HETEROCYCLES

■ Contents

■ Preface to Heterocycles Issue Honoring the 70th Birthday of Professor Dr. Masakatsu Shibasaki

Hiroaki Sasai*

*The Institute of Scientific and Industrial Research (ISIR), Osaka University, Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan

■ Preface to Heterocycles Issue Honoring the 70th Birthday of Professor Masakatsu Shibasaki

Takashi Ohshima*

*Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan

■ Curriculum Vitae

Masakatsu Shibasaki*

*

■ Publication List by Masakatsu Shibasaki

Masakatsu Shibasaki*

*

■ Asymmetric Hydrogenation of Six-Membered Monocyclic N-Heteroaromatic Compounds

Atsuhiro Iimuro, Kosuke Higashida, Haruki Nagae, and Kazushi Mashima*

*Department of Chemistry, Graduate School of Engineering Science, Osaka University, Toyonaka, Osaka 560-8531, Japan

Abstract

Six-membered chiral cyclic amines are important skeletal structures found in natural products as well as bioactive species. Asymmetric hydrogenation of six-membered N-heteroaromatic compounds is considered one of the most straightforward protocols for preparing six-membered chiral cyclic amines, because asymmetric hydrogenation is an atom economical reaction and applicable to industrial scales. In this review, we summarize the development of asymmetric hydrogenation of six-membered N-heteroaromatic compounds, such as pyridines, pyrazines, pyrimidines, and pyridones.

■ Strategies for Brevisamide Synthesis, Based on the Method for Constructing the Tetrahydropyranyl Core

Takeo Sakai and Yuji Mori*

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

Abstract

Brevisamide is a monocyclic ether alkaloid produced by the red tide dinoflagellate Karenia brevis. Brevisamide has attracted the attention of organic chemists because it is the smallest molecule that can be used to understand the biosynthetic 6-endo epoxide cyclization of polycyclic ethers. Within nine years of its discovery, several diverse approaches to synthesizing this monocyclic ether amide have been explored, culminating in the publication of eight total and seven formal total syntheses. In the first part of this review, we discuss strategies for the introduction of the key elements—the (2E,4E)-3,4-dimethyl-2,4-heptadienal side chain, acetamide side chain, C9 axial methyl group, and tetrahydropyran (THP) core. In the following sections, each of the total and formal syntheses is overviewed, based on the method for constructing the THP core.

■ Total Synthesis of (+)-Linoxepin

Minami Odagi,* Kota Furukori, Yoshiharu Yamamoto, and Kazuo Nagasawa*

*Department of Biotechnology and Life Science, Faculty of Technology, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan

Abstract

(+)–Linoxepin is a lignan-type natural product with a synthetically challenging fused dihydronaphthalene/dihydroxepine structure. It also has multiple biological activities, including antitumor, antioxidant, and antiviral activities. Here, we review three recent total syntheses of (+)–linoxepin.

■ A Water-Soluble Cavitand Sequesters 2-Nonenal, the Odor Component of the Elderly

Yang Yu, Simone Mosca, and Julius Rebek, Jr.*

*Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, U.S.A.

Abstract

Long chain aldehydes are principal components of odor in older populations. Here we show that a synthetic container molecule, a deep water-soluble cavitand forms complexes in aqueous (D2O) solution. The cavitands bind the aldehyde in a compressed conformation that reduces exposure to the medium. The aldehyde is extracted from the complex by tetrachloroethane and sodium dodecyl sulfate, chemical agents of dry cleaning or laundering, respectively. The large-scale synthesis of the cavitand opens possibilities for its attachment to clothing fibers.

■ Total Synthesis of Oenothein C

Hitoshi Abe,* Daichi Ogura, and Yoshikazu Horino

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

Abstract

The simple total synthesis of oenothein C (1), ellagitannin, originally isolated from the leaves of Oenothera erythrosepala, was achieved by successive esterification of the glucose derivative with the protected valoneic acid dilactone (2) and gallic acid (3). The lactonized valoneic acid (11), which is the key structural part, was prepared by the intermolecular Ullmann cross coupling reaction.

■ Oxidative Self-Annulation of 2,5-Diaryl-3,4-diaminothiophene via C–C and C–S Bond Cleavage of the Thiophene Ring: A New Synthesis of an Amino-Substituted Triarylthieno[3,4-b]pyrazines and Their Photophysical Properties

Youhei Takeda,* Satoshi Ueta, and Satoshi Minakata*

*Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan

Abstract

A novel oxidative self-annulation of 2,5-diaryl-3,4-diaminothiophenes that accompanies C–C and C–S bonds cleavage of a thiophene ring to produce 3,5,7-triaryl-2-aminothieno[3,4-b]pyrazines in moderate to good yields has been discovered. Photophysical properties of this new family of thienopyrazines have also been disclosed.

■ Growth Mechanism of Uncultured Actinobacterial Strain Leucobacter sp. ASN212 by Zinc Coproporphyrin

Ryogo Takai, Kengo Shigetomi, Yoichi Kamagata, and Makoto Ubukata*

*Division of Applied Bioscience, Graduate School of Agriculture, Hokkaido University, Kita-9, Nishi-9, Kita-ku, Sapporo 060-8589, Japan

Abstract

We propose HemH as a primary target of Zn coproporphyrin, which stimulates the growth of uncultured Leucobacter sp. ASN212, based on the structure-activity relationship for transition-metal complexes of coproporphyrin.

■ Rhodium(I)-Catalyzed Silylation of Aryl Iodides with Di(2-furyl)methylsilane

Yoshihito Kohari, Yusuke Kano, Yusuke Matsuoka, Takeshi Namikoshi, Shinji Watanabe, and Miki Murata*

*Department of Materials Science and Engineering, Kitami Institute of Technology, 165 Koen-cho, Kitami, Hokkaido 090-8507, Japan

Abstract

The efficient silylation of aryl iodides with di(2-furyl)methylsilane has been developed utilizing a rhodium catalyst. The substrate scope is broad and includes electron-rich and -deficient aryl iodides.

■ Catalytic Aromatic Borylation via in situ-Generated Borenium Species

Fumiya Kitani, Ryo Takita,* Tatsushi Imahori, and Masanobu Uchiyama*

*RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan

Abstract

We have developed a catalytic direct borylation of arenes via in situ-generated borenium species. The choice of appropriate Lewis base was crucial to achieve the catalytic system. Electron-rich arenes were borylated in a regioselective manner.

■ Efficient D-Fructopyranosylation Method Catalyzed by Scandium Triflate and Preparation of New Sucrose Analogs

Takashi Yamanoi,* Takanori Saitoh, Yoshiki Oda, Noriko Misawa, Mikio Watanabe, Junko Ishikawa, and Akihiko Koizumi

*Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan

Abstract

We successfully established a highly efficient β-fructopyranosylation method that used a fully benzoylated β-D-fructopyranosyl acetate as the glycosyl donor and Sc(OTf)3 as the catalytic activator. The syntheses of non-reducing disaccharide units as new sucrose analogs were achieved based on the β-fructopyranosylation reaction of 1-hydroxy group of glucose derivatives.

■ Gold(III)-Catalyzed Synthesis of 2,3,4-Trisubstituted Dihydropyrans from Propargylic Alcohols with 1,3-Dicarbonyl Compounds

Nobuyoshi Morita,* Kazuki Oguro, Saori Takahashi, Midori Kawahara, Shintaro Ban, Yoshimitsu Hashimoto, and Osamu Tamura*

*Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan

Abstract

2,3,4-Trisubstituted dihydropyrans were efficiently synthesized by tandem reaction of propargylic alcohols with 1,3-dicarbonyl compounds in the presence of 5 mol% gold(III) catalyst (dichloro[2-pyridinecarboxylato]gold) and 10 mol% silver catalyst (AgNTf2).

■ Design and Synthesis of 4-Chlorocolchicine-Derived Prodrug Capable of Forming Nanoparticles by Self-Assembly

Mariko Kitajima, Akihiro Morita, Shimpei Endo, Noriyuki Kogure, Kenjirou Higashi, Kunikazu Moribe, and Hiromitsu Takayama*

*Laboratory of Biofunctional Molecular Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan

Abstract

We have designed and synthesized colchicine-derived prodrug 7, which is composed of a 4-chlorocolchicine derivative, a dipeptide side chain cleavable by cathepsin B, a spacer containing a disulfide bond, and hydrophobic vitamin E. Prodrug 7 was capable of forming nanoparticles by self-assembly. Mean particle diameter evaluated by dynamic light scattering measurement was ca. 205 nm.

■ Synthetic Study towards Construction of Potential Scaffold of Antitumor Agents Andrastins

Shuqiang Yin, Kenji Sugimoto, Hideo Nemoto, and Yuji Matsuya*

*Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Sugitani 2630, Toyama, 930-0194, Japan

Abstract

For a construction of potential scaffold of antitumor agents andrastins, intramolecular Diels-Alder reaction of the triene composed of trans-fused AB ring with tethered D ring was examined. The reaction in refluxing toluene afforded a desired cis-fused hydrindane skeleton, the relative stereochemistries of which were unambiguously determined by X-ray crystallographic analysis.

■ Synthesis of 3-Bromoquinoline-2(1H)-thiones and 2-(Alkylsulfanyl)-3-bromoquinolines Based on the Reaction of 2-(2,2-Dibromoethenyl)phenyl Isothiocyanates with Butyllithium

Kazuhiro Kobayashi,* Ippei Nozawa, and Takashi Nogi

*Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan

Abstract

The synthesis of 3-bromoquinoline-2(1H)-thiones and 2-(alkylsulfanyl)-3-bromoquinolines from readily available starting materials was accomplished. Thus, 2-(2,2-dibromoethenyl)phenyl isothiocyanates were treated with butyllithium to afford, after aqueous workup, 3-bromoquinoline-2(1H)-thiones. When haloalkanes were added prior to workup, 2-(alkylsulfanyl)-3-bromoquinolines were obtained. An elaboration of one of these compounds to a thieno[2,3-b]quinoline derivative and one-pot preparation of 3-substituted quinoline-2(1H)-thiones were also achieved.

■ Isolation and Evaluation of Hedgehog Inhibitors from Christmas Grass (Themeda arguens)

Tatsuro Yoneyama, Midori A. Arai,* Takashi Koyano, Thaworn Kowithayakorn, and Masami Ishibashi*

*Department of Natural Products Chemistry, Graduate School of Pharmaceutical Science, Chiba University, 1-8-1 Inohana, Chuo, Chiba, Japan

Abstract

The hedgehog (Hh) signaling pathway is an important regulator of embryonic development, tissue patterning, cellular proliferation and differentiation. However, aberrant activation of the pathway is associated with tumorigenesis. In this study, the Hh signal inhibitory activity of plant extracts was measured with a cell-based assay system that targets GLI1-mediated transcription. Activity guided analysis of MeOH extracts of christmas grass (Themeda arguens) led to the isolation of four inhibitory compounds: aciculatin (1), 7-de-O-methylaciculatin (2), 8-C-β-D-boivinopyranosylapigenin (3) and aciculatinone (4). Compound 1 strongly inhibited Hh/GLI1-mediated transcriptional activity with an IC50 value of 1.8 μM, and disrupted the formation of the GLI1-DNA complex by EMSA. 1 and 3 were cytotoxic for human prostate (DU-145) and breast (MCF-7) cancer cells. These compounds may serve as new tools for the molecular dissection of Hh pathway activation.

■ [3+2] Cycloadditions of N-Protected ‘(S)-Diazoproline’ with Selected Acetylenes

Grzegorz Mlostoń,* Paulina Pipiak, and Heinz Heimgartner*

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

Abstract

Acetylene carboxylates and an acetylene phosphonate reacted with N-protected (S)-2-(diazoacetyl)pyrrolidines ((S)-diazoprolines) to give optically active bis-heterocyclic pyrazole derivatives in a regioselective [3+2] cycloaddition. The reactions occurred at 60 °C in THF solution in the absence of a catalyst. However, diethyl ethynylphosphonate reacted significantly slower than the carboxylates. The obtained products were shown to exist in CDCl3 solution at room temperature as mixtures of rotamers. The reactions of diethyl ethynylphosphonate with a selected cyclic α-oxodiazo compound, i.e. 2-diazoacenaphthen-1-one, yielded a fused tricyclic pyrazole derivative.

■ N-Heterocyclic Carbene-Promoted [3+2] Cycloaddition of Allenyl Sulfone and Arylidenemalononitriles

Satoru Kuwano,* Toshinobu Masuda, Koki Yamaguchi, and Takayoshi Arai

*Department of Chemistry, Graduate School of Science, Chiba University, , Japan

Abstract

N-Heterocyclic carbenes promote the [3+2] cycloaddition of allenyl sulfone and arylidenemalononitriles, accompanied by 1,2-migration of the sulfonyl group. This reaction provides a new route to highly substituted cyclopentenes.

■ Total Synthesis of Fargesine Using a Platinum-Catalyzed Intramolecular Friedel-Crafts-Type C–H Coupling–Allylic Amination Cascade

Yuito Tanaka, Yuta Suzuki, Yasumasa Hamada, and Tetsuhiro Nemoto*

*Pharmaceutical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba, Japan

Abstract

Total synthesis of fargesine was described herein. The synthesis was based on the platinum-catalyzed intramolecular Friedel-Crafts-type C–H coupling–allylic amination cascade to construct the 3,4-fused tricyclic indole skeleton.

■ One-Pot Synthesis of Fused 2-Pyridones from Heteroarylacrylic Acid via Curtius Rearrangement and Microwave-Assisted Thermal Electrocyclization

Takashi Nishiyama, Noriyuki Hatae, Kaori Hayashi, Manami Obata, Kimiko Taninaka, Masahiro Yamane, Shota Oda, Takumi Abe, Minoru Ishikura, Satoshi Hibino, and Tominari Choshi*

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

Abstract

We investigated the one-pot synthesis of several fused 2-pyridone ring systems based on a Curtius rearrangement, followed by a microwave-assisted thermal electrocyclization of a 2-aza-6π-electron system including isocyanate. We synthesized seven heterocyclic compounds containing a fused 2-pyridone ring. In these results, the one-pot synthesis of fused 2-pyridone ring system 5 from (E)-acrylic acids 1 under microwave irradiation conditions was more effective than the conventional reaction conditions in terms of the yield and the reaction time.

■ Synthesis of Unsymmetrical Heterobiaryls with Winding Vine-Shaped Molecular Asymmetry through a Condensation Pathway

Atsunori Mori,* Daichi Matsuoka, Shiomi Ashida, Ryo Inoue, Kazuki Maruhashi, Yoichi Okayama, Guan Hong Jin, and Kentaro Okano

*Chemical Science & Technology, Graduate School of Engineering, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan

Abstract

Oxidative condensation of N-(3-buten-1-yl)-1,2-phenylenediamine with a formylated heteroarene bearing 3-buten-1-yl substituent gives unsymmetrical heterobiaryl in 42–86% yields. Ring-closing metathesis of the thus obtained product affords the cyclized product, which resulted in separation of each enantiomer by HPLC with a chiral column showing molecular asymmetry.

■ Kinetic Resolution of Racemic 2-Hydroxyacetals by Asymmetric Esterification Using a Mixed Anhydride Protocol

Kenya Nakata,* Eri Tokumaru, Takahiro Saitoh, Takayoshi Nakahara, Keisuke Ono, Takatsugu Murata, and Isamu Shiina*

*Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan

Abstract

The non-enzymatic kinetic resolution of racemic 2-hydroxyacetals via asymmetric esterification with diphenylacetic acid and pivalic anhydride catalyzed by the chiral acyl transfer catalyst (R)-BTM is reported. The reaction transition states were elucidated using theoretical calculations; it was found that 1,3-dioxolane is a suitable reagent for attaining high selectivity.

■ The Synthesis of Polyfunctionalized, Cyclohexene-Based Chirons from Tartaric Acid

Joshua N. Buckler, Brett D. Schwartz, and Martin G. Banwell*

*Research School of Chemistry, Australian National University, Canberra, ACT 0200, Australia

Abstract

Compound ent-1 as well as certain related homochiral and polyfunctionalized cyclohexenes have been prepared from the 1,2-diacetal 4 that is itself readily derived from L-tartaric acid (3). Grignard addition and ring-closing metathesis processes constitute the key steps associated with the reaction sequences involved. This work provides a method for obtaining a range of potentially useful cyclohexenone-containing chirons that are enantiomerically related to those that have been prepared from the homochiral cis-1,2-dihydrocatechol 2, the product of the microbial biotransformation of bromobenzene.

■ Synthesis of Enantioenriched Indolopiperazinones via Iridium(I) N-Heterocyclic Carbene Complex Catalyzed Asymmetric Intramolecular Allylic Amination Reaction

Ke-Yin Ye, Ke-Jia Wu, Guo-Tai Li, Li-Xin Dai, and Shu-Li You*

*State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, 345 Lingling Road, Shanghai 200032, China

Abstract

Systematic study on employing the D-camphor derived carbenes as the chiral ligands in iridium-catalyzed intramolecular allylic amination reaction was carried out. Under mild reaction conditions, enantioenriched indolopiperazinones were obtained in good yields (75-95%) and high enantioselectivity (88-94% ee).

■ Phosphine-Promoted Migrative Cyclization of Sulfonylalkynol and Sulfonylalkynamide for the Synthesis of Oxa- and Azacycles

Yinli Wang, Raphaël Oriez, Shougun Ou, Yasunori Miyakawa, Yousuke Yamaoka, Kiyosei Takasu, and Ken-ichi Yamada*

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

Abstract

A catalytic amount of phosphine or DMAP promoted the migrative cyclization of propargyl sulfones bearing an internal nucleophilic functionality in a γ-umpolung manner.

■ Efficient Synthesis of Fluorine-Containing Dibenzo[b,h][1,6]naphthyridines and Thiochromeno[3,2-c]quinolines Using Highly Chemoselective Nucleophilic Substitution Reaction of 4-Dimethylamino-2-methoxy-3-trifluoroacetylquinoline

Etsuji Okada,* Mizuki Hatakenaka, Yoshinori Takezawa, and Keisuke Iwakuni

*Department of Chemical Science and Engineering, Graduate School of Engineering, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan

Abstract

Aromatic nucleophilic substitution reaction of N,N-dimethyl-2-methoxy-3-trifluoroacetyl-4-quinolylamine with various nucleophiles (NuH) such as amines, thiols, and alcohols proceeded chemoselectively at the 4-position to give the corresponding Me2N-Nu exchanged products. Novel fluorine-containing 6-methoxydibenzo[b,h][1,6]naphthyridines (11) and 6-methoxythiochromeno[3,2-c]quinolines (12) were synthesized in moderate to high yields by the trifluoromethanesulfonic acid catalyzed cyclization of thus obtained N-aryl-2-methoxy-3-trifluoroacetyl-4-quinolylamines (8) and aryl 2-methoxy-3-trifluoroacetyl-4-quinolyl sulfides (9), respectively.