Enantioselective total synthesis of(+)-Hydroxyapparicine, potent antimalarial indole alkaloid.

• Project/Area Number: 22790017
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Chemical pharmacy
• Research Institution: Kitasato University
• Principal Investigator: HIROSE Tomoyasu 北里大学, 大学院・感染制御科学府, 准教授 (00370156)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2011: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2010: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 有機化学 / 天然物 / 抗マラリア活性 / アパリシン類 / ヒドロキシアパリシン / インドールアルカロイド / ワンポットカスケード反応 / 擬アミナール / 不斉全合成

Research Abstract

Hydroxyapparicine was isolated from Tabernaemontana dichotoma in 1984.Then, the relative stereochemistry was proposed that recorded spectral data. However, C15 stereochemistry was not showed. Therefore, absolute stereochemistry of Hydroxyapparicine has never determined. Structure fearture of hydroxyapparicine is 1-azabicyclo[4.2.2] decane and C16 chiral tertiary alchol moiety connected indole 2-position. Moreover, tertiary alchol moiety is unstable under acidic conditions. It was easliy dedydration of similar compound. From synthetic standpiont, synthesis of pseudo-aminal type alkaloids need to novel method under mild conditions. Herein, we repored the stereoselective total synthsis and determination of absolute stereochemistry of 16R-hydroxy-16, 22-dihydroapparicine(Hydroxyapparicine).

Research Products

• [Journal Article] The first total synthesis and reassignment of the relative stereochemistry of 16-hydroxy-16, 22-dihydroapparicine (2012)
  • Author(s): Noguchi, Y.; Hirose, T.; Furuya, Y.; Ishiyama, A.; Otoguro, K.; Omura, S.; Sunazuka, T.
  • Journal Title: Tetrahedron Lett Volume: 53(14) Issue: 14 Pages: 1802-1807
  • DOI: 10.1016/j.tetlet.2012.01.110
  • Peer Reviewed
• [Journal Article] Three-Dimensional Solution Structure of Bottromycin A2: A Potent Antibiotic Active against Methicillin-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci (2012)
  • Author(s): Hiroaki Gouda, Yutaka Kobayashi, Takeshi Yamada, Tetsuya Ideguchi, Akihiro Sugawara, Tomoyasu Hirose, Satoshi Omura, Toshiaki Sunazuka, Shuichi Hirono
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 60 Issue: 2 Pages: 169-171
  • DOI: 10.1248/cpb.60.169
  • NAID: 130001852392
  • ISSN: 0009-2363, 1347-5223
  • Peer Reviewed
• [Journal Article] Solution-phase total synthesis of the hydrophilic natural product argifin using 3,4,5-tris(octadecyloxy)benzyl tag (2011)
  • Author(s): T.Hirose, T.Kasai, T.Akimoto, A.Endo, A.Sugawara, K.Nagasawa, K.Shiomi, S.Omura, T.Sunazuka
  • Journal Title: Tetrahedron Volume: 67 Issue: 35 Pages: 6633-6643
  • DOI: 10.1016/j.tet.2011.05.073
  • NAID: 130006995593
  • Peer Reviewed
• [Journal Article] Novel 12-membered non-antibiotic macrolides from erythromycin A ; EM900 series as novel leads for anti-inflammatory and/or immunomodulatory agents (2011)
  • Author(s): Akihiro Sugawara, Akito Sueki, Tomoyasu Hirose, Kenichiro Nagai, Hiroaki Gouda, Shuichi Hirono, Hideaki Shima, Kiyoko S. Akagawa, Satoshi Omura, Toshiaki Sunazuka
  • Journal Title: Bioorg. Med. Chem. Lett Volume: 21(11) Issue: 11 Pages: 3373-3376
  • DOI: 10.1016/j.bmcl.2011.04.004
  • Peer Reviewed
• [Journal Article] Three-Dimentional Solution Structure of Bottromycin A_2 : A Potent Antibiotic Active against Methicillin-Resistant Staphylococcus aureus and Van comycin-Resistant Enterococci (2011)
  • Author(s): Hiroaki Gouda, et al
  • Journal Title: Chem.Pharm.Bull. Volume: 60 Pages: 169-171
  • Peer Reviewed
• [Journal Article] Bottromycin derivatives efficient chemical modifications of the ester moiety and evaluation of anti-MRSA and anti-VRE activities (2010)
  • Author(s): Yutaka Kobayashi, Maki Ichioka, Tomoyasu Hirose, Kenichiro Nagai, Atsuko Matsumoto, Hidehiro Matsui, Hideaki Hanaki, Rokuro Masuma, Yoko Takahashi, Satoshi Omura and Toshiaki Sunazuka
  • Journal Title: Bioorg. Med. Chem. Lett Volume: Vol.20 Issue: 20 Pages: 6116-6120
  • DOI: 10.1016/j.bmcl.2010.08.037
  • Peer Reviewed
• [Journal Article] NMR spectroscopy and computational analysis of interaction between Serratia marcescens chitinase B and a dipeptide derived from natural-product cyclopentapeptide chitinase inhibitor argifin (2010)
  • Author(s): Hiroaki Gouda, Toshiaki Sunazuka, Tomoyasu Hirose, Kanami Iguchi, Noriyuki Yamaotsu, Akihiro Sugawara, Yoshihiko Noguchi, Yoshifumi Saito, Tsuyoshi Yamamoto, Takeshi Watanabe, Kazuro Shiomi, Satoshi Omura, Shuichi Hirono
  • Journal Title: Bioorg. Med. Chem Volume: 18(16) Issue: 16 Pages: 5835-5844
  • DOI: 10.1016/j.bmc.2010.06.093
  • Peer Reviewed
• [Journal Article] Recent development of two chitinase inhibitors, Argifin and Argadin, produced by soil microorganisms (2010)
  • Author(s): Tomoyasu Hirose, Toshiaki Sunazuka, Satoshi Omura
  • Journal Title: Proceedings of the Japan Academy, Series B Volume: 86 Issue: 2 Pages: 85-102
  • DOI: 10.2183/pjab.86.85
  • NAID: 130000168766
  • ISSN: 0386-2208, 1349-2896
  • Peer Reviewed
• [Journal Article] Recent development of two chitinase inhibitor, Argifin and Argadin, produced by soil microorganisms (2010)
  • Author(s): Tomoyasu Hirose, Toshiaki Sunazuka, Satoshi Omura
  • Journal Title: Proc.Jpn.Acad., Ser.B Volume: 86 Pages: 85-102
  • NAID: 130000168766
  • Peer Reviewed
• [Journal Article] NMR spectroscopy and computational analysis of interaction between Serratia marcescens chitinase B and a dipeptide derived from natural-product cyclopentapeptide chitinase inhibitor argifin (2010)
  • Author(s): Hiroaki Gouda, Toshiaki Sunazuka, Tomoyasu Hirose, Kanami Iguchi, Noriyuki Yamaotsu, Akihiro Sugawara, Yoshihiko Noguchi, Yoshifumi Saito, Tsuyoshi Yamamoto, Takeshi Watanabe, Kazuro Shiomi, Satoshi Omura, Shuichi Hirono
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 18 Pages: 5835-5844
  • Peer Reviewed
• [Journal Article] Bottromycin derivatives ; efficient chemical modifications of the ester moiety and evaluation of anti-MRSA and anti-VRE activities (2010)
  • Author(s): Yutaka Kobayashi, Maki Ichioka, Tomoyasu Hirose, Kenichiro Nagai, Atsuko Matsumoto, Hidehiro Matsui, Hideaki Hanaki, Rokuro Masuma, Yoko Takahashi, Satoshi Omura, Toshiaki Sunazuka
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 20 Pages: 6116-6120
  • Peer Reviewed
• [Presentation] ベンジル系疎水性タグを利用した親水性天然物アージフィンの液相全合成 (2012)
  • Author(s): 廣瀬友靖, 笠井尚子, 秋元隆史, 遠藤綾子, 菅原章公, 長澤和夫, 大村智, 砂塚敏明
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 札幌(北海道大学)
  • Year and Date: 2012-03-31
• [Presentation] 天然物を基にした特異的かつ強力なキチナーゼ阻害剤の創製研究 (2011)
  • Author(s): 廣瀬友靖
  • Organizer: 第55回日本薬学会関東支部大会
  • Place of Presentation: 習志野(東邦大学習志野キャンパス)
  • Year and Date: 2011-10-08
• [Presentation] 天然物を基にした特異的かつ強力なキチナーゼ阻害剤の創製研究 (2011)
  • Author(s): 廣瀬友靖
  • Organizer: 第55回日本薬学会関東支部大会
  • Place of Presentation: 習志野(東邦大学習志野キャンパス)(招待講演)
  • Year and Date: 2011-10-08
• [Presentation] In Situクリックケミストリーを利用した生物活性天然物からの創薬研究 (2011)
  • Author(s): 廣瀬友靖
  • Organizer: 第3回全国利用・共同研究「酵素学拠点」シンポジウム～酵素学から始まる新たな創薬研究～
  • Place of Presentation: 徳島(徳島大学長井記念ホール)
  • Year and Date: 2011-10-03
• [Presentation] In Situクリックケミストリーを利用した生物活性天然物からの創薬研究 (2011)
  • Author(s): 廣瀬友靖
  • Organizer: 第3回全国利用・共同研究「酵素学拠点」シンポジウム
  • Place of Presentation: 徳島(徳島大学長井記念ホール)(招待講演)
  • Year and Date: 2011-10-03
• [Presentation] Type III分泌機構阻害活性を有するGuadinomine類の不斉全合成と絶対立体構造決定 (2011)
  • Author(s): 廣瀬友靖、土屋智史、森龍真、田中利知、小嶋康裕、岩月正人、高橋洋子、大村智、砂塚敏明
  • Organizer: 第4回有機触媒シンポジウム
  • Place of Presentation: 東京(東京理科大学神楽坂キャンパス)
  • Year and Date: 2011-09-17
• [Presentation] 疎水性タグを用いたキチナーゼ阻害剤Argifinの液相全合成 (2011)
  • Author(s): 廣瀬友靖、笠井尚子、秋元隆史、遠藤綾子、菅原章公、長澤和夫、塩見和朗、大村智、砂塚敏明
  • Organizer: 第37回反応と合成の進歩シンポジウム
  • Place of Presentation: 徳島(あわぎんホール)
• [Presentation] Extraction of the active framework from natural argifin and use of in situ click chemistry (2011)
  • Author(s): Tomoyasu Hirose, et al
  • Organizer: 242^<nd> ACS National Meeting
  • Place of Presentation: Denver, Colorado, USA
• [Presentation] Argifinの全合成と高活性キチナーゼ阻害剤の創製研究 (2010)
  • Author(s): 廣瀬友靖
  • Organizer: 第3回日本薬学会関東支部若手シンポジウム
  • Place of Presentation: 東京薬科大学
  • Year and Date: 2010-10-02
• [Presentation] Argifinの全合成と高活性キチナーゼ阻害剤の創製研究 (2010)
  • Author(s): 廣瀬友靖
  • Organizer: 第3回 日本薬学会関東支部若手シンポジウム
  • Place of Presentation: 東京薬科大学
  • Year and Date: 2010-10-02
• [Presentation] Chitinase inhibitors : Extraction of the active framework from natural argifin and use of in situ click chemistry (2001)
  • Author(s): Tomoyasu Hirose, Akihiro Sugawara, Ayako Endo, Tsuyoshi Yamamoto, Kzuro Shiomi, Takeshi Watanabe, K. Barry Sharpless, Satoshi Omura, Toshiaki Sunazuka
  • Organizer: 242nd American Chemical Society National Meeting
  • Place of Presentation: Denver, Colorado, USA
• [Remarks]
  • URL: http://seibutuyuuki.sakura.ne.jp/index.html