HETEROCYCLES

■ Contents

■ Preface — Dr. Keiichiro Fukumoto

Hiroshi Irie*

*, Japan

■ Preface — To Special Anniversary Issue of Heterocycles

Masataka Ihara*

*Research Centre of Medicinal Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan

■ Preface — Dr. Keiichiro Fukumoto

Hideo Nemoto*

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

■ Bibliographical Data

Keiichiro Fukumoto*

*The Japan Institute of Heterocyclic Chemistry, 1-7-17, Motoakasaka, Minato-ku, Tokyo 107-0051, Japan

■ Publications of Keiichiro Fukumoto

Keiichiro Fukumoto*

*The Japan Institute of Heterocyclic Chemistry, 1-7-17, Motoakasaka, Minato-ku, Tokyo 107-0051, Japan

■ Syntheses of Peptidyl Nucleoside Antibiotics

Hiroyuki Akita*

*Department of Pharmaceutical Sciences, Nihon Pharmaceutical University, , Japan

Abstract

Polyoxins and nikkomycins are an important class of peptidyl nucleoside antibiotics isolated from the culture broths of Streptomyces cacaoi var. asoensis and Streptomyces tendae. For the syntheses of these antibiotics, efficient syntheses of 1-(5-amino-5-deoxy-β-D-allofurano-uronosyl)pyrimidines such as thymine polyoxin C, uracil polyoxin C and their congeners as a basic component corresponding to the right half were achieved based on the nucleophic 1,2-addition to methyl 2,3-O-isopropylidene-β-D-ribopentodialdo-1,4-furanoside. Then the syntheses of polyoxamic acid derivatives and their congeners corresponding to the left acid part were carried out based on 1,2-addition of carbon nucleophile to 4-O-protected-2,3-O-isopropylidene-L-threose. Coupling reaction of the activated ester derived from the left half acid part and amine part derived from the right half gave the N,O-protected peptidyl nucleoside congeners which were subjected to deprotection to afford polyoxins B, D, J, L, M, C and nikkomycin B.

■ Progress towards the Total Synthesis of the Bioactive Calothrixins A and B

Tominari Choshi and Satoshi Hibino*

*Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan

Abstract

During the past decade, the total synthesis of calothrixin A and B, bioactive metabolites from cyanobacteria Calothrix sp., has been independently reported by six groups. Here, we describe the development of these synthetic efforts, including two biomimetic routes via indolo[2,3-a]carbazole.

■ Bryophytes: Bio- and Chemical Diversity, Bioactivity and Chemosystematics

Yoshiori Asakawa,* Agnieszka Ludwiczuk, Fumihiro Nagashima, Masao Toyota, Toshihiro Hashimoto, Motoo Tori, Yoshiyasu Fukuyama, and Liva Harinantenaina

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

Abstract

The bryophytes contain the Marchantiophyta (liverwort), Bryophyta (moss) and Anthocerotophyta (hornwort) among which the Marchantiophyta contain cellular oil body and they produce a number of mono-, sesqui- and diterpenoids, aromatic compounds like bibenzyl, bis(bibenzyls) and acetogenins. Several of these compounds show interesting biological activity such as insecticide, insect antifeedant, cytotoxic, piscicidal, muscle relaxing, allergenic contact dermatitis, anti-HIV, DNA polymerase β, 5-lipoxygenase, calmodium inhibitory, anti-obesity, neurotrophic, cyclooxygenase, hyaluronidase and NO production inhibitory, antimicrobial and antifungal activities. Each liverwort biosynthesizes peculiar components, which are valuable for classification of liverworts. The typical chemical structures and bioactivity of the selected liverwort constituents as well as chemosystematics of several species of the Marchantiophyta are surveyed.

■ Use of NaOH as a New Activator for the Palladium-Catalyzed Direct CH Arylation of Thiazole Derivatives

Takayuki Miyaoku and Atsunori Mori*

*Chemical Resources Laboratory, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan

Abstract

Sodium hydroxide is found to serve as a new activator for the palladium-catalyzed C-H arylation of thiazole derivatives with aryl bromides and aryl iodides. The reaction of benzothiazole proceeds smoothly with 4-bromoanisole to afford the corresponding coupling product in an excellent yield.

■ An Oxidative Dearomatization Cyclization Model for Cortistatin A

Mingji Dai and Samuel J. Danishefsky*

*Department of Chemistry, Columbia University, 3000 Broadway, New York, NY 10027, U.S.A.

Abstract

The feasibility of a hypervalent iodine-mediated oxidative dearomatization/cyclization to produce the oxabicyclo[3.2.1]octene of cortistatin A has been demonstrated through a model study. An interesting tandem cyclization via a Ritter intermediate has been observed when a slightly different substrate was used.

■ Workable Synthetic Route to Functionalized 1,6-Benzodiazocines

Nicolas Proust, Adam J. Preston, and Leo A. Paquette*

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

Abstract

Two strategies for fusing a medium-sized building block to a benzene ring in the form of a functionalized 1,6-diazocine unit via one-pot procedures are presented.

■ Enantioselective Synthesis of a 3,5,5-Trialkylated Tetronic Acid Derivative

Ken-ichi Takao,* Yuki Kojima, Tomo Miyashita, Kentaro Yashiro, Tatsuya Yamada, and Kin-ichi Tadano*

*Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi, Kohoku-ku Yokohama 223-8522, Japan

Abstract

A convenient and enantioselective method for the synthesis of 3,5,5-trialkylated tetronic acid has been developed. The Dieckmann-type condensation of enantioenriched α-acyloxy-α,α-dialkylated acetic acid ester (11) proceeded in the presence of lithium hexamethyldisilazide, providing the expected tetronic acid derivative (12) after quenching with methoxymethyl chloride. The product (12) was converted into a doubly prenylated tetronic acid derivative (13), which constitutes a substructure of perforatumone, a newly isolated polycyclic polyprenylated acylphloroglucinol-type natural product.

■ Concise Assembly of the BCD Ring Part of Ginkgolide C via a Novel Cyclization Reaction

Ayaka Hibi, Kazutaka Takeda, and Masahiro Toyota*

*Department of Chemistry, Graduate School of Science, University of Osaka Prefecture, Sakai, Osaka 593-8531, Japan

Abstract

Efforts to synthesize a 6-oxatricyclo[6.3.0.01.5]undecane ring system are described. A novel Pd(II)-promoted oxidative cyclization of the lactone ester constructs the tricyclic core of ginkgolide C.

■ Synthesis of Chaetomellic Anhydride A, a Potent Inhibitor of Ras Protein Farnesyltransferase

Takehiko Yoshimitsu,* Yoshimasa Arano, Tomohiro Kaji, Tatsunori Ino, Hiroto Nagaoka, and Tetsuaki Tanaka*

*Medicinal and Organic Chemsitry, Graduate School of Pharmaceutical Science, Osaka University, 1-6 Yamadaoka, Suita, Osaka 560-0871, Japan

Abstract

Chaetomellic anhydride A, a potent inhibitor of Ras protein farnesyltransferase, was synthesized in 61% yield over four steps from methyl propionate. The synthesis features palladium-catalyzed carboxylation reaction under Cacchi conditions, efficiently incorporating carbon monoxide generated in situ from acetic formic anhydride into β-carbomethoxyalkenyl triflate, and giving rise to the maleic anhydride motif of chaetomellic anhydride A. Noteworthy is the remarkable reactivity of the carboxylation reaction that takes place at room temperature despite the fact that common palladium-catalyzed carboxylations generally require rather harsh conditions. The scope of the method is also presented.

■ Triflic Imide Catalyzed [3+2] Cycloaddition of Aldimines with α,α-Dimethylallylsilane

Naoya Shindoh, Hidetoshi Tokuyama, Yoshiji Takemoto,* and Kiyosei Takasu*

*Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-machi, Sakyo-ku, Kyoto 606-8501, Japan

Abstract

Tf₂NH-catalyzed [3 + 2] cycloaddition of N-aryl imines with α,α-dimethylallylsilane to give substituted pyrrolidines is described. We have found the mode of cycloaddition depends upon α-substituents of allylsilanes.

■ Rhodium-Catalyzed Diastereoselective Coupling of Propargylic Oxiranes with Arylboronic Acids in Water

Masahiro Yoshida,* Maiko Hayashi, Kennosuke Matsuda, and Kozo Shishido

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

Abstract

A diastereoselective coupling of propargylic oxiranes with arylboronic acids in aqueous condition is described. 4-Aryl-substituted 2,3-allenols having syn-geometries were selectively synthesized by the rhodium-catalyzed reactions in water.

■ An Efficient Synthetic Method for 3-Bromofuran Derivatives via Stereoselective Cyclization of γ,δ-Epoxy (E)-α-Bromoacrylates

Fumihiko Yoshimura, Masaki Takahashi, Keiji Tanino, and Masaaki Miyashita*

*Department of Applied Chemistry, Faculty of Engineering, Kogakuin University, 2665-1 Nakano-cho, Hachioji, Tokyo 192-0015, Japan

Abstract

A novel and efficient synthetic method for 3-bromofuran derivatives via stereoselective cyclization of γ,δ-epoxy-(E)-α-bromoacrylates is described. The reaction of a γ,δ-epoxy-(E)-α-bromoacrylate with MeAl₃-H₂O gave rise to a 3-bromo-2-methylfuran derivative, i.e., methylated bromofuran at the 2-position, while the reaction with Me₃Al-(CF₃)₂CHOH reagent produced a 2-alkoxy-3-bromofuran derivative in high yield. The 3-bromofuran obtained was transformed into various functionalized furan derivatives.

■ Synthesis and Biological Properties of a Rhodacyanine Derivative, SSJ-127, having High Efficacy against Malaria Protozoa

Khanitha Pudhom, Jian-Feng Ge, Chika Arai, Mei Yang, Mercel Kaiser, Sergio Wittlin, Reto Brun, Isamu Itoh, and Masataka Ihara*

*Research Centre of Medicinal Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan

Abstract

One of rhodacyanine derivatives, SSJ-127 (1), showed a complete cure of a mouse model infected with Plasmodium berghei by subcutaneous administration. The synthesis, in vitro activities against several protozoa and in vivo antimalarial test and PK study of SSJ-127 (1) are reported.

■ Pd(II)-Catalyzed Cyclization to Ether and Its Application to the Synthesis of the trans-Fused Polyether Core

Hajime Yokoyama, Satoshi Nakayama, Masayuki Murase, Masahiro Miyazawa, Seiji Yamaguchi, and Yoshiro Hirai*

*Department of Chemistry, Graduate School of Science and Engineering, Toyama University, Gofuku 3190, Toyama 930-8555, Japan

Abstract

We employed an iterative Pd(II)-catalyzed cyclization reaction to ether from tri-O-acetyl-D-glucal to synthesize trans-fused polyethers. This approach should be applicable to synthesize the core structure of marine ladder toxins.

■ Synthetic Studies towards the Identification of Novel Capuramycin Analogs with Mycobactericidal Activity

Michio Kurosu* and Kai Li

*Immunology & Patholog, Department of Microbiology, Colorado State University, 1682 Campus Delivery, Fort Collins, CO 80523-1682, U.S.A.

Abstract

Expeditious syntheses of capuramycin, an effective MraY inhibitor in vivo, analogs are described. Synthetic schemes reported here are extremely useful for the generation of capuramycin analogs to identify minimum structure requirement to exhibit antimycobactericidal activity.

■ Effective Friedel-Crafts Acylations of O- and C-Aryl Glycosides with Triflic Acid

Makoto Hashimoto* and Miho Takahashi

*Department of Agricultural and Life Science, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido 080-8555, Japan

Abstract

Triflic acid is well known not only as a Friedel-Crafts promoter, but also as a deglycosidation reagent. In this study, we promote effective Friedel-Crafts acylations for O- or C- arylglucosides without deglycosidation and check their inhibitory activities for ″-glucosidase.

■ Palladium-catalyzed Coupling of N-Heteroaryl Sulfides with Organozinc Reagents

Takahiro Koshiba, Tohru Miyazaki, Hidetoshi Tokuyama, and Tohru Fukuyama*

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

Abstract

The palladium-catalyzed cross-coupling of N-heteroaryl sulfides with organozinc reagents was developed. Scope and limitation of the reaction regarding generality of zinc reagents and substrate were also investigated.

■ Facile Construction of Furan-fused Methano[11]annulenone Skeleton by Successive Aldol Condensations from 3,4-Furan-dicarbaldehydes

Yanmei Zhang, Nobuhiko Takezawa, oshikazu Horino, Ayumi Takai, Yasutomo Tsuji, Ryuta Mityatake, Mitsunori Oda,* Shigeyasu Kuroda*

*Faculty of Engineering, Toyama University, Gofuku 3190, Toyama 930-8555, Japan

Abstract

Aldol condensation of furan-3,4-dicarbaldehyde with pentanedial in acetic acid gave 6H-cyclohepta[c]furan-5,7-dicarbaldehyde in a good yield. Then, successive condensation of 6H-cyclohepta[c]furan-5,7-dicarbaldehyde with dimethyl 1,3-acetonedicarboxylate under azeotropic conditions gave a diester derivative of furan-fused methano[11]annulenone also in a good yield. The hydrolysis of the diester groups and subsequent decarboxylation provided a non-substituted furan-fused methano[11]annulenone. A similar sequence starting from 2,5-dimethylfuran-3,4-dicarbaldehyde gave its dimethyl derivative. Cycloaddition and protonation of these furan-fused methano[11]annulenones were also studied.

■ Enantioselective Route to Aryl(1,3-butadien-2-yl)methanols: Formal Synthesis of (-)-Sporochnol A

Daisuke Yanagimoto, Kazuyuki Kawano, Keisuke Takahashi, Jun Ishihara, and Susumi Hatakeyama*

*Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

Ti(IV)-promoted reaction of the chiral acetals derived from aromatic aldehydes with 1-(tri-n-butyl)stannyl-2,3-butadiene followed by removal of the chiral auxiliary gave aryl(1,3-butadien-2-yl)methanols with high enantiomeric purity (>90% ee). The synthetic utility of this method was demonstrated by the formal synthesis of (-)-sporochnol A, a terpene possessing a chiral benzylic quaternary carbon center.

■ One-Pot Synthesis of 3,3-Dimethylpyrrolidine-2-carbonitriles from 4-Chloro-2,2-dimethylbutanal in Water

Matthias D’hooghe, Berten Van Driessche, and Norbert De Kimpe*

*Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium

Abstract

Treatment of 4-chloro-2,2-dimethylbutanal, prepared in high yield by means of a three-step procedure starting from ethyl isobutyrate, with successively sodium bisulphite, a primary amine and potassium cyanide in water afforded novel 1-alkyl- and 1-aryl-3,3-dimethylpyrrolidin-2-carbonitriles in a convenient and environmentally benign way.

■ Diels-Alder Reaction of 2-Pyridones Having an Acyl or a Sulfonyl Group on Nitrogen

Masato Hoshino, Kazuhiro Watanabe, Yosuke Ohtake, Takeshi Sato, Hisao Matsuzaki, and Reiko Fujita*

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

Abstract

Diels-Alder (DA) reaction of 5-methoxycarbonyl-2-pyridone, which has an electron-withdrawing acyl group at nitrogen, with 1,3-diene afforded 2-quinolone derivatives in modest yields. Further, DA reaction of 5,4-dimethoxycarbonyl-1-sulfonyl-2-pyridone gave 2-quinolone and 1-isoquinolone (1:1). DA reaction of 2-sulfonyl-1-isoquinolone afforded a functionalized phenanthridone. The site-selectivity was well correlated with the corresponding activation energies calculated using an ab initio molecular orbital method.

■ Novel Process to 4,4-Dialkyl-1,4-dihydro-6-methoxy-3-phenylcinnolines via Grignard Reaction

Dongdong Chen, Chunhao Yang,* Yuyuan Xie, and Jian Ding

*State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, SIBS, Chinese Academy of Science, 555 Zu Chong Zhi Road, Shanghai 201203, China

Abstract

4,4-Dialkyl-1,4-dihydro-6-methoxy-3-phenylcinnolines were obtained from 2-(5-methoxy-2-nitrophenyl)acetonitrile analogues and phenylmagnesium bromide by one step, and the possible mechanism was speculated.

■ Benzothiazines in Organic Synthesis. An Approach to the Synthesis of seco-Pseudopteroxazole

Michael Harmata* and Pinguan Zheng

*Room 125, Department of Chemistry, University of Missouri-Columbia, 601 South College Avenue, Columbia, Missouri 65211, U.S.A.

Abstract

As part of our approach to the synthesis of seco-pseudopteroxazole, we have succeeded in establishing the stereochemistry of the methyl-bearing stereocenter (C-11) with good diastereoselectivity. Though seemingly straightforward, the process was not simple and revealed some interesting aspects of benzothiazine chemistry.

■ Natural Products-Based Insecticidal Agents 1. Semisynthesis and Insecticidal Activity of 4β-Benzenesulfonamide Derivatives of Podophyllotoxin against Mythimna separata Walker

Hui Xu,* Lei Zhang, Bao-Feng Su, Xing Zhang, and Xuan Tian

*Laboratory of Pharmaceutical Synthesis, College of Sciences, Northwest A & F University, Yangling, Shaanxi, 712100, China

Abstract

Eleven 4β-benzenesulfonamide derivatives of podophyllotoxin were synthesized and evaluated for insecticidal activity against the third-instar larvae of Mythimna separata Walker in vivo at the concentration of 1 mg/mL. All derivatives showed delayed insecticidal activity, which was different from the traditional neurotoxic insecticides. Compounds 4a-4f and 4i-4k were found to be more potent than podopyllotoxin in the mortality rate after 20 d against M. separata. Especially compounds 4i, the corresponding final mortality rate of which was 88.9%, exhibited more potent insecticidal activity than toosendandin (81.4%), a commercial insecticide derived from Melia azedarach. Furthermore, some preliminary qualitative structure-activity relationships were also observed.