HETEROCYCLES

■ Synthesis of (6R,7R)-Phenylacetylmethyl-3-(1-methyl-IH-tetrazol-5-yl)thiomethyl-1-oxa-1-dethiacephalosporanic Acid

Shoichiro Uyeo,* Kyo Okada and Wataru Nagata

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

Abstract

Synthesis of the title compound 8 from the 7α-methoxy, 7β-amino-1-oxacephem 3, involving stereocontrolled reduction of the 7-phenylacetylmethylene derivatives 6 to 7β-phenylacetylmethyl derivative 7, is described.

■ Partial Synthesis of 3-Deoxydihydromorphine from (—)-4-Hydroxy-6-keto-N-methylmorphinan

Fu-Lian Hsu, Arthur E. Jacobson, Kenner C. Rice, and Arnold Brossi*

*Laboratory of Chemistry, Metabolism and Digestive Diseases, National Institute of Arthritis, Bethesda, Marylanf 20014, U.S.A.

Abstract

Conversion of (-)-3-deoxydihydromorphine (2) into (-)-4-hydrony-6-keto-N-methylmorphinan (5) and reconversion of 5 into 2 via the ketone 4 is described. The morphinan structure of 5 was proven by reduction to the known (-)-4-hydroxy-N-methylmorphinan (7).

■ Photochemistry of Conjugated Nitrogen-Carbonyl Systems. 1. Photoaddition of 2-Pyrimidone and Some Properties of the Resulting Ene-Urea System

Yuichi Kanaoka,* Masato Hasebe, and Yasumaru Hatanaka

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

Abstract

Photoexcited 2-pyrimidone 5 reacts with such hydrogen donors 6 as alcohol, ether and amine, to give cyclic ene-urea derivatives 7 in addition to a dimer 8. The ene-urea system 7 is fairly reactive and treatment of 7 with alcohol or thiol leads to adducts 9, 10 which are candidates as possible intermediates for enzymatic studies. Photochemical behaviors of fundamental nitrogen-carbonyl systems 11, 5, 12 are compared.

■ Isolation and Structure of Brefeldin C

Masayuki Sunagawa, Tomihisa Ohta, and Shigeo Nozoe*

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

Abstract

The title macrolide has been isolated from Eupenicillium brefeldianum. This communication describes the isolation and the structural elucidation of brefeldin C which might give a clue to the biogenetic study of brefeldin A.

■ The Terminal Aminoguanidine Chain of Phleomycin G

Noel K. Hart, Albert Hofmann, John A. Lamberton,* and M. Neil Galbraith

*Division of Applied Organic Chemistry, CISRO, P. O. Box 4331, Melbourne 3001, Australia

Abstract

The terminal aminotriguanidine obtained by hydrolysis of phleomycin G is identical with synthetic 1-[[4-((3-[4-{3-(4-aminobutyl)guanidino}butyl]guanidino)butyl]]guanidine (4). The branched isomer 1-(4-aminobutyl)-2,3-bis(4-guanidinobutyl)guanidine (5) has also been prepared for comparison with the hydrolysis base.

■ The Mechanism of the Garryfoline-Cuauchichicine Rearrangement

S. William Pelletier,* Haridutt K. Desai, and Naresh V. Mody

*Institute for Natural Products Research, The Department of Chemistry, University of Georgia, Athens, Georagia 30602, U.S.A.

Abstract

The acid-catalyzed rearrangement of garryfoline to cuauchichicine has been studied by deuterium labeling and ¹³C NMR spectroscopy to establish its mechanism. Treatment of isogarryfoline with 10% DCI in D₂O yielded a product with a C(16αD) - βCH₂D group, a fact which demonstrates that the rearrangement involves enol formation followed by exo-protonation.

■ Synthesis of 10-Methoxydaunorubicins and of 10(R)-Methoxydoxorubicin via Opening of an Oxirane Intermediate

Sergio Penco,* Fausto Gozzi, Aristide Vigevani, Marzia Ballabio, and Federico Arcamone

*Farmitalia Carlo Erba S.p.A, Ricerca & Sviluppo Chimico, Via dei Gracchi,35 20146 Milan, Italy

Abstract

Epoxidation of 9,10-anhydro-13-dihydro-N-trifluoroacetyldaunorubicin provides stereoselectively the corresponding α oxirane derivative. Opening of the intermediate by methanol affords 10(R)- and 10(S)-methoxydaunorubicins. From ¹H n.m.r. studies it appears that the conformation of ring A of 10(S)-derivative has changed to half-boat. The preliminary biological data of these analogs, as well as of 10(R)-methoxydoxorubicin are reported.

■ Selective Migration of the 0-Alkylthiophenyl Group in Stevens Rearrangement

Yoshio Ohara, Kin-ya Akiba,* and Naoki Inamoto

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

Abstract

2-Aryl-3,3-dimethylbenzothiazolinium tetrafluoroborate (1) suffers nucleophilic attack at the ring sulfur atom by butyllithium to afford the ring-opened ammonium ylide (A), which collapses to the radical pair (B) to give unusual Stevens rearrangement product (2) as a major product, where the o-alkylthiophenyl group migrated selectively in preference to the methyl group.

■ Studies on Hetero-cage Compounds. 9. Synthesis and Chemical Reactivity of 8-Thiabicyclo [3.2.1] octan-3-one System in Comparison with 9-Thiabicyclo [3.3.1] nonan-3-one System

Tadashi Sasaki,* Shoji Eguchi, and Tadashi Hioki

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

Abstract

Treatment of cyclohepta-2,6-dienone (5) with Na₂S in H₂O-MeOH afforded 8- thiabicyclo[3.2.1]octan-3-one (6) in 38% yield. Oxidation of 6 with m-CPBA gave sulfone 8 and reduction of 6 with NaBH₄ gave endo- (9) and exo-alcohols (10) in 33:67 ratio. The carbene 12 generated via Na salt of tosylhydrazone 11a yielded only 8-thiabicyclo[3.2.1]oct-2-ene (13), a H migration product.

■ Synthesis of Unsymmetrically Substituted 1,3,4,6-Tetraaza-6a-thia(S^IV)pentalenes and Their Alkylation

Yohsuke Yamamoto and Kin-ya Akiba*

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

Abstract

Unsymmetrically substituted 1,3,4,6-tetraaza-6a-thia (S^IV)pentalenes (1) with a methyl group at N(6) were prepared and alkylated with Meerwein reagents to give N(3) [or N(4)] monoalkylated products, i.e., 1,3,4,6-tetraaza-6a-thia(S^IV)pentalenium tetrafluoroborates (4).

■ Stereoselective Synthesis of Yohimbane and Alloyohimbane

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

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

Abstract

A general method for the stereoselective synthesis of yohimbane and alloyohimbane is described. The preparation of pentacyclic ring systems as contained in yohimbine and reserpine showed should make possible the synthesis of such alkaloids by this method.

■ A New Synthesis of the Synthons for the Functionalized Aspidosperma Alkaloids via α-Ketocarbonium Ion Intermediate

Seiichi Takano,* Kozo Shishido, Jun-ichi Matsuzaka, Masaaki Sato, and Kunio Ogasawara

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

Abstract

Acid catalyzed rearrangements of the diazoketones, 14 and 29(a and b) have been examined. On acidic treatments 14 gives the α,β-unsaturated ketone(21), while 29(a and b) give the vinylogous amides 7(a and b) which are converted into the aminoketones 5(a and b), synthons for the synthesis of the functionalized aspidosperma alkaloids, by the dissolving metal reduction.

■ Oxidation of Methylpyridines and Methylpyridine-N-oxides with Electro-generated Superoxide Ion

Hiromitsu Sagae, Masamichi Fujihira, Henning Lund, and Tetsuo Osa*

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

Abstract

The oxidation of methylpyridines and methylpyridine-N-oxides with electro-generated superoxide ion in DMF was studied by cyclic voltammetry and controlled potential macro-electrolysis. The electrochemical reduction of oxygen in the presence of these compounds yielded the corresponding carboxylic acids. The reactivity of the methyl groups towards the oxidation varied according to the location of such groups on the heterocyclic ring and was in each case greater for the methylpyridine-N-oxide than for the corresponding methylpyridine.

■ A Novel Synthesis of Cyclic Imides and Quinolone by Use of PalIadium Catalyzed Carbonylation

Miwako Mori, Katsumi Chiba, Nahoko Ohta, and Yoshio Ban*

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

Abstract

The palladium catalyzed carbonylation of aryl and vinyl bromides bearing the internal amide group proceeded smoothly to give cyclic imides, such as phthalimide, N-acetylisoindolinone and N-acetylisoquinolone and quinolone.

■ The Polyoxins: Pyrimidine Nucleoside Peptide Antibiotics Inhibiting Fungal Cell Wall Biosynthesis

Kiyoshi Isono* and Saburo Suzuki

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

■ MethyIenomycin A, an Antibiotic with Chemically Versatile Functions

Akira Terahara,* Tatsuo Haneishi, and Mamoru Arai

*Fermentation Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan

■ Synthesis and Biological Activities of Mitomycin Derivatives

Kin-ichi Nakano*

*Kyowa Hakko Kogyo Co., Ltd.,

Abstract

The synthesis, biological activities and structure-activity relationships of mitomycin derivatives and analogs are described.

■ Transformations on Diazaquinone Adducts

Feranando Gómez Contreras and Manuel Lora-Tamayo*

*Department de Química, Colegio Universitario Integrado Univ.Complutense, Arcos de Jalón, s/n. Madrid-17, Spain

Abstract

Chemical transformations performed on diazaquinone adducts prepared by the authors research group, and stereochemical features of derivatives synthesized from them, are reviewed.

■ Synthetic Studies on Mitomycins and Related Compounds

Kimio Takahashi and Tetsuji Kametani*

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

Abstract

Synthetic approaches towards mitomycins and their analogs are described. The strategy of this study includes a simple synthesis of mitosene derivatives and their transformation to seco-mitosane type compounds which have been shown to be key intermediates in the total synthesis of the mitomycins. Synthetic studies on mitomycins appearing in the literature are also reviewed.

■ Pepleomycin, the Second Generation Bleomycin Chemically Derived from Bleomycin A2

Wataru Tanaka* and Tomohisa Takita

*Pharmaceutical Division, Nippon-Kayaku Co. Ltd., 3-31-12, Shimo, Kita, Tokyo 115-0042, Japan

Abstract

Pepleomycin, 3-(S-1-phenylethylamino)-propylaminobleomycin, has been synthesized from bleomycin A2, the main component of natural bleomycins, by a series of the following reactions: demethylation, cyclic iminoether formation, hydration and aminolysis with 3-(S-1-phenylethylamino)-propylamine. Pepleomycin has stronger activity and less pulmonary toxicity than natural bleomycin mixture clinically used today in the treatment of cancer and will become the second generation bleomycin in its cancer therapy.

■ Structures of Bu-2313 A and B, New Anti-anaerobic Antibiotics and Syntheses of Their Analogs

Susumu Nakagawa,* Takayuki Naito, and Hiroshi Kawaguchi

*Bristol-Banyu Research Institute, Ltd., 2-9-3, Shimomeguro, Meguro, Tokyo 153, Japan

Abstract

An oligosporic actinomycete strain, No. E864-861, produced two new antibiotics, Bu-2313 A (C₂₇H₃₅NO₉) and Bu-2313 B (C₂₆H₃₃NO₉). Both Bu-2313 A and B exhibited a broad antimicrobial spectrum against gram-positive and gram-negative anaerobic bacteria, and also inhibited the growth of some aerobic bacteria such as streptococci. The structures of Bu-2313 A and B have been elucidated. They belong to the family of antibiotics classified as dienoyltetramic acids. Semi-synthesis of Bu-2313 A and B was performed by C-acylation of tetramic acids with the dienoic moiety obtained by periodate oxidation of Bu-2313. In a similar manner Bu-2313 analogs were prepared by using a variety of tetramic acids and cyclic 1,3-diketones.

■ Chemical and Biochemical Aspects of Isoquinoline Alkaloids

Tetsuji Kametani* and Masataka Ihara

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

Abstract

Some chemical and biochemical aspects of isoquinoline alkaloids are reviewed.

■ New-typed Heterocyclic Compounds

Tadashi Sasaki*

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

Abstract

The recent advance in new-typed heterocyclic compound is reviewed focused on 1) new heterocyclic systems of heteroaromatic character and 2) saturated fused polycyclic heterocycles.