Synthetic Strategy for Construction of Unique Polycyclic Indole Alkaloids by cascade reactions

• Project/Area Number: 25460020
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Chemical pharmacy
• Research Institution: Kitasato University
• Principal Investigator: Sunazuka Toshiaki 北里大学, 感染制御科学府, 教授 (30226592)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥260,000 (Direct Cost: ¥200,000、Indirect Cost: ¥60,000); Fiscal Year 2014: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2013: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: インドール / 多環式含窒素化合物 / 生理活性天然物 / カスケード / 抗トリパノソーマ / ネオキサリン / マジンドリン / インドリン / 特異構造 / カスケード反応 / グラムスケール / 細胞周期阻害 / スピロアミナール / 抗マラリア活性 / 抗トリパノソーマ活性

Outline of Final Research Achievements

The total synthesis of the indole alkaloids, neoxaline, oxaline and meleagrin A, all containing a unique indoline spiroaminal framework, was accomplished through the stereoselective introduction of a reverse prenyl group to the congested benzylic carbon of furoindoline, a two-pot transformation of indoline (containing three nitrogen atoms at appropriate positions) to the featured indoline spiroaminal framework, and elimination of carbonate assisted by the adjacent imidazole moiety to construct the (E)-dehydrohistidine. The absolute stereochemistry of neoxaline was elucidated
through our total synthesis. In addition, we evaluated the bioactivity, especially the anti-infectious properties, of neoxaline and oxaline, and of some synthetic intermediates.

Research Products

• [Journal Article] Towards the total synthesis of the anti-trypanosomal macrolide, Actinoallolides; construction of a key linear intermediate (2016)
  • Author(s): Jun Oshita, Yoshihiko Noguchi, Akito Watanabe, Goh Sennari, Shogo Sato, Tomoyasu Hirose, Daiki Oikawa, Yuki Inahashi, Masato Iwatsuki, Aki Ishiyama, Satoshi Omura and Toshiaki Sunazuka
  • Journal Title: Tetrahedron Lett. Volume: 57 Pages: 357-360
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Asymmetric Total Synthesis of Indole Alkaloids Containing An Indoline Spiroaminal Framework (2015)
  • Author(s): Takeshi Yamada, Tetsuya Ideguchi-Matsushita, Tomoyasu Hirose, Tatsuya Shirahata, Rei Hokari, Aki Ishiyama, Masato Iwatsuki, Akihiro Sugawara, Yoshinori Kobayashi, Kazuhiko Otoguro, Satoshi Omura and Toshiaki Sunazuka
  • Journal Title: Chem. E. J. Volume: 21 Pages: 11855-11864
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Creation of customised bioactivity within a 14-membered macrolide scaffold: design, synthesis, and biological evaluation using a family-18 chitinase. (2015)
  • Author(s): Akihiro Sugawara, Nobuo Maita, Hiroaki Gouda, Tsuyoshi Yamamoto, Tomoyasu Hirose, Saori Kimura, Yoshifumi Saito, Hayato Nakano, Takako Kasai, Hirofumi Nakano, Kazuro Shiomi, Shuichi Hirono, Takeshi Watanabe, Hisaaki Taniguchi, Satoshi Omura and Toshiaki Sunazuka
  • Journal Title: J. Med. Chem. Volume: 58 Pages: 4984-4997
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Jietacins with potent nematocidal activity; efficient isolation of novel analogues and divergent total synthesis of jietacin A, B, C, and D (2015)
  • Author(s): 4) Akihiro Sugawara, Masahiko Kubo, Takuji Nakashima, Tomoyasu Hirose, Noriaki Tsunoda, Kyoichi Yahagi, Yukihiro Asami, Takeshi Yamada, Kazuro Shiomi, Yoko Takahashi, Satoshi Omura, Toshiaki Sunazuka
  • Journal Title: Tetrahedron Volume: 71 Issue: 14 Pages: 2149-2157
  • DOI: 10.1016/j.tet.2015.02.038
  • Peer Reviewed
• [Journal Article] An architectonic macrolide library based on a C2-symmetric macrodiolide toward pharmaceutical compositions. (2015)
  • Author(s): Hayato Nakano, Akihiro Sugawara, Tomoyasu Hirose, Hiroaki Gouda, Shuichi Hirono, Satoshi Omura and Toshiaki Sunazuka
  • Journal Title: Tetrahedron Volume: 71 Issue: 37 Pages: 000-000
  • DOI: 10.1016/j.tet.2015.01.030
  • Peer Reviewed
• [Journal Article] Organocatalytic α-Addition of Isocyanides to Aldehydes (2015)
  • Author(s): Takeshi Yamada, Tomoyasu Hirose, Satoshi Omura and Toshiaki Sunazuka
  • Journal Title: Eur. J. Org. Chem. Volume: 2015 Issue: 2 Pages: 296-301
  • DOI: 10.1002/ejoc.201403313
  • Peer Reviewed
• [Journal Article] Leucomycin A3, a 16-membered macrolide antibiotic, inhibits influenza A virus infection and disease progression (2014)
  • Author(s): Ryuichi Sugamata, Akihiro Sugawara, Tomokazu Nagao, Koya Suzuki, Tomoyasu Hirose, Ki-ichi Yamamoto, Masamichi Oshima, Kazuo Kobayashi, Toshiaki Sunazuka, Kiyoko S Akagawa, Satoshi Omura, Toshinori Nakayama, Kazuo Suzuki
  • Journal Title: J Antibiot Volume: 67 Pages: 213-222
  • Peer Reviewed
• [Journal Article] Borrelidin analogues with antimalarial activity: design, synthesis and biological evaluation against Plasmodium falciparum parasites (2013)
  • Author(s): Akihiro Sugawara, Toshiaki Tanaka, Tomoyasu Hirose, Aki Ishiyama, Masato Iwatsuki, Yoko Takahashi, Kazuhiko Otoguro, Satoshi Omura, Toshiaki Sunazuka
  • Journal Title: Bioorg Med Chem Lett Volume: 23 Issue: 8 Pages: 2302-2305
  • DOI: 10.1016/j.bmcl.2013.02.075
  • Peer Reviewed
• [Journal Article] Human acidic mammalian chitinase as a novel target for anti-asthma drug design using in silico screening (2013)
  • Author(s): Masaki Wakasugi, Hiroaki Gouda, Tomoyasu Hirose, Akihiro Sugawara, Tsuyoshi Yamamoto, Kazuro Shiomi, Toshiaki Sunazuka, Satoshi Omura, Shuichi Hirono
  • Journal Title: Bioorg Med Chem Volume: 21 Issue: 11 Pages: 3214-3220
  • DOI: 10.1016/j.bmc.2013.03.047
  • Peer Reviewed
• [Journal Article] Asymmetric total synthesis of neoxaline (2013)
  • Author(s): Tetsuya Ideguchi, Takeshi Yamada, Tatsuya Shirahata, Tomoyasu Hirose, Akihiro Sugawara, Yoshinori Kobayashi, Satoshi Omura, Toshiaki Sunazuka
  • Journal Title: J Am Chem Soc Volume: 135 Issue: 34 Pages: 12568-12571
  • DOI: 10.1021/ja406657v
  • Peer Reviewed
• [Journal Article] Observation of the controlled assembly of preclick components in the in situ click chemistry generation of a chitinase inhibitor (2013)
  • Author(s): Hirose T, Maita N, Taniguchi H, Sharpless KB, Omura S, Sunazuka T
  • Journal Title: Proc.Natl.Acad.Sci. USA. Volume: 110 Issue: 40 Pages: 15892-15897
  • DOI: 10.1073/pnas.1315049110
  • Peer Reviewed
• [Presentation] Drug discovery based on microbial bioactive natural products (2015)
  • Author(s): Toshiaki Sunazuka, and Satoshi Omura
  • Organizer: Pacifichem 2015
  • Place of Presentation: Hawaii, USA
  • Year and Date: 2015-12-15
  • Int'l Joint Research / Invited
• [Presentation] Total Synthesis of Unique Polycyclic Bioactive Natural Products- Failure Leads to Success - (2015)
  • Author(s): Toshiaki Sunazuka
  • Organizer: Symposium in Honor of Professor Amos B. Smith, III; The Recipient of the 2015 Allan R. Day Award
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2015-10-17
  • Int'l Joint Research / Invited
• [Presentation] Total Synthesis of Novel Polycyclic Biological Active Indole Alkaloids (2015)
  • Author(s): Toshiaki Sunazuka
  • Organizer: The 6th Japanese-Sino Symposium on Organic Chemistr
  • Place of Presentation: Akiu Resort Hotel Crescent, Sendai
  • Year and Date: 2015-09-07
  • Int'l Joint Research / Invited
• [Presentation] 天然有機化合物の魅力を引き出す有機合成化学の醍醐味 (2015)
  • Author(s): 砂塚敏明
  • Organizer: 日本化学会関東支部群馬地区講演会
  • Place of Presentation: 群馬大学（群馬県桐生市）
  • Year and Date: 2015-07-07
  • Invited
• [Presentation] Total synthesis of unique polycyclic bioactive indole alkaloids (2015)
  • Author(s): Toshiaki Sunazuka
  • Organizer: 16th Tetrahedron Symposium, Grand Hyatt Berlin, Germany
  • Place of Presentation: Berlin, Germany
  • Year and Date: 2015-06-16
  • Int'l Joint Research / Invited
• [Presentation] Practical synthesis of bioactive natural products using organocatalysts (2014)
  • Author(s): Toshiaki Sunazuka
  • Organizer: 第2回 国際会議(兼)第7回 有機触媒シンポジウム
  • Place of Presentation: 東大（東京）
  • Year and Date: 2014-11-21 – 2014-11-22
  • Invited
• [Presentation] 天然有機化合物を基盤とした新しい創薬研究 (2014)
  • Author(s): 砂塚敏明
  • Organizer: 第29回 農薬デザイン研究会
  • Place of Presentation: ホテルニューアカオ（熱海）
  • Year and Date: 2014-11-06 – 2014-11-07
  • Invited
• [Presentation] Harmonization between natural products and organic synthesis for drug discovery (2014)
  • Author(s): Toshiaki Sunazuka
  • Organizer: International Conference on Advances in Engineering, Technology and science 2014
  • Place of Presentation: China, Beijing
  • Year and Date: 2014-06-02 – 2014-06-03
  • Invited
• [Presentation] Practical Synthesis of Bioactive Natural products by Organocatalysts (2013)
  • Author(s): Toshiaki Sunazuka
  • Organizer: 新学術領域（有機触媒）第４回公開シンポジウム
  • Place of Presentation: 滋賀県
  • Invited
• [Presentation] Total Synthesis of Novel Polycyclic Bioactive Natural Products (2013)
  • Author(s): Toshiaki Sunazuka
  • Organizer: Total Synthesis of Novel Polycyclic Bioactive Natural Products
  • Place of Presentation: アメリカ、ボストン
  • Invited
• [Presentation] マクロライド骨格をテンプレートとした新規キチナーゼ阻害剤の創製 (2013)
  • Author(s): 菅原章公、廣瀬友靖、大村智、砂塚敏明
  • Organizer: 新学術領域第４回公開シンポジウム
  • Place of Presentation: 茨城県
• [Presentation] マクロライド骨格をテンプレートとした新規キチナーゼ阻害剤の創製 (2013)
  • Author(s): 菅原章公、真板宣夫、廣瀬友靖、木村紗穂莉、斉藤佳史、井上浄、山本剛、渡 邉剛志、塩見和朗、中野洋文、谷口寿章、大村智、砂塚敏明
  • Organizer: 日本ケミカルバイオロジー学会第８回年会
  • Place of Presentation: 東京都
• [Presentation] マクロライド骨格をテンプレートとした新規キチナーゼ阻害剤の創製 (2013)
  • Author(s): 菅原章公、 真板宣夫、廣瀬友靖、合田浩明、木村紗穂莉、斉藤佳史、井上浄、山本剛、渡邉剛志、塩見和朗、中野洋文、広野修一、谷口寿章、大村智、砂塚 敏明
  • Organizer: 第５５回天然有機化合物討論会
  • Place of Presentation: 京都府
• [Remarks] 北里大学北里生命科学研究所・大学院感染制御科学府 生物有機化学研究室
  • URL: http://seibutuyuuki.sakura.ne.jp/
• [Remarks] http://seibutuyuuki.sakura.ne.jp
• [Remarks] 北里大学北里生命科学研究所、大学院感染制御科学府 生物有機化学研究室
  • URL: http://seibutuyuuki.sakura.ne.jp