylidene α-Amino Acid Esters via 1,3-Dipolar Cycloaddition of Azomethine Ylides

Andreas Gebert, Anthony Linden, and Heinz Heimgartner*

*Institute of Organic Chemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland

Abstract

The reaction of N-benzylidenephenylglycine methyl ester (2a) and N-benzylidenalanine methyl ester (2b) with thiobenzophenone (5a) and fluorene-9-thione (5b) in acetonitrile in the presence of lithium bromide and DBU gave a mixture of two corresponding diastereoisomeric [2+3] cycloadducts of types (6) and (7). The products were formed regioselectively and in good yields from the in situ generated metallo-azomethine ylides (8). The relative configurations of the two products (6c) and (7c) formed from fluorene-9-thione (5b) and 2a were established by X-Ray crystallography.

■ Preparation of Meso-unsubstituted Porphyrins Substituted with Mono- and Tetraformyl and Other Electron- withdrawing Groups

Yumiko Fumoto, Hidemitsu Uno, Takashi Murashima, and Noboru Ono*

*Department of Chemistry, Faculty of Science, Ehime University, Matsuyama 790-8577, Japan

Abstract

A meso-unsubstituted porphyrin having a formyl group was synthesized both from a mono(ethoxycarbonyl)porphyrin by reduction with LiAlH₄ followed by oxidation with MnO₂ and from a monocyanoporphyrin by reduction with DIBALH. The monoethoxycarbonyl and monocyanoporphyrins were prepared by the acid catalyzed mixed condensation of the corresponding 4-ethoxycarbonyl- and 4-cyano-2-(hydroxymethyl)pyrroles with 3-mesityl-4-methyl-2-(hydroxymethyl)pyrrole. A porphyrin with four formyl groups at the β-positions was prepared from ethyl 4-(dithiolan-2-yl)-3-methylpyrrole-2-carboxylate by the sequential treatment of LiAlH₄, p-TsOH, and NBS. Cyclic voltammetry and UV-VIS spectroscopic analyses of these porphyrins revealed the highly electron-deficient property of the porphyrin chromophore.

■ The Identification, Mechanism, and Improved Synthesis of a New and Unique Heterocyclic System with a Fused Imidazole Ring

Isamu Katsuyama, Ashraf A. Khalil, Jianwei Ren, and Jordan K. Zjawiony*

*Department of Pharmacognosy and National Center for Natural Products Research, Research Institute of Pharmaceutical Science, School of Pharmacy, The University of Mississippi, University, MS 38677-1848, U.S.A.

Abstract

The reaction of sampangine (1) with arylalkylamines resulted in unexpected formation of a new and unique sampangine derivative with a fused imidazole ring (3). The identification and formation mechanism of 3, as well as its improved synthesis, are described.

■ Synthesis of Brevicompanines, Plant Growth Regulators

Koji Matsumura 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

Brevicompanine A (1) and B (2) are plant growth regulators isolated from Penicillium brevicompactum. The synthesis of brevicompanine A (1) and B (2) was accomplished via a known intermediate.

■ Stereospecific Substitution of 1-(2- Pyridinyl)ethyl Methanesulfonate with S- and O-Nucleophiles

Jun'ichi Uenishi,* Masahiro Hamada, Tomoko Takagi, and Osamu Yonemitsu

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

Abstract

Nucleophilic substitution reactions of (S)- and (R)-1-(2-pyridinyl)ethyl methanesulfonate with S- and O-nucleophiles are described. The reaction of S-nucelophiles, such as aryl- and alkylthiols, and thioacetic acid, gave substituted sulfide and thioacetate with inversion of the configurations. For the reaction of O-nucleophiles, sodium phenoxides gave aryl ethers in good yields stereospecifically, but sodium alkoxide gave complex mixtures including racemic alkyl ether. Reactions with sodium carboxylate afforded the corresponding ester stereospecifically.

■ Regioselective Synthesis of Bridged Azabicyclic Compounds Using Radical Translocation/Cyclization Reactions of 4-Alkynyl-1-(o-iodobenzoyl)piperidines

Tatsunori Sato, Kazuya Okamoto, Yûko Nakano, Jun'ichi Uenishi, and Masazumi Ikeda*

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

Abstract

Bu₃SnH-mediated radical translocation/cyclization reactions of 4-alkynyl-1-(o-iodobenzoyl)piperidines were examined. The 4-[3-(trimethylsilyl)-prop-2-ynyl]- (12) and 4-[4-(trimethylsilyl)but-3-ynyl]piperidine derivatives (16), upon treatment with Bu₃SnH in the presence of azobisisobutyronitrile in boiling toluene, gave the isomeric 2-azabicyclo[3.2.1]octanes (17a,b) (34 and 51% yields, respectively) and 2-azabicyclo[3.3.1]nonane (morphan) (22) (20% yield as a diastereomeric mixture), respectively.

■ Synthesis and Properties of Benzimidazole and Naphthoimidazole Derivatives of Perylenedicarboximide

Yukinori Nagao,* Koji Tsuda, Kozo Kozawa, and Tokiko Uchida

*Department of Industrial Chemistry, Faculty of Science and Technology, Science University of Tokyo, Noda, Chiba 278-8510, Japan

Abstract

Benzimidazole and naphthoimidazole derivatives of N-alkylperylenedicarboximide were prepared by the condensation of N-alkyl-3,4:9,10-perylenetetracarboxylic acid monoanhydride monoimide with o-phenylenediamine and diaminonaphthalenes. Properties of these derivatives as pigments were tested, and the thermal stability and solubility of these derivatives were also investigated.

■ Intramolecular Photocycloaddition of 2-Cycloalkenyl-1,3-dioxin-4-one. Stereoselective Synthesis of cis-Eudesmane-4,11-diols

Toshihide Hatsui,* Ka Li, Akira Mori,* and Hitoshi Takeshita

*Institute of Advanced Material Study, 86 Kyushu University, Kasuga, Fukuoka 816-8580, Japan

Abstract

Two isomeric eudesmane-4,11-diols having a cis-decalin skeleton were synthesized via intramolecular photocycloaddition of 6-methyl-2-(4-methyl-3-cyclohexen-1-yl)-1,3-dioxin-4-one. Comparison of their NMR spectra with the natural diol, isolated from the Pakistanii medicinal plant, Pluchea arguta (Compositae), indicated that it should be a trans-eudesmanoid.