HETEROCYCLES

■ Preface

Lord Todd

*Cambridge, President of the Royal Society

■ Profile and Scientific Contributions of Professor Shigehiko Sugasawa

Yoshio Ban*

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

■ Bibliography

Shigehiko Sugasawa

*Medical Faculty, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8567, Japan

■ Heterocycles. V. Key Intermediates for Corynoline Analogues

Masayuki Onda,* Yoshihiro Harigaya, and Junya Horie

*School of Pharmaceutical Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan

Abstract

The 2-aryl-2-methyl-1-tetralone (2), which is derived from the 2-aryl-1-tetralone (1), affords the cis (5) and trans tetrahydrobenzo[c]phenanthridine (6) by the Leuckart and Bischler-Napieralski reactions. The methiodide (7) of 5 is converted into the cis lactam (10) via oxidation of the pseudo cyanide (9). On bromination and successive dehydrobromination 2 gives the enone (13) which affords the cis (16) and trans dihydrobenzo[c]phenanthridine (17) by the same procedures as above. The methiodide (18) of 16 is reduced to give the cis tetrahydrobenzo[c]phenanthridine (19). The compounds (10) and (19) can be connected with the synthetic methods of corynoline analogues, which were already known.

■ Synthesis of a Benzo[a]phenanthridine Isomeric with Apomorphine

Chung-Chen Wei and Sidney Teitel*

*The Department of Chemistry Research, Hoffman-La Roghe Inc., Nutley, New Jersey 07110, U.S.A.

Abstract

The synthesis of the benzo[a]phenanthridine (2), an isomer of apomorphine (1) with the identical rigid spatial arrangement of the dopamine moiety, is described. Conversion of the β-tetralone (9) into the N-benzoyl enamine (10) followed by photolysis furnished the trans-lactam (11) which was reduced, N-methylated and O-demethylated to afford the target compound (2).

■ Chemical Transformation of α-Santonin into Balchanin, Colartin, and Arbusculin A, B, C, and E

Koji Yamakawa,* Kiyoshi Nishitani, and Kazutoyo Azusawa

*Faculty of Pharmaceutical Sciences, Science University of Tokyo, 2641 Yamazaki, Noda, Chiba 278-8510, Japan

Abstract

Some sesquiterpene α-methylene-γ-lactones are worthy of attention for their biological activities. The chemical transformation of santonin into sesquiterpene α-methylene-γ-lactones, balchanin, arbusculin A, B, C, and E, and their precursor, colartin, is described.

■ Reaction of Diophenylketene with Conjugated Sulfilimines

Yoshio Tomimatsu,* Kanako Satoh, and Masanori Sakamoto

*Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan

Abstract

Cycloaddition reactions of diphenylketene (I) with N-pyridin-2-yl-S,S-dimethylsulfilimine (II), N-benzoxazol-2-yl-S,S-dimethylsulfilimine (IV), and N-benzthiazol-2-yl-S,S-dimethylsulfilimine (VI) were investigated. I reacted with II, IV, and VI giving cycloadducts, 2,3-dihydro-3-keto-2,2-diphenylimidazo[1,2-a]pyridine (IIIa), 2,3-dihydro-3-keto-2,2-diphenylimidazo[2,1-b]benzoxazole (V), and 2,3-dihydro-3-keto-2,2-diphenylimidazo[2,1-b]benzthiazole (VII) by accompanying an elimination of dimethyl sulfide, respectively.
On the other hand, N-benzimidoyl-S,S-dimethylsulfilimine (VIII), contrary to our expectation, was not cyclized, but gave a Michael type adduct (IX).

■ Synthesis of Tetrahydro-6H-benzo[4,5]pyrano[2,3-c]pyridin-6-one. A Novel Ring System

Friedhelm Lotz, Udo Kraatz, and Friedhelm Korte*

*Lehrstuhl für Makromolekulare Stoffe, Institut für Chemie, Technische Universität München, Lichtenbergstrasse 4, D-85747 Garching, Germany

Abstract

1-Bromo-(8),9-(di)methyl-6a,10a-trans-6a,7,10,10a-tetrahydro-6H-benzo[4,5]pyrano[2,3-c]pyridin-6-one is synthesized by means of a Diels-Alder reaction, starting from trans-4-(3,5-dibromo)pyridilacrylic acid, in a one-step procedure.

■ A Stereoselective Formal Total Synthesis of Emetine

Tetsuji Kametani,* Yukio Suzuki, Hirofumi Terasawa, Masataka Ihara, and Keiichiri Fukumoto

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

Abstract

Condensation of 3,4-dihydro-6,7-dimethoxy-1-methylisoquinoline (2) with dimethyl 3-methoxyallylidene-malonate (3) gave 2,3,6,7-tetrahydro-9,10-dimethoxy-3-methoxycarbonyl-2-(α,β-dimethoxyethyl)benzo[a]quinolizin-4-one (4) which was converted to (±)-dihydroprotoemetine (10a). Decarboxylation of the 3-carboxybenzo[a]quinolizin-4-one (6) gave mainly the cis-isomer (7b), whose stereochemistry could be transformed to the thermodynamically stable form (8a) by epimerization at the stage of the hexahydrobenzo[a]quinolizin-4-one (8b).

■ C-Glycosyl Nucleosides. VII. Syntheses of Modified Nucleosides Analogs with Isothiocynates

Haruo Ogura* and Hiroshi Takahashi

*School of Pharmaceutical Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan

Abstract

Syntheses of modified nucleoside analogs with glycosyl isothiocyanate and gluconyl isothiocyanate are reported. These reagents react with simple amines, hydrazines, amino acids, enamines, and diamines to yield modified nucleoside analogs. In case of enamines, isothiazolopyrimidines and pyrimidopyrimidines were obtained from the reaction with glycosyl and gluconyl isothiocyanate, respectively. Similarly, the reaction of diamines with glycosyl isothiocyanate and gluconyl isothiocyanate yield imidazole and triazepinethione derivatives, respectively.

■ Kinetic Comparison of Acid-catalyzed Intramolecular Reaction between Penicillin and Cephalosporin

Akira Tsuji, Eiichi Takahashi, and Tsukinaka Yamana*

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

Abstract

The rates of acid-catalyzed intramolecular degradation of ampicillin (1) and cephalexin (3) were assessed by specified kinetic treatment.

■ Reactive D-Alanyl-D-alanine Peptide Derives from Cycloserine

Akira Tsuji, Tsukinaka Yamana,* Shigeru Matsutani, and Naoki Tsuji

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

Abstract

N-Phenylacetyl-2-(1’-carboxyethyl)cycloserine (1) was synthesized and its acylation was examined. Like penicillin and cephalosporin, the L-cycloserine derivative (1a) could be regarded as D-alanyl-D-alanine peptide containing a reactive peptide bond, but it displayed no antibacterial activity.

■ The Reaction of Quinazoline with Aromatic Compounds in Dilute Sulfuric Acid

Takeo Higashino,* Yutaka Kawade, and Eisaku Hayashi

*Shizuoka College of Pharmacy, 2-2-1, Oshika, shizuoka-shi, 442 Shizuoka, Japan

Abstract

The reaction of quinazoline with aromatic compounds substituted by electron donating groups such as aniline, N-methyl-, N,N-dimethylaniline, phenol, anisole, and indole in dilute sulfuric acid was carried out. Thus, the corresponding 4-aryl-3,4-dihydroquinazoline (IIa-IIf) was obtained.
Some of the compounds (II) were converted into 4-arylquinazoline (IV) by the oxidation with potassium ferricyanide.

■ Reaction of 1-Methyl-2(1H)-pyridone with Fumaric Acid and Its Ester

Hiroshi Tomisawa,* Hiroshi Hongo, Reiko Fujita, Hideki Kato, and Akira Sato

*Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan

Abstract

The further studies on the Diels-Alder reaction of 1-methyl-2(1H)-pyridone (I) with fumaric acid and its ester were carried out in various conditiocs. Reaction of I with dimethyl fumarate in toluene gave dimethyl 2- methyl-3-oxo-2-azabicycl[2,2,2]oct-7-ene-5-endo-6-exodicarboxylate (IV). Boiling of I and fumaric acid in water afforded 6-methyl-7-oxo-6-azabicycl[3,2,1]oct-2-ene-2,8-endo-dicasboxylic acid (VI). Heating of I and fumaric acid at 170° gave VI and 6-methyl-7-oxo-6-azabicyclo[3,2,1]oct-2-ene-2,8-exo-dicarboxylic acid (VII).

■ The Structure of a Termolecular Condensation Product Obtained by the Action of Strong Acids on Toluquinone

Holger G. H. Erdtman* and Hans-Erik Högberg

*Department of Organic Chemistry, Royal Institute of Technology, SE-100 44 Stockholm, Sweden

Abstract

When treated with sulfuric acid in acetic acid, toluquinone 1 (R¹ = CH₃, R² = H) gives the termolecular compound 4 (R¹ = H, R² = CH₃) as the major product.

■ Absolute Stereochemistry of Alangicine: Synthetic Incorporation of Cincholoipon into (+)-Alangicine

Tozo Fujii,* Shigeyuki Yoshifuji, Shinzaburo Minami, Satyesh C. Pakrashi, and Esahak Ali

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

Abstract

The chemical correlation of cinchonine (v) with the Alangium alkaloid alangicine, through ethyl cincholoiponate [(+)-VI], lactam acids (-)-IX, (+)-X, tricyclic amino acid (-)-XIV, and amide (-)-XV, unequivocally established the absolute stereochemistry of alangicine as I.

■ Photocyclization of 4-Substituted Isoquinolinone. An Approach to the Synthesis of Phenanthridine Alkaloids

Hans-Paul Soetens and Upendra K. Pandit*

*Organic Chemistry Department, University of Amsterdam, Nieuwe Achtergracht 129 1018 WS Amsterdam, The Netherlands

Abstract

A facile conversion of N-methylisoquinolinone to phenanthridine derivatives is described.

■ Base Catalyzed Selective Disproportionation Reactions of 3’,5’-Di-O-aroyl Derivatives of 1-β-D-Arabinofuranosyluracil

Tadashi Sasaki,* Katsumaro Minamoto, and Takamasa Okugawa

*Institute of Applied Organic Chemistry, Faculty of Engineering, Nagoya University, Chikusa, Nagoya, Aichi 464-8601, Japan

Abstract

The mechanism for the base catalyzed information of a 2’,3’,5’-tri-O-aroyl derivative (iii) of spongouridine from the corresponding 3’,5’-diaroyl derivative (ii) was concluded to be an intermolecular disproportionation reaction of the latter, the first observed example in the nucleoside area.

■ Synthesis of 6-(2-Phenylethenyl)-2H-pyran-2-one

Yoshinori Tominaga, Atsuyuki Ushirogochi, Yoshiro Matsuda, and Goro Kobayashi*

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

Abstract

3-Cyano-4-methylthio-6-(2-phenylethenyl)-2H-pyran-2-ones (IIIa, b, c) were synthesized by the reaction of benzalacetone derivatives with methyl 2-cyano-3,3-bis(methylthio)acrylate in the presence of powdered potassium carbonate. Compounds III easily reacted with alkoxy anions and amines to give the corresponding 4-substituted 2H-pyran-2-one derivatives (dehydrokawain and yangonin derivatives).

■ Chemical Ionization Mass Spectra of New Macrolide Antibiotics, M-4365 A₂ and G₂

Makoto Suzuki,* Ken-ichi Harada, Naohito Takeda, and Akira Tatematsu

*Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tenpaku, Nagoya 468-8503, Japan

Abstract

Ammonia and isobutane chemical ionization (CI) mass spectra of basic 16-membered ring macrolide antibiotics, M-4365 A₂ and G₂, are described.
The spectra show protonated molecular ions (MH⁺, m/e 582 and 566, respectively) as the base peak in all cases. Cleavage of desosamine moiety from M-4365 A₂ and G₂ affords the protonated (m/e 176)- and oxonium (m/e 174)-type ions. These ions are shown to be useful in the structural characterization of new macrolide antibiotics.

■ Structure of Gigactonine. A New Diterpenoid Alkaloid from Aconitum gigas Lév. et Van

Shin-ichiro Sakai,* Nobuo Shinma, and Toshihiko Okamoto

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

Abstract

The structure of gigactonine (I), isolated from Aconitum gigas, was determined by IR, NMR and mass spectroscopy and chemical transformations. Thus 18-O-methylgigactonine (II) and the known alkaloid, delsoline, were shown to be identical.

■ Studies on the Structure-Activity Relationship of Adrenergic β-Mimetic Benzylamine Derivatives. III. 9-Aryl-1H-2,3,7,8,9,10-tetrahydrobenzo[d,e]quinolines

Shiro Yamamura,* Kuniyuki Oda, Seiichi Saito, Michio Yamazaki, Yoshio Iwasawa, Akio Kiyomoto, and Kyuji Abe

*Biological and Chemical Research Laboratories, Tanabe Seiyaku Co.Ltd., 2-2-50, Kawagishi, Toda, Saitama 335-8505, Japan

Abstract

The synthesis and adrenergic activity of stereoisomeric 5,6-dihydroxy-9-aryl-1H-2,3,7,8,9,10-hexahydrobenzo[d,e]quinolines (4a, 4b, 4’a, and 4’b), rigid structures related to the compounds (1, 2, and 3), are presented.

■ Total Synthesis of (±)-Furanoeremophilone, (±)-9-Hydroxyfuranoeremophilane, and (±)-4-Epifuranoeremophilanes

Koji Yamakawa* and Tsuyoshi Satoh

*Faculty of Pharmaceutical Sciences, Science University of Tokyo, 2641 Yamazaki, Noda, Chiba 278-8510, Japan

Abstract

Total syntheses of (±)-furanoeremophilone (2), (±)-9- hydroxyfuranoeremophilane (3), and (±)-4-epifuranoeremophilanes starting from the diene adduct (4) are described.

■ An Approach to the Synthesis of Intermediate Sized Oligoribonucleitides

Alexander F. Markham, Tetsuo Miyake, Eiko Ohtuska, and Morio Ikehara*

*Faculty of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Toyonaka, Osaka 560-0043, Japan

Abstract

A mixed phosphodiester-phosphotriester stepwise addition method for the synthesis of oligoribonucleotides is described. Using this method CpCpCpCpCpG and UpCpCpGpG which correspond to bases 66 to 71 and 61 to 65 of E. coli tRNA_f^Met thave been synthesized.

■ Selective Methyl and Methylene Migration in the Epoxy Derivatives Derived from 1-Abietic Acid

Masayuki Shimagaki,* Akira Anazawa, Takeshi Oishi, and the late Akira Tahara

*The Institute of Physical and Chemical Research, Wako-shi, Saitama 351-0198, Japan

Abstract

The α-epoxide (6) derived from l-abietic acid (1) caused a stereoselective methyl migration to its 13β-position giving, 8 in 54.2 % yield on BF₃·Et₂O treatment in benzene. On the other hand, the β-epoxide (7) gave rise to a methylene migration to give 9 or 10 in 63.5 % yield. The 13β-methyl derivative (8) was converted to isohibane (13).

■ Reactions of Nitrones with Some Thiophosphoryl Compounds. Formations of Thiazoles and Oxazoles

Rihei Nagase, Takayuki Kawashima, Masaaki Yoshifuji, and Naoki Inamoto*

*Department of Chemistry, Scool of Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033

Abstract

α,N-Diarylnitrones reacted with phenylphosphonothioic dichloride to give 2-arylbenzothiazoles in fairly good yield, while the reactions of nitrones with O-methyl diphenylphosphinothioate gave benzoxazoles. Reactions of nitrones with some other thiophosphoryl compounds are also described.

■ Catalytic Asymmetric Synthesis of (S)- and (R)-Salsolidine

Kazuo Achiwa*

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

Abstract

Catalytic asymmetric synthesis of (S)- and (R)-salsolidine (7) with BPPM(1)-, APPM(3)- and PPPM(4)-rhodium complexes was found to proceed in 34-45% optical yields, while its optical yields and absolute configuration depended markedly on the used hydrogenation conditions.

■ Intramolecular Exciplex Formation and Photochemical Synthesis of 1,2,3,4-Tetrahydroisoquinolin-3-ones and Oxindoles from N-Chloroacetyl Derivatives of Benzylamines and Anilines

Tatsuo Hamada, Yohmei Okuno, Masayuki Ohmori, Takao Nishi, and Osamu Yonemitsu*

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

Abstract

On the basis of fluorescence quenching and disappearance quantum yield measurements, the efficiency of exciplex formation and photochemical reaction of N-chloroacetyl-(3,4-dimethoxyphenyl)alkylamines (1) was clarified to be dependent on the length of alkyl chain. The apparent unreactivity of benzylamine derivatives (1a, 4) for photocyclization, therefore, is attributable to the trans form of the amide groups. Since introduction of N-alkyl groups increases the stability of the cis isomers, on irradiation N-alkylbenzylamine derivatives (7, 8, 9) gave the corresponding isoquinolin-3-ones (10, 11, 12). This photocyclization was further extended to the synthesis of oxindoles (16, 17, 18) from N-alkylaniline derivatives (13, 14, 15).

■ On the Structural Ditermination of Pyrimidine N-Oxides

Takao Sakamoto, Setsuko Niitusma, Michinao Mizugaki, and Hiroshi Yamanaka*

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

Abstract

Direct N-oxidation of 2-alkyl-4-ethyl-6-methylpyrimidines with hydrogen peroxide in glacial acetic acid afforded their 1-oxides and 3-oxides. Acid hydrolysis of the 1-oxides and the 3-oxides caused the ring transformation leading to 3-methyl-5-ethyl- (VII) and 3-ethyl-5-methyl-isoxazole (VIII), respectively. This result obviously demonstrated the structure of the N-oxides.
Observing displacements of signals on the NMR spectra of the N-oxides induced by adding a shift reagent, tris(heptafluorobutanoylpivaloylmethanato)europium_III), it is concluded that the NMR spectroscopy with the lanthanide is generally applicable to structural elucidation of pyrimidine N-oxides.

■ A Novel Ring Expansion Reaction of 4-Aminoantipyrines to 5-Amino-4(3H)-pyrimidinones

Taisei Ueda,* Noriichi Oda, and Isoo Ito

*Faculty of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan

Abstract

4-Amino(or anilino)antipyrines (I, II) were transformed into 5-amino(or anilino)-4(3H)-pyrimidinones (III, IV) in the presence of bases such as sodium hydride, sodium amide, sodium hydroxide, or sodium ethoxide in refluxing xylene. Treatment of III with hydrazine hydrate gave 4-anilino-5-hydroxy-3-methylpyrazole (V). However, the reaction of IV with hydrazine hydrate gave 3,5-diamino-6-methyl-4(3H)-pyrimidinone (VII) and 4-(5-oxo-3-methyl-pyrazolinyliden-4-amino)-5-hydroxy-3-methyl-pyrazole (VIII).