HETEROCYCLES

■ Preface

Edward P. Abraham

*,

■ Foreword

John C. Sheehan*

*Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, U.S.A.

■ Scientific Contributions of Prof. Hamao Umezawa

Kyosuke Tsuda*

*Faculty of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113, Japan

■ Profile of Professor Hamao Umezawa

Tetsuji Kametani*

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

■ Thirty-five Years with Bioactive Microbial Products

Hamao Umezawa*

*Institute of Microbial Chemistry, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan

■ Recent Chemical Studies of Bioactive Microbial Products: Genetics, Active Structures, Development of Effective Agents with Potential Usefulness

Hamao Umezawa*

*Institute of Microbial Chemistry, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan

Abstract

Antibiotics can be divided into various groups, each containing a characteristic structural part common to antibiotics of the same group. A gene and gene set involved in the biosynthesis of a characteristic structural part is shown by chemical structures of antibiotics to be widely distributed among various strains of microorganisms. On the basis of this fact, genetics of microbial secondary metabolites was studied and the reason why various compounds were produced by microorganisms was elucidated. On the basis of the fact that microorganisms produce various compounds, the author searched for compounds which bound to the cell surface, that is, he searched for inhibitors of enzymes on the cellular surface and was successful in finding immunomodulators. Mechanisms of actions and toxicities of useful antibiotics and enzyme inhibitors such as aminoglycoside antibiotics, bleomycins, bestatin etc. were studied in relation to their structures, and on the basis of their results, more effective useful derivatives of them were synthesized and successful results were obtained. Microbial products were shown to be one of the most important areas of application in organic chemistry to develop bioactive compounds useful in the treatment of diseases.

■ Chemical Studies on Antibiotics and Other Bioactive Microbial Products by Prof. Hamao Umezawa

Kenji Maeda* and Masaji Ohno

*Institute of Microbial Chemistry, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan

■ Selected Papers of Dr. Hamao Umezawa

Hamao Umezawa*

*Institute of Microbial Chemistry, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan

■ List of New Antibiotics and Their Derivatives Discovered by Dr. Hamao Umezawa

Hamao Umezawa*

*Institute of Microbial Chemistry, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan

■ Summary of Structures of Microbial Secondary Metabolited Determines by Dr. H. Umezawa

Hamao Umezawa*

*Institute of Microbial Chemistry, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan

■ Papers of Dr. Hamao Umezawa

Hamao Umezawa*

*Institute of Microbial Chemistry, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan

■ Synthesis of Homoshowdomycin and Homopyrazomycin

T.Sato and R. Noyori*

*Department of Chmistry, Graduate School of Science, Nagoya University, Chikusa, Nagoya, Aichi 464-8601, Japan

Abstract

An efficiently stereocontrolled entry to the title homo-C-nucleosides is described.

■ Structural Investigation of an Antibiotic Sporaviridin III. Structures of Viridopentaose A and C

Ken-ichi Harada, Susumu Ito, Toshiaki Murase, and Makoto Suzuki*

*Faculty of Pharmacy, Meijo University, 150 Yagoto, Tempaku-ku, Nagoya, Aichi 468-8503, Japan

Abstract

Viridopentaose A (1) and C (2) are new heteropentasaccharides, degradation products of sporaviridin. These structures were established by chemical degradative reactions, mass spectrometry, and ¹³C-NMR spectroscopy.

■ Synthesis of Bicyclic Coriolin Models

Hisanobu Hashimoto, Toshio Ito, Haruhisa Shirahama, and Takeshi Matsumoto*

*Faculty of Science, Hokkaido University, Kita 10 Nishi 8, Kita-ku, Sapporo, Hokkaido 060-0810, Japan

Abstract

Bicyclic coriolin models 10a and 13 have been obtained in a stereoselective manner from 3, through methylenation at C-4, epoxidation at the C-1 double bond, borohydride reduction and subsequent epoxidation at the methylene group. Similar transformation of 16b, obtained from the enol acetate of 3 through oxidation (mCPBA), afforded dihydroxydiepoxide 23, Jones oxidation of which gave a bicyclic diketocoriolin B model 26.

■ Synthesis of 3’-Epi-4’-deoxykanamycin B through 3’-Epi-3’,4’-anhydro Intermediate.

Eiichi Akita,* Yukio Horiuchi, and Takeo Miyazawa

*Library, Pharmaceutical Research Center, Meiji Seika Kaisha Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan

Abstract

3’-Epi-4’-deoxykanamycin B was synthesized from a protected derivative of 3’-O-tosylkanamycin B by the reductive ring opening of the assumed intermediate epoxide with sodium borohydride, and the structure of the objective compound was confirmed by PMR, molecular rotation value of its copper complex, and periodate oxidation of its hydrolysate.

■ Terrein, an Optically Active Prostaglandin Synthon of Fungal Origin. III. Chemical Conversion to 1(S), 4(R), 7(R)-Acetoxy-5(S)-hydroxy-2-oxabicyclo [2.2.1]heptan-3-one, a Flexible Intermediate for Prostaglandin Synthesis

George W. Clark, III, Paul D. Hammesfahr, P. Bryan Hudson, Lester A. Mitscher,* Kunikatsu Shirahata, Jerzy Sulko, and Tarik Veysoglu

*Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66045, U.S.A.

Abstract

1(S),4(R),7(R)-Acetoxy-5(S)-hydroxy-2-oxabicyclo[2.2.1]heptane-3-one (2), a flexible intermediate for the synthesis of novel optically active prostaglandins, has been synthesized from the optically active and readily available mold metabolite, terrein (1). Some reactions of 2 are described.

■ The Synthesis of a Variety of Aminodeoxy-α-D-glycopyranosides by Way of a Novel Replacement Reaction

Raymond U. Lemieux,* Fawzy F. Z. Georges, and Zygfryd Smiatacz

*Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada

Abstract

Ethyl 3,4,6-tri-O-acetyl-2-deoxy-2-oximino-α-D-arabino-hexopyranoside was found to undergo replacement of the 3-acetoxy group when reacted with nucleophilic reagents such as sodium azide, potassium phthalimide, sodium borohydride and sodium thiophenoxide. The resulting products could be transformed, depending on the reaction sequence, to 3-deoxy, 3,4-dideoxy, 3-amino-3-deoxy, 2-amino-2,3-dideoxy, 2,3-diamino-2,3-dideoxy, or 2-amino-2,3,4-trideoxy derivatives of an ethyl α-D-glycopyranoside.

■ Synthesis and Geometric Configuration of 2-(Hydroxyiminomethyl)thiazole-4-carboxylic Acid in Antibiotic Althiomycin

Tetsuo Shiba,* Kaoru Inami, Kozo Sawada, and Yoshihiro Hirotsu

*Department of Chemistry, Faculty of Science, Osaka University, Toyonaka, Osaka 560-8531, Japan

Abstract

2-(Hydroxyiminomethyl)thiazole-4-carboxylic acid, a component of an antibiotic althiomycin, was synthesized. A configuration of the aldoxime group in the natural althiomycin was unambiguously determined to be syn-form by means of nuclear Overhauser enhancement and the behavior of methylation by reference to the synthetic compound.

■ Regioselective Phenylcarbamoylation of the Hydroxyl Groups of Purine and Pyrimidine Ribonucleosides with Bis(tributyltin)Oxide-Phenyl Isocyanate

Yoshiharu Ishido,* Ichiro Hirao, Nobuo Sakairi, and Younosuke Araki

*Department of Chemistry, Faculty of Science, Tokyo Instituteof Technology, Meguro-ku, Tokyo 152-8552, Japan

Abstract

N⁶-Benzyladenosine (1) was found to give the corresponding 5’-phenylcarbamate (2) (83% yield) by treating with (Bu₃Sn)₂O in toluene under reflux and then with phenyl isocyanate at room temperature (Procedure A), and to give the corresponding 3’- (73% yield) and 2’-phenylcarbamate (10% yield) by treating with (Bu₃Sn)₂O and PhNCO in toluene - DMF (10:1, v/v) at 0°C (Procedure B). The procedure B was also successful in the partial phenylcarbamoylation of N⁶-benzoyladenosine (11), inosine (12) and uridine (13), giving the corresponding 3’-phenylcarbamates (60%, 67%, and 55% yields) and 2’-phenylcarbamates (17%, 31%, and 15% yields), respectively. On the other hand, thymidine (14) (2’-deoxyribonucleoside) afforded the corresponding 5’-phenylcarbamate (93% yield) through the procedure B.

■ Boron Trifluoride-promoted Transformation of 3,5-Bis(methoxycarbonyl)-4-phenylisoxazoline N-Oxide into 3H-Indole N-Oxide Derivative

Eisuke Kaji* and Shonosuke Zen

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

Abstract

3,5-Bis(methoxycarbonyl)-4-phenylisoxazoline N-oxide (1a) was readily transformed into 3H-indole N-oxide derivative (2a) by the reaction with boron trifluoride etherate in reasonable yield. Mechanism of the transformation was found to involve an ionic intermediate (5), generated by rupture of the nitrogen-oxygen bond, which cyclizes to 3H-indole N-oxide through an intramolecular aromatic substitution. Evidence for the proposed mechanism was obtained by the reaction of 4-phenylisoxazoline-4-d N-oxide (1b) with boron trifluoride to form the expected 3H-indole-3-d N-oxide (2b), as well as by stereochemical consideration.

■ Transformation of α-Dihydroionol to Dihydroedulan and Theaspyrane by Photosensitized Oxygenation

Hideki Okawara, Susumu Kobayashi, and Masaji Ohno*

*Faculty of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113, Japan

Abstract

Racemic dihydroedulan (1) and theaspyrane (2) have been synthesized starting with racemic α-dihydroionol (3) in a few steps using photosensitized oxygenation as the key step. Two isomeric hydroxy allyl alcohols 4 and 5 were obtained upon treatment with singlet oxygen and also prepared from an epoxide 7 by treatment with lithium diethylamide and organoselenium reagents, respectively. The allyl alcohol 5 afforded dihydroedulan (1) predominantly with BF₃ in THF and another allyl alcohol 4 was converted selectively to theaspyrane (2) through a diene 9.

■ Synthesis of 3-(1-Methyl-1,2,3,4-tetrazol-5-yl and 2-Methyl-1,3,4-thiadiazol-5-yl-oxymethyl)-3-cephem Derivatives

Morio Kishi, Hiroyuki Ishitobi, Wataru Nagata, and Teruji Tsuji*

*Shionogi Research Laboratories, Shionogi & Co. Ltd., Fukushima-ku, Osaka 553-0002, Japan

Abstract

Cephem derivatives possessing a heterocyclic oxymethyl group at position 3 were synthesized by two methods as the benzhydryl 1 or p-nitrobenzyl esters 2 and 3. However, removal of the ester protecting groups to obtain the free acids was unsuccessful.

■ A Synthetic Approach to Reserpine and Related Compounds

Toshio Suzuki, Akiko Tomino, Seiko Kagaya, Katsuo Unno, and Tetsuji Kametani*

*Pharmaceutical Institute, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan

Abstract

Key intermediates in the synthesis of the Rauwolfia alkaloids deserpidine (8) and reserpine (9) are compounds (6a), (6b), (16), and (17) whose stereoselective syntheses are described.

■ Studies on the Syntheses of Heterocyclic Compounds. Part 808. Total Synthesis of (±)-O-Methyltubulosine

Tetsuji Kametani,* Yukio Suzuki, and Masataka Ihara

*Pharmaceutical Institute, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan

Abstract

Pictet-Spengler condensation of (±)-4-oxoprotoemetine (5) with 5-methoxytryptamine (10) in acetic acid gave (±)-4-oxo-O-methyltubulosine (12a) which was converted to (±)-O-methyltubulosine (13a) by reduction with sodium bis(2-methoxyethoxy)-aluminium hydride. Modified syntheses of (±)-4-oxoprotoemetine (5) and (±)-protoemetine (9) are also described.

■ Synthesis of Isomeric Pyrido-pyrrolo[1,2-a]pyrimidines

Miha Tisler,* Branko Stanovnik, and Zdenka Zrimsek

*Department of Chemistry, University of Ljubljana, 61000 Ljubljana, Slovakia

Abstract

5-Oxo derivatives of three new isomeric pyridopyrrolo[1,2-a]pyrimidines were synthesized from the corresponding carbalkoxy 2- or 3-[N-pyrrolo]pyridines. These were transformed into the corresponding hydrazides and further to acylazides which decomposed into acylnitrenes followed by insertion into C-H bond with ring closure.

■ Carbon Transfer via N⁵, N¹⁰-Methylenetetrahydrofolate Models

H. Bieräugel, R. Plemp, H.C. Hiemstra, and U.K. Pandit*

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

Abstract

1-Acyl or 1-tosyl-3,4,4-trimethylimidazolidine derivatives react with tryptamine or 2-(3,4-dimethoxyphenyl)ethylamine, under acidic conditions, to yield tetrahydro-β-carboline or tetrahydroisoquinoline derivatives.

■ Reactions of β, β, β-Trichloroethyl 6-Diazopenicillanate with Aldehydes and Schiff Bases

John C. Sheehan,* Kiichiro Nakajima, and Elsie Chacko

*Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, U.S.A.

Abstract

New 6-substituted penicillins (mainly 6-spiro derivatives) and several non-β-lactam compounds have been prepared by treating aldehydes and Schiff bases with β,β,β-trichloroethyl 6-diazopenicillanate. Identity and stability of the products depend mainly on the nature of the aldehyde components of the starting materials.

■ Studies on Pyrimidine Derivatives. XVII. Synthesis of Pyrimidine-4-carboxylic Esters

Takeji Sakasai, Takao Sakamoto, and Hiroshi Yamanaka*

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

Abstract

During the controlled oxidation of polymethylpyrimidines with selenium dioxide in pyridine, it was observed that the 4-methyl group on the pyrimidine ring was selectively oxidized to give pyrimidine-4-carboxylic acids. In addition to this investigation, the transformation of pyrimidinecarboxamides into methyl pyrimidinecarboxylates was successfully achieved in methanol in the presence of boron trifluoride etherate.

■ A Convenient Synthesis of 1,4-Dihydro-4-oxonicotinic Acid Derivatives

Osamu Makabe,* Yasushi Murai, and Shunzo Fukatsu

*Library, Pharmaceutical Research Center, Meiji Seika Kaisha Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan

Abstract

The cyclization of β-ketoesters with β-aminocrotonates in the presence of molecular sieves gave 6-substituted or 5,6-disubstituted-1,4-dihydro-4-oxonicotinic acid esters by one step reaction.

■ Utilization of ¹³C -¹³C Coupling in Structural and Biosynthetic Studies. XII. Biosynthesis of 2-(But-1,3-dienyl)-3-hydro-4-(penta-1,3-dienyl)-tetrahydrofuran, A Metabolite of Chaetomium coarctaum

Haruo Seto,* Mariko Saito, Jun Uzawa, and Hiroshi Yonehara

*Institute of Applied Microbiology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8567, Japan

Abstract

The titled metabolite of Chaetomium coarctatum was proved to derive from seven acetate units. The labeling pattern obtained by the use of ¹³C-labeled precursors implies the involvement of epoxide rearrangement to give a tetrahydrofuran ring. Incorporation of C²H₃CO₂Na was also investigated by ²H-nmr spectrometry.