HETEROCYCLES

■ Contents

■ Preface to Heterocycles Issue Honoring the 70th Birthday of Professor Tohru Fukuyama

Satoshi Yokoshima*

*Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8601, Japan

■ Curriculum Vitae

Tohru Fukuyama*

*

■ Publication List by Tohru Fukuyama

Tohru Fukuyama*

*

■ Design and Synthesis of Artificial Ladder-Shaped Polyethers for Exploring Biological Functions

Tohru Oishi*

*Department of Chemistry, Faculty of Science, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan

Abstract

Ladder-shaped polyethers (LSPs) are marine natural products produced by dinoflagellates. The unique molecular structure and interesting biological activities have attracted considerable attention of the synthetic community. On the other hand, artificial ladder-shaped polyethers (ALPs) have been designed and synthesized for exploring biological functions. In this review, design and synthesis of ALPs are summarized focusing on the development of synthetic strategies and methodologies.

■ Chemistry of Nitroaziridines

Feiyue Hao and Nagatoshi Nishiwaki*

*School of Environmental Science and Engineering, Kochi University of Technology, Tosayamada-cho, Kami, Kochi, 782-8502, Japan

Abstract

This review article introduced synthetic procedures for the preparation of structurally diverse nitroaziridines. In addition, this article also summarized reactivity of nitroaziridines caused by the inherent strain and high electrophilicity of the small ring. These properties facilitate their use as a functionalized building blocks in synthetic and medicinal chemistry.

■ Renovation of Glycomolecules for Molecular Imaging Studies: Low-Affinity Glycan Ligands can be Used for Selective Cell Imaging?

Shogo Nomura and Katsunori Tanaka*

*Biofunctional Synthetic Chemistry Laboratory, Cluster for Pioneering Research, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan

Abstract

Since the interaction of single molecule of glycans is very weak to the lectins, in most cases they have been formed into clusters for binding studies. Then, a glycan molecule cannot be used for efficient cell imaging or targeting? We established a new strategy to selectively image the cells by using synergistic interaction of peptide and glycan ligands on cell surface. Namely, the peptide ligand with high affinity to the target surface receptor was pretargeted, and then the low-affinity glycan ligand with fluorescent label was interacted to the same cell; Bioorthogonal reaction between them can anchor the label on the target cells when both receptors are expressed and close in space on the surface. When the lectin is not expressed on the target or two receptors are separated, the weakly interacting glycan ligands are washed away the cells, hence the target cells are selectively imaged. While new idea and proof-of-concept data were exemplified based on our previous research, using this strategy, we would like to report the new data to visualize cell surface dynamics in response to the treatment with bioactive compounds.

■ Synthesis of Orthogonally Protected Actinoidic Acid Trimethyl Ether

Yusuke Amino* and Robert M. Williams*

*Department of Chemistry, Colorado State University, 301 West Pitkin Street, 80523, U.S.A.

Abstract

We describe the asymmetric synthesis of actinoidic acid trimethyl ether with orthogonal protecting groups on the respective amino and carboxyl groups. The Stille biaryl coupling reaction of suitably functionalized aryl bromide and (trimethylstannyl)benzaldehyde gave the key intermediate biaryl aldehyde. Synthesis was accomplished by applying the asymmetric Strecker reaction to this aldehyde, followed by selectively removing the chiral auxiliary. By comparing its 1H-NMR spectra with those obtained from vancomycin, the stereochemistry of the synthesized diastereoisomer of actinoidic acid trimethyl ether was confirmed as an atropisomer of the (αS,α′R)-isomer.

■ Diastereoselective Synthesis of 5-Iodoalkenyl-2-oxazolines by Electrophilic Cyclization of Allenyl Amides

Tsukasa Hirokane, Ayaka Kawakami, Kenji Matsumoto, and Masahiro Yoshida*

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

Abstract

The electrophilic cyclization of allenyl amides is described. Allenyl amides were easily prepared from the propargyl aziridines via the [1,5]-hydrogen shift followed by the conversion of the imine moiety to the amides. 5-Iodoalkenyl-2-oxazolines having a variety of substituents were diastereoselectively obtained by the reaction of the allenyl amides with iodine.

■ An Efficient Silver Tetrafluoroborate-Catalyzed Cycloisomerization of Ynamides

Winai Ieawsuwan* and Somsak Ruchirawat

*Chulabhorn Research Institute, Laboratory of Medicinal Chemistry, 54 Kamphaeng Phet 6 Road, Laksi, Bangkok 10210, Thailand

Abstract

A silver catalyzed-cycloisomerization of N-Boc protected ynamides has been developed under mild reaction conditions to provide a wide range of oxazol-2(3H)-ones in good to excellent yields. Moreover, the acid-promoted Pictet-Spengler cyclization of oxazol-2(3H)-ones was described to furnish the corresponding trans-oxazolidones in moderate yields.

■ Total Synthesis of (–)-Zephyranthine

Koki Ishii, Yuna Seki-Yoritate, Mizuki Ishibashi, Ming Wai Liaw, Takeshi Oishi, Takaaki Sato,* and Noritaka Chida*

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

Abstract

Stereoselective total synthesis of (–)-zephyranthine 1 based on the chiral pool approach starting from D-arabinose is described. The three consecutive chiral centers in (–)-zephyranthine were effectively constructed by the sequential [3,3] sigmatropic rearrangements (Claisen, Overman, and Claisen rearrangements) with chirality transfer of the hydroxy groups in D-arabinose.

■ One-Step Synthesis of 4H-3,1-Benzoxazin-4-ones from Weinreb Amides and 1,4,2-Dioxazol-5-ones via Cobalt-Catalyzed C–H Bond Activation

Iku Tanimoto, Kentaro Kawai, Akane Sato, Tatsuhiko Yoshino,* and Shigeki Matsunaga*

*Faculty of Pharmaceutical Sciences, Hokkaido University, Kiat12, Nishi 6, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan

Abstract

A one-step synthesis of 4H-3,1-benzoxazin-4-ones from readily available Weinreb amides and 1,4,2-dioxazol-5-ones under Cp*Co(III) catalysis is described. The reactions proceeded in moderate to good yields with high functional group compatibility.

■ Acetal Elimination Reaction Accompanied with Regioselective Ring Opening of 1,4-Bisacetal-1,4-epoxy-1,4-dihydronaphthalenes

Yoshinari Sawama,* Takahiro Kawajiri, Yuta Yamamoto, Yuko Shishido, Ryota Goto, and Hironao Sajiki*

*Laboratory of Organic Chemistry, Gifu Pharmaceutical University 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan

Abstract

1,4-Epoxy-1,4-dihydronaphthalenes are useful precursors to synthesize 1-naphthols by an acid-catalyzed ring opening of their 1,4-epoxy moieties. 1-Acetal-substituted 1,4-epoxy-1,4-dihydronaphthalene was also converted to 1-naphthol via the unique iron-catalyzed ring opening of the 1,4-epoxy moiety followed by the elimination of the acetal moiety. The present method could be applied to the regioselective syntheses of highly-functionalized 4-formyl-1-naphthols from the unsymmetrical 1,4-bisacetal-substituted 1,4-epoxy-1,4-dihydronaphthalenes.

■ A Novel Rearrangement Reaction of Morphinan to Arylmorphan Skeletons and the Pharmacologies of Arylmorphan Derivatives

Masahiro Yata, Noriki Kutsumura, Yasuyuki Nagumo, Naoshi Yamamoto, Tsuyoshi Saitoh, Yukiko Ishikawa, Yoko Irukayama-Tomobe, Masashi Yanagisawa, and Hiroshi Nagase*

*International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan

Abstract

A novel rearrangement reaction of the morphinan skeleton by using zinc iodide was developed. The substrate-specific rearrangement afforded two types of novel 5-arylmorphan derivatives, i.e., compounds produced by either a 1,5-shift of the nitrogen bridge or a 1,3-shift of the nitrogen bridge in a starting morphinan derivative. The 5-arylmorphan derivatives showed selective κ opioid receptor activities even though many 5-arylmorphan compounds reported previously have shown selective µ opioid receptor activities. In addition, other related 5-arylmorphan derivatives showed potent dual antagonistic activities toward orexin 1 and 2 receptors.

■ CsF-Promoted Desilylation and Ring-Contraction Reaction of Electron-Deficient 3-Silyl-2H-chromenes to 2-Benzylbenzofurans

Kenta Tanaka, Mayumi Sukekawa, Mami Kishimoto, Yujiro Hoshino, and Kiyoshi Honda*

*Graduate School of Environment and Infomation Science, Yokohama National University, Tokiwadai 156, Hodogaya-ku, Yokohama 240-8501, Japan

Abstract

The ring-contraction reaction of electron-deficient 3-silyl-2H-chromenes to 2-benzylbenzofurans under mild conditions was developed. CsF efficiently promoted the reaction at room temperature or 80 ºC to afford a variety of 2-benzylbenzofurans in good yields. 3-Silyl-2H-chromenes having strong electron-withdrawing groups smoothly afforded the desired products. The reaction is proposed to proceed through an allenyl intermediate or dyotropic rearrangement.

■ Synthesis and Cytotoxicity of Novel Bis-Ellipticines and Bis-Isoellipticines

Judy A. Obaza-Nutaitis and Gordon W. Gribble*

*6128 Burke Laboratory, Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, U.S.A.

Abstract

A series of bis-ellipticines 7–9 and bis-isoellipticines 10–12 tethered through the indole nitrogen was synthesized and screened for antitumor cytotoxicity in the L-1210 murine leukemia assay. Activity was only displayed by 1,10-bis(6-ellipticinyl)-n-decane (8).

■ Stereodivergent and Stereoselective Synthesis of cis- and trans-4-Substituted Prolinols

Junki Ando, Aoi Tazawa, Kohei Ishizawa, Minoru Tanaka,* and Hiroyoshi Takamura*

*Department of Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Okayama 700-8530, Japan

Abstract

Stereoselective synthesis of 4-substituted prolinol derivatives has been developed. Thus, Suzuki–Miyaura cross-coupling of vinyl triflate provided the common synthetic intermediates toward the stereodivergent synthesis of cis- and trans-4-substituted prolinols. These two kinds of target compounds were obtained by diastereoselective hydrogenation of the coupling products with Pd/C and Crabtree catalyst, respectively. In addition, the obtained 4-substituted prolinol was transformed to the corresponding proline derivative via oxidation in one step.

■ Efficient Synthesis of O-Linked Glycoconjugates of Amino Acids from Carbohydrate-Derived Donor-Acceptor Cyclopropanes

Gade Kishore, Vibha Gautam, Shrutisagar Dattatraya Haveli, and Srinivasan Chandrasekaran*

*Department of Organic Chemistry, Indian Institute of Science, Bangalore-560 012, India

Abstract

N-Iodosuccinimide (NIS) mediated ring opening of carbohydrate-derived donor-acceptor-cyclopropanes with free “CO2H” group of N-protected L-amino acids at ambient conditions afforded iodo derivatives of glycosyl ester of L-amino acids. The iodides were subsequently converted easily into corresponding azides using NaN3 in DMF followed by reduction with Zn/AcOH to produce ester linked glycosyl amino acids. A similar strategy was adopted to synthesize C-linked glycoamino acid derivatives from different N-protected L-amino alcohols. By using an orthogonal strategy C- and O-linked glycopeptides were also synthesized.

■ New Indole Alkaloids from Ervatamia cumingiana

Mariko Kitajima, Shumpei Nakano, Noriyuki Kogure, Sanan Subhadhirasakul, and Hiromitsu Takayama*

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

Abstract

Two new Iboga-vobasine-type bisindole alkaloids N-demethylervahanine A (1) and N-demethylervahanine B (2) and one new chippiine-type alkaloid 3-O-methyl-10,11-demethoxychippiine (3) were isolated from the roots of Ervatamia cumingiana collected in Thailand. Their chemical structures were determined by spectroscopic analyses. Compounds 1 and 2 are bisindole alkaloids having a linkage between C-3 in the vobasine unit and C-11' or C-10' in the Iboga unit, respectively.

■ Exploration of Moderate Conditions and Substrate Variation in the Direct Condensation between Phthalide and Primary Amine Catalyzed by GaCl3. Are Aliphatic Amines Less Reactive than Aromatic Ones?

Ichiro Takahashi,* Yoshinori Nishiwaki, Kenta Saitoh, Takatoshi Matsunaga, Akihiro Aratake, Toshio Morita, and Shinzo Hosoi

*Department of Applied Chemistry and Biotechnology, Faculty of Engineering, University of Fukui, 9-1 Bunkyo 3-chome, Fukui-shi, 910-8507, Japan

Abstract

Direct condensation between phthalide and a primary amine in the presence of Lewis acid was achieved for the first time in organic solvent-diluted reaction systems catalyzed by GaCl3. The peripheral aspects of this reaction is discussed.

■ Structure–Activity Relationship Study of Gatastatin Based on the Topliss Tree Approach

Ichiro Hayakawa,* Shuya Shioda, Takumi Chinen, Takeo Usui, and Hideo Kigoshi*

*Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Okayama 700-8530, Japan

Abstract

Various analogues of gatastatin, a γ-tubulin-specific inhibitor, were designed and synthesized by systematically optimizing the aromatic ring at the O7-benzyl group in accordance with an operational Topliss tree, and their biological activities were evaluated. Some derivatives showed stronger cytotoxicity against HeLa cells than gatastatin. Especially, the cytotoxicity of the meta-chloro derivative was about 18-fold stronger than that of gatastatin. However, these derivatives did not exhibit binding ability to the yeast γ-tubulin small complex or inhibitory activity against α,β-tubulin polymerization. These results suggested that γ-tubulin strongly recognized the unsubstituted phenyl ring of the O7-benzyl group in gatastatin.

■ Indium Mediated Allylation of N-tert-Butanesulfinyl Imines with 1,3-Dibromopropene: Stereoselective Synthesis of Aziridines

Edgar Maciá, Francisco Foubelo,* and Miguel Yus*

*Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99 03080 Alicante, Spain

Abstract

The reaction of N-tert-butanesulfinyl imines 1 with 1,3-dibromopropene (2), in the presence of indium metal, in saturated aqueous solution of sodium bromide, produced bromohomoallylamine derivatives 3 with total facial diastereoselectivity for the imine addition, and moderate yields. These compounds were easily transformed into the corresponding vinyl aziridines 5 upon deprotonation with KHMDS in THF, the intramolecular cyclization taking place in a stereospecific manner in moderate to high yields.

■ Diastereoselective Synthesis of Poly-Substituted syn-Imidazolidine-2-thiones via Microwave-Assisted Three-Component [2+2+1] Heterocyclizations

Jie-Yu Hu, Yi-Yun Gao, Wen-Wen Zhang, Ke-Ying Zhang, Wen-Lian Li, Wen-Juan Hao,* Bo Jiang, and Guigen Li*

*Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, U.S.A.

Abstract

An efficient and simple three-component reaction of arylglyoxals, isothiocyanates and arylamines has been developed, delivering poly-substituted syn-imidazolidine-2-thione derivatives with high diastereo- and regioselectivity (up to > 99:1). The microwave-assisted transformation is easy to perform simply by mixing readily available starting materials, thereby featuring mild reaction conditions, bond-forming efficiency and atom-economy.

■ Palladium-Catalyzed Arylation of N-Aminoimidazol-2-ones towards Synthesis of Constrained Phenylalanine Dipeptide Mimics

Julien Poupart, Ngoc-Duc Doan, Damien Bérubé, Yousra Hamdane, Caleb Medena, and William D. Lubell*

*Département de chimie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Québec H3C3J7, Canada.

Abstract

N-Aminoimidazol-2-ones (e.g., 6) offer potential to serve as constrained amino amide components that can induce turn conformation in peptide sequences. To add side chain functionality onto this amino amide surrogate, mild conditions have now been developed for palladium-catalyzed arylation of N-aminoimidazol-2-ones. A diverse array of aryl iodides reacted at the 5-position of N-aminoimidazol-2-one dipeptides 7 and 10 in a general approach for making constrained arylalanine dipeptide turn mimics (e.g., 8 and 11).

■ Computational Studies on the Racemization Barriers of Winding Vine-Shaped Heterobiaryls with Molecular Asymmetry

Atsunori Mori,* Shiomi Ashida, Yukiko Ito, Jiaqiang Cheng, Toyoko Suzuki, Kentaro Okano, and Takayoshi Hashimoto

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

Abstract

DFT calculation studies were performed for the estimation of racemization barrier of winding vine-shaped heterobiaryls showing molecular asymmetry. The calculated value showed good agreement compared with that derived from experimental studies. Effects of hetroaromatic structure, carbon-carbon double bond at the winding-vine moiety, substituent at the double bond, and substituent at the heteroaromatic rings were studied.

■ Four-Component Coupling Strategy for 2,3,4-Trisubstituted 3,4-Dihydroquinoline

Hiroki Yamagishi, Shun Tsuchiya, Hayate Saito, Keisuke Nogi, Jun Shimokawa, and Hideki Yorimitsu*

*Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan

Abstract

Trimethylsilyllithium attacked selectively at the 4-position of 2-(methylsulfanyl)quinoline. The lithium enamide intermediate generated in situ reacted with a series of electrophiles to introduce a substituent at the 3-position of the dihydroquinoline skeleton. Combined with the conversion of the 2-methylsulfanyl group to an aryl group via palladium-catalyzed Negishi-type coupling reaction, the net four-component coupling transformation in two steps provided a 2,3,4-trisubstituted 3,4-dihydroquinoline skeleton.

■ Synthetic Studies on Plakinidines

Takahito Satoh, Touma Adachi, Kentaro Okano, Juri Sakata, and Hidetoshi Tokuyama*

*Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan

Abstract

Synthetic studies on plakinidines are described. As a model study for the construction of the dihydropyridone ring at the final stage of the synthesis, we investigated a Meyer–Schuster rearrangement/aza-Michael cyclization cascade. The B,C,D,E ring system possessing a pyrrolo[2,3,4-kl]acridine structure was constructed via a benzyne-mediated cyclization/functionalization sequence that involved the formation of a β,β-diarylethylamine derivative and a palladium-catalyzed double aryl amination of a 3-arylindoline intermediate as key processes.

■ Heterosubstituted 4-Vinylimidazoles – Preparation and Diels-Alder Reactions

Abhisek Ray, Sabuj Mukherjee, Jayanta Das, Manoj Bhandari, Apsara Herath, Muhammed Yousufuddin, and Carl J. Lovely*

*Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, Texas 76019-0065, USA.

Abstract

The Diels-Alder reactions of vinylimidazole derivatives provide an expedient stereocontrolled entry into polysubstituted tetrahydrobenzimidazole derivatives. Prior studies from our group have described methods for postcycloaddition functionalization of these adducts, however, in several cases we have been unable to achieve appropriate elaboration of cycloadducts and have sought alternatives. To circumvent this problem we have investigated pre-cycloaddition functionalization through the preparation of vinyl-substituted derivatives. Initial studies with vinyl halides or silyl enol ethers were compromised either by poor yields or postcycloaddition elimination. However, vinylsilanes and vinylstannanes participate in Diels-Alder reactions with retention of the heterosubstituent and provide a means for further elaboration, for example through Fleming-Tamao oxidation.

■ Arylboronic Acid-Mediated Glycosylation of 1,2-Dihydroxyglucoses

Sanae Izumi, Yusuke Kobayashi, and Yoshiji Takemoto*

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

Abstract

We explored direct dehydrative coupling of tetrahydro-2H-pyran-2,3-diol or a 1,2-dihydroxy sugar with various alcohols using a range of arylboronic acids. Among the catalysts, 2-borono-4-trifluoromethylbenzoic acid efficiently promoted acetalization of tetrahydro-2H-pyran-2,3-diol. Ferroceniumboronic acid showed the best catalytic activity for glycosylation of the 1,2-dihydroxy sugar. The major products were 1,2-cis-α-D-glucopyranosides.

■ Synthesis of γ-Difluoromethylated Tetronate Derivatives from Squarates Using Difluoromethylphosphonate

Yoshihiko Yamamoto,* Yuki Ishida, Takashi Kurohara, Masatoshi Shibuya, and Takeshi Yasui

*Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8601, Japan

Abstract

A new method for the synthesis of γ-difluoromethylated tetronates was developed using diethyl difluoromethylphosphonate as a difluoromethyl (CF2H) surrogate. The addition of a lithiated difluoromethylphosphonate to (semi)squarates at –90 °C afforded 4-hydroxycyclobutenones, which were converted into the corresponding tetronates by oxidative ring expansion using Pb(OAc)4. The final dephosphorylation was performed in MeOH using Cs2CO3 as the base, affording the desired γ-difluoromethyltetronates.