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Studies on the Comprehensive Syntheses of Erythrina Alkaloids for Medical Research of Central Nervous System

Research Project

Project/Area Number 15H05641
Research Category

Grant-in-Aid for Young Scientists (A)

Allocation TypeSingle-year Grants
Research Field Chemical pharmacy
Research InstitutionKyoto University (2016-2018)
Nagoya University (2015)

Principal Investigator

Shimokawa Jun  京都大学, 理学研究科, 准教授 (60431889)

Research Collaborator Fukuyama Tohru  
Kitamura Masato  
Project Period (FY) 2015-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥24,180,000 (Direct Cost: ¥18,600,000、Indirect Cost: ¥5,580,000)
Fiscal Year 2017: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
Fiscal Year 2016: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
Fiscal Year 2015: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
Keywordsエリスリナアルカロイド / 天然物全合成 / ニコチン性アセチルコリン受容体 / 多分化能性合成中間体 / 全合成 / 一重項酸素 / 天然物合成化学 / 多様性志向型合成 / 天然物合成 / 光反応 / 多様性指向型合成
Outline of Final Research Achievements

Erythrina alkaloids are a group of compounds with a 4-ring structure centered on the spiroamine structure, and are expected to have physiological activity as nicotinic acetylcholine receptor (nAChR) antagonists. Many natural analogs with similar structures are known, each of which has a different partial skeleton with different oxidation states. The authors designed a synthetic late-stage pluripotent intermediate capable of synthesizing these comprehensively, and synthesized it independently by utilizing axial stereochemistry of a medium-membered ring and singlet oxygen oxidation. Asymmetric synthesis of four erythrina alkaloids was achieved for the first time by subsequent conversion. Structural developments have established the basis for the development of new nAChR antagonists.

Academic Significance and Societal Importance of the Research Achievements

学術的な意義としては、まず合成後期中間体の具体的な設計指針を提示し、実際にそこから多様な類縁体化合物を合成してみたこと。また中間体の中員環化合物において非常に興味深い異性化現象を発見し、それを実際の化学合成に応用したことが挙げられる。
社会的な意義としてはにはニコチン性アセチルコリン受容体アンタゴニストとして知られるエリスリナアルカロイドについてその一般的な合成法を示すことで、今後サブタイプ選択的アンタゴニストの開発が可能になりうるため、サブタイプの機能の違いやその知見をもとにした新薬の開発などが期待できるようになったことが挙げられる。

Report

(4 results)
  • 2018 Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • Research Products

    (18 results)

All 2019 2018 2017 2016 2015

All Journal Article (10 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 8 results,  Open Access: 1 results) Presentation (8 results) (of which Int'l Joint Research: 4 results,  Invited: 3 results)

  • [Journal Article] Synthesis of the core structure of phalarine2019

    • Author(s)
      Douki Kazuya、Shimokawa Jun、Kitamura Masato
    • Journal Title

      Organic & Biomolecular Chemistry

      Volume: 17 Issue: 7 Pages: 1727-1730

    • DOI

      10.1039/c8ob02320d

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Four-Component Coupling Strategy for 2,3,4-Trisubstituted 3,4-Dihydroquinoline2019

    • Author(s)
      Yorimitsu Hideki、Yamagishi Hiroki、Tsuchiya Shun、Saito Hayate、Nogi Keisuke、Shimokawa Jun
    • Journal Title

      HETEROCYCLES

      Volume: 99 Issue: 1 Pages: 301-301

    • DOI

      10.3987/com-18-s(f)24

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Synthetic Studies on Heteropolycyclic Natural Products: Development of Divergent Strategy2018

    • Author(s)
      Shimokawa Jun
    • Journal Title

      Chemical and Pharmaceutical Bulletin

      Volume: 66 Issue: 2 Pages: 105-115

    • DOI

      10.1248/cpb.c17-00819

    • NAID

      130006328172

    • ISSN
      0009-2363, 1347-5223
    • Related Report
      2017 Annual Research Report
  • [Journal Article] The cryo-EM structure of gastric H+,K+-ATPase with bound BYK99, a high-affinity member of K+-competitive, imidazo[1,2-a]pyridine inhibitors2017

    • Author(s)
      Abe Kazuhiro、Shimokawa Jun、Naito Mao、Munson Keith、Vagin Olga、Sachs George、Suzuki Hiroshi、Tani Kazutoshi、Fujiyoshi Yoshinori
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 6632-6632

    • DOI

      10.1038/s41598-017-06698-8

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Synthetic Studies on Heteropolycyclic Natural Products: Strategies via Novel Reactions and Reactivities2017

    • Author(s)
      Shimokawa Jun、Fukuyama Tohru
    • Journal Title

      Journal of Synthetic Organic Chemistry, Japan

      Volume: 75 Issue: 11 Pages: 1115-1124

    • DOI

      10.5059/yukigoseikyokaishi.75.1115

    • NAID

      130006196251

    • ISSN
      0037-9980, 1883-6526
    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
  • [Journal Article] Development of a Divergent Synthetic Route to the Erythrina Alkaloids: Asymmetric Syntheses of 8-Oxo-erythrinine, Crystamidine, 8-Oxo-erythraline, and Erythraline2016

    • Author(s)
      Hirotatsu Umihara, Tomomi Yoshino, Jun Shimokawa, Masato Kitamura, Tohru Fukuyama
    • Journal Title

      Angewandte Chemie International Edition

      Volume: 55 Issue: 24 Pages: 6915-6918

    • DOI

      10.1002/anie.201602650

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Antiproliferative Activity of Amathaspiramide Alkaloids and Analogs2016

    • Author(s)
      Jun Shimokawa, Koji, Chiyoda, Hirotatsu Umihara, Tohru Fukuyama
    • Journal Title

      Chemical and Pharmaceutical Bulletin

      Volume: 64 Issue: 8 Pages: 1239-1241

    • DOI

      10.1248/cpb.c16-00256

    • NAID

      130005253895

    • ISSN
      0009-2363, 1347-5223
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Unified Total Synthesis of Five Gelsedine-Type Alkaloids: (-)-Gelsenicine, (-)-Gelsedine, (-)-Gelsedilam, (-)-14-Hydroxygelsenicine, and (-)-14,15-Dihydroxygelsenicine2016

    • Author(s)
      Takaaki Harada, Jun Shimokawa, Tohru Fukuyama
    • Journal Title

      Org. Lett.

      Volume: 18 Issue: 18 Pages: 4622-4625

    • DOI

      10.1021/acs.orglett.6b02263

    • NAID

      120005946825

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Enantioselective Total Synthesis of (+)-Hinckdentine A via a Catalytic Dearomatization Approach2016

    • Author(s)
      Kazuya Douki, Hiroyuki Ono, Tohru Taniguchi, Jun Shimokawa, Masato Kitamura, Tohru Fukuyama
    • Journal Title

      Journal of the American Chemical Society

      Volume: 138 Issue: 44 Pages: 14578-14581

    • DOI

      10.1021/jacs.6b10237

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Synthesis of the Common Core Structure of the Stemofoline Alkaloids2015

    • Author(s)
      Eiji Ideue, Jun Shimokawa, Tohru Fukuyama
    • Journal Title

      Organic Letters

      Volume: 17 Issue: 20 Pages: 4964-4967

    • DOI

      10.1021/acs.orglett.5b02373

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Presentation] 多官能性化合物の合成戦略開拓2018

    • Author(s)
      下川淳
    • Organizer
      第6回慶應有機化学若手シンポジウム
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Short Synthesis of Phalarine Core Structure2018

    • Author(s)
      下川淳
    • Organizer
      IKCOC-14
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 多能性中間体が拓く網羅的天然物合成2017

    • Author(s)
      下川淳
    • Organizer
      日本薬学会年会第137年会
    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Invited
  • [Presentation] Hinckdentine Aの不斉全合成2016

    • Author(s)
      下川 淳, 道木 和也, 小野 裕之,北村 雅人,福山 透
    • Organizer
      日本薬学会年会第136年会
    • Related Report
      2016 Annual Research Report
  • [Presentation] Hinckdentine Aの不斉全合成2016

    • Author(s)
      下川 淳, 道木 和也, 小野 裕之,福山 透,北村 雅人
    • Organizer
      日本薬学会62回東海支部大会
    • Related Report
      2016 Annual Research Report
  • [Presentation] Synthetic Studies on Polycyclic Natural Products: Enantioselective Total Synthesis of (+)-Hinckdentine A2016

    • Author(s)
      Jun Shimokawa
    • Organizer
      ACP ICCEOCA-11 & ARNCEOCA-2
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Aiming Divergent Syntheses of Polycyclic Natural Products2015

    • Author(s)
      Jun Shimokawa
    • Organizer
      Pacifichem 2015
    • Place of Presentation
      ホノルル
    • Year and Date
      2015-12-15
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Synthetic Studies on Erythrina Alkaloids2015

    • Author(s)
      Jun Shimokawa, Hirotatsu Umihara, Tomomi Yoshino, Masato Kitamura, Tohru Fukuyama
    • Organizer
      16th Tetrahedron Symposium
    • Place of Presentation
      ベルリン
    • Year and Date
      2015-06-16
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research

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Published: 2015-04-16   Modified: 2020-03-30  

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