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Convergent synthesis of dimeric alkaloids possessing highly complex structures based on the development of catalysts for aerobic oxidation

Research Project

Project/Area Number 20K06936
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
Research InstitutionTohoku University

Principal Investigator

Ueda Hirofumi  東北大学, 薬学研究科, 講師 (50581279)

Co-Investigator(Kenkyū-buntansha) 小林 長夫  信州大学, 繊維学部, 特任教授 (60124575)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords天然物 / アルカロイド / 二量体化合物 / 酸素酸化 / 鉄触媒 / フタロシアニン / 全合成 / 二量体 / 鉄フタロシアニン / 化学選択性
Outline of Research at the Start

二量体型天然物は、有用な活性から薬学的に注目を集めているが、その多くが複雑な構造を有している。本研究では、これら二量体型化合物の収束的合成を実現する、画期的なカップリング反応の開発を目指す。本方法論の確立は、化合物供給の困難さがボトルネックとなり立ち後れていた本化合物群の合成効率を飛躍的に高め、創薬天然物ライブラリーの拡充ならびに新たな医薬のシーズの発掘に繋がるものと期待される。

Outline of Final Research Achievements

In this research, we conducted synthetic studies on dimeric natural products with highly complex structures, which are expected to be utilized as lead compounds for drug discovery, based on the development of enzyme-mimicking catalyst for aerobic oxidation. We achieved the efficient asymmetric total synthesis of pleiocarpamine and deoxoapodine, which contained in pharmaceutically important dimeric alkaloids. The establishment of the highly concise and scalable synthetic method of monomers is expected to allow efficient synthesis of their dimeric alkaloids in near future. Furthermore, our originally developed dimerization was applied to not only natural product synthesis but also dimerization of peptides. These results would contribute to the development of pharmaceutical sciences by developing novel and useful methodologies for the synthesis of natural products and chemical modification of peptides.

Academic Significance and Societal Importance of the Research Achievements

天然化合物の中には、天然からの単離量が乏しく、かつ複雑な構造のため化学合成による供給が困難であり、創薬研究において埋没した化合物が数多く存在する。本研究では、薬としての可能性を秘めているにも関わらず、化学合成が困難な二量体構造を持つアルカロイドに焦点を当て、新たな化学合成法の提供を通じて、化合物の医薬品シーズとしての可能性を引き出す。本方法論の確立は、新たな医薬品シーズの発掘に繋がるだけでなく、医薬品を安価かつ大量に供給可能な低分子創薬の発展は、近年社会問題の一つである医療費高騰の抑制につながることが期待される。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (60 results)

All 2023 2022 2021 2020 Other

All Journal Article (10 results) (of which Peer Reviewed: 10 results,  Open Access: 2 results) Presentation (48 results) (of which Int'l Joint Research: 8 results,  Invited: 6 results) Remarks (2 results)

  • [Journal Article] Efficient and Scalable Asymmetric Total Synthesis of (-)-Emetine with Pharmaceutical Grade Quality; First Multigram Scale Synthesis2023

    • Author(s)
      Yamada Masatoshi、Azuma Kazuki、Takizawa Iori、Ejima Yuki、Yamano Mitsuhisa、Satoh Kimio、Doi Takayuki、Ueda Hirofumi、Tokuyama Hidetoshi
    • Journal Title

      Organic Process Research & Development

      Volume: 27 Issue: 2 Pages: 343-357

    • DOI

      10.1021/acs.oprd.2c00355

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Iron‐Catalyzed Biomimetic Dimerization of Tryptophan‐Containing Peptides2023

    • Author(s)
      Ueda Hirofumi、Sato Soichiro、Noda Kenta、Hakamata Hiroyuki、Kwon Eunsang、Kobayashi Nagao、Tokuyama Hidetoshi
    • Journal Title

      Angewandte Chemie International Edition

      Volume: - Issue: 22

    • DOI

      10.1002/anie.202302404

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Total synthesis of (±)-vinoxine: construction of the bridged pyrido[1,2-a]indole skeleton via Tf2O-mediated Bischler-Napieralski reaction and stereoselective radical cyclization2022

    • Author(s)
      Okada Kosuke、Ueda Hirofumi、Tokuyama Hidetoshi
    • Journal Title

      Organic & Biomolecular Chemistry

      Volume: 20 Issue: 30 Pages: 5943-5947

    • DOI

      10.1039/d2ob00274d

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Construction of Tetrahydroquinolines with Spirocyclic Structures at the 4-Position2022

    • Author(s)
      Yuko Wakahara、Takahiro Noro、 Juri Sakata、 Hirofumi Ueda、 Hidetoshi Tokuyama
    • Journal Title

      Heterocycles

      Volume: 102 Issue: 1 Pages: 438-438

    • DOI

      10.3987/com-22-s(r)16

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Catalytic enantioselective 5-endo-bromocycloetherification of unactivated cyclic alkenes2022

    • Author(s)
      Xiong Haoran、Yoshida Kei、Okada Kosuke、Ueda Hirofumi、Tokuyama Hidetoshi
    • Journal Title

      Tetrahedron Letters

      Volume: 101 Pages: 153906-153906

    • DOI

      10.1016/j.tetlet.2022.153906

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Synthesis of substituted anilines via a gold-catalyzed three-component reaction2021

    • Author(s)
      Ueda Hirofumi、Yamamoto Ryota、Yamaguchi Minami、Tokuyama Hidetoshi
    • Journal Title

      Organic & Biomolecular Chemistry

      Volume: 19 Issue: 4 Pages: 765-769

    • DOI

      10.1039/d0ob02018d

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Synthesis of leuconoxine, leuconodine B, and rhazinilam by transformation of melodinine E via 6-hydro-21-dehydroxyleuconolam2021

    • Author(s)
      Umehara Atsushi、Ueda Hirofumi、Tokuyama Hidetoshi
    • Journal Title

      Tetrahedron

      Volume: 79 Pages: 131809-131809

    • DOI

      10.1016/j.tet.2020.131809

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Aerobic Dehydrogenation of N-Heterocycles with Grubbs Catalyst: Its Application to Assisted‐Tandem Catalysis to Construct N-Containing Fused Heteroarenes2020

    • Author(s)
      Kawauchi Daichi、Noda Kenta、Komatsu Yoshiyuki、Yoshida Kei、Ueda Hirofumi、Tokuyama Hidetoshi
    • Journal Title

      Chemistry - A European Journal

      Volume: 26 Issue: 68 Pages: 15793-15798

    • DOI

      10.1002/chem.202001961

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Nitrile Synthesis by Aerobic Oxidation of Primary Amines and in situ Generated Imines from Aldehydes and Ammonium Salt with Grubbs Catalyst2020

    • Author(s)
      Utsumi Tatsuki、Noda Kenta、Kawauchi Daichi、Ueda Hirofumi、Tokuyama Hidetoshi
    • Journal Title

      Advanced Synthesis & Catalysis

      Volume: 362 Issue: 17 Pages: 3583-3588

    • DOI

      10.1002/adsc.202000663

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] A Concise Enantioselective Total Synthesis of (-)‐Deoxoapodine2020

    • Author(s)
      Yoshida Kei、Okada Kosuke、Ueda Hirofumi、Tokuyama Hidetoshi
    • Journal Title

      Angewandte Chemie International Edition

      Volume: 59 Issue: 51 Pages: 23089-23093

    • DOI

      10.1002/anie.202010759

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Presentation] 金触媒によるドミノ環化反応を鍵とするIsocrambescidin 800の合成研究2023

    • Author(s)
      千葉七瀬、牧亮太、阿部祐大、植田浩史、徳山英利
    • Organizer
      第143薬学会年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Chartelline C の合成研究2022

    • Author(s)
      長沢浩、植田浩史、徳山英利
    • Organizer
      第33回万有仙台シンポジウム
    • Related Report
      2022 Annual Research Report
  • [Presentation] 酸化反応を基軸とする高次構造多環性アルカロイドの合成研究2022

    • Author(s)
      植田浩史
    • Organizer
      第55回天然物談話会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Synthetic Studies on Bipleiophylline Based on the Oxidative Dimerization Reaction2022

    • Author(s)
      Kosuke Okada, Hirofumi Ueda, Hidetoshi Tokuyama
    • Organizer
      第8回野依フォーラム若手育成塾
    • Related Report
      2022 Annual Research Report
  • [Presentation] Synthetic Studies on Mavacurine Alkaloids2022

    • Author(s)
      Kosuke Okada, Hirofumi Ueda, Hidetoshi Tokuyama
    • Organizer
      Tohoku University's Chemistry Summer School 2022
    • Related Report
      2022 Annual Research Report
  • [Presentation] マバクリンアルカロイドの合成研究2022

    • Author(s)
      岡田康佑、植田浩史、徳山英利
    • Organizer
      第64回天然物有機化合物討論会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Chartelline C の合成研究2022

    • Author(s)
      熊浩然、植田浩史、徳山英利
    • Organizer
      第51回複素環化学討論会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Synthetic Studies on Aspernomine2022

    • Author(s)
      寺地穂果、三原大輝、若原裕子、植田浩史、徳山英利
    • Organizer
      令和4年度化学系東北大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Synthetic Studies on Isocrambescidin 800 by Gold-Catalyzed Domino Cyclization2022

    • Author(s)
      牧亮太、千葉七瀬、阿部祐大、植田浩史、徳山英利
    • Organizer
      令和4年度化学系東北大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 鉄触媒による酸化反応を用いたレスベラトロール類の合成研究2022

    • Author(s)
      町田圭吾、西室創太、植田 浩史、徳山 英利
    • Organizer
      第61回日本薬学会東北支部大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] (+)-Spegatrineの合成研究2022

    • Author(s)
      西室創太、植田 浩史、徳山 英利
    • Organizer
      第61回日本薬学会東北支部大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Melinacidin IVの合成研究2022

    • Author(s)
      武田 陸、 佐藤 壮一郎、植田 浩史、徳山 英利
    • Organizer
      第61回日本薬学会東北支部大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Development of Aerobic Oxidation of Amines with Grubbs Catalyst and Its Application2022

    • Author(s)
      Kenta Noda, Daichi Kawauchi, Tatsuki Utsumi, Hirofumi Ueda, Hidetoshi Tokuyama
    • Organizer
      International Congress on Pure & Applied Chemistry 2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Synthesis of Substituted Nitrogen-Containing Heterocyclic Compounds via Gold-Catalyzed Cascade Reaction2022

    • Author(s)
      Hirofumi Ueda, Minami Yamaguchi, Hiroshi Kameya, Daichi Itagaki, Kazuya Marumo, Yudai Abe, Ryota Maki, Nanase Chiba, Kenji Sugimoto, Hidetoshi Tokuyama
    • Organizer
      SICC-11
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 二量体型マバクリンアルカロイドの合成研究2022

    • Author(s)
      岡田康佑、小島健一、植田浩史、徳山英利
    • Organizer
      第37回有機合成化学若手研究者の仙台セミナー
    • Related Report
      2022 Annual Research Report
  • [Presentation] 二量体型天然物の効率的合成を指向した収束的合成戦略2022

    • Author(s)
      植田浩史
    • Organizer
      ハイブリッド触媒 若手道場Online
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 二量体型アルカロイドの収束的合成に向けた合成戦略2022

    • Author(s)
      植田浩史
    • Organizer
      日本農芸化学会2022年度大会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] (+)-10-Methoxystrictamineの合成研究2022

    • Author(s)
      山梨政人、小松巧征、元木大介、植田浩史、徳山英利
    • Organizer
      第142回薬学会年会
    • Related Report
      2021 Research-status Report
  • [Presentation] 金触媒による連続環化反応を鍵とするIsocrambescidin 800の合成研究2022

    • Author(s)
      阿部祐大、牧亮太、植田浩史、徳山英利
    • Organizer
      第142回薬学会年会
    • Related Report
      2021 Research-status Report
  • [Presentation] Grubbs触媒を用いたアミン類の酸素酸化反応の開発とその応用2021

    • Author(s)
      野田健太、河内大知、内海樹、植田浩史、徳山英利
    • Organizer
      第19回次世代を担う有機化学シンポジウム
    • Related Report
      2021 Research-status Report
  • [Presentation] 酸素酸化を活用した二量体型アルカロイドの収束的合成戦略の開発2021

    • Author(s)
      植田浩史
    • Organizer
      第8回慶應有機化学若手シンポジウム
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] フェノールの酸化的カップリング反応の開発及び二量体型天然物の収束的合成への応用2021

    • Author(s)
      西室創太、植田浩史、徳山英利
    • Organizer
      第32回万有仙台シンポジウム
    • Related Report
      2021 Research-status Report
  • [Presentation] フタロシアニン金属錯体を用いたジチオアセタールの新規触媒的脱保護法の開発とその応用2021

    • Author(s)
      山梨政人、佐藤 綾、植田浩史、徳山英利
    • Organizer
      創薬懇話会2021 in 京都
    • Related Report
      2021 Research-status Report
  • [Presentation] 新規スピロインダノン合成法の開発を基盤としたAspernomineの合成研究2021

    • Author(s)
      寺地穂果、若原裕子、野呂尭広、坂田樹理、古田未有、植田浩史、徳山英利
    • Organizer
      創薬懇話会2021 in 京都
    • Related Report
      2021 Research-status Report
  • [Presentation] Development and Generality of Enantionselective Bromocycloetherification Catalyzed by Chiral Phosphoric Acid2021

    • Author(s)
      Hiroshi Nagasawa、Kosuke Okada、Kei Yoshida、Hirofumi Ueda、Hidetoshi Tokuyama
    • Organizer
      International Summer Seminar on Organic Chemistry
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Synthetic Studies on Melinacidin IV2021

    • Author(s)
      Riku Takeda、Soichiro Sato、Hirofumi Ueda、Hidetoshi Tokuyama
    • Organizer
      令和3年度化学系学協会東北大会
    • Related Report
      2021 Research-status Report
  • [Presentation] Development of an oxidative coupling of phenols and its application to the convergent synthesis of dimeric natural products2021

    • Author(s)
      Sota Nishimuro、Hirofumi Ueda、Hidetoshi Tokuyama
    • Organizer
      令和3年度化学系学協会東北大会
    • Related Report
      2021 Research-status Report
  • [Presentation] Synthetic Studies on Chartelline C2021

    • Author(s)
      Hiroshi Nagasawa、Hirofumi Ueda、Hidetoshi Tokuyama
    • Organizer
      令和3年度化学系学協会東北大会
    • Related Report
      2021 Research-status Report
  • [Presentation] 新規スピロインダノン合成法の開発を基盤としたaspernomineの合成研究2021

    • Author(s)
      寺地穂果、若原裕子、野呂尭広、坂田樹理、古田未有、植田浩史、徳山英利
    • Organizer
      第50回複素環化学討論会
    • Related Report
      2021 Research-status Report
  • [Presentation] (+)-Strictamineの合成研究2021

    • Author(s)
      小松巧征、山梨政人、元木大介、植田浩史、徳山英利
    • Organizer
      第60回日本薬学会東北支部大会
    • Related Report
      2021 Research-status Report
  • [Presentation] ラジカル環化反応によるスピロインダノン骨格構築を介したAspernomineの合成研究2021

    • Author(s)
      寺地穂果、若原裕子、野呂尭広、坂田樹理、古田未有、植田浩史、徳山英利
    • Organizer
      第60回日本薬学会東北支部大会
    • Related Report
      2021 Research-status Report
  • [Presentation] (-)-Mycoleptodiscin Aの合成研究2021

    • Author(s)
      高杉梨花、植田浩史、古田未有、徳山英利
    • Organizer
      第60回日本薬学会東北支部大会
    • Related Report
      2021 Research-status Report
  • [Presentation] 寺地穂果、若原裕子、野呂尭広、坂田樹理、古田未有、植田浩史、徳山英利2021

    • Author(s)
      Aspernomineの合成研究
    • Organizer
      第36回有機合成化学若手研究者の仙台セミナー
    • Related Report
      2021 Research-status Report
  • [Presentation] Total Synthesis of (-)-Deoxoapodine2021

    • Author(s)
      Kosuke Okada、Kei Yoshida、Hirofumi Ueda、Hidetoshi Tokuyama
    • Organizer
      Pacifichem 2020
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Total Synthesis of (-)-Dehydrobatzelladine C via Gold-Mediated Auto Tandem Catalysis2021

    • Author(s)
      Hirofumi Ueda、Daichi Itagaki、Kazuya Marumo、Yudai Abe、Hiroshi Kameya、Hidetoshi Tokuyama
    • Organizer
      Pacifichem 2020
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Synthetic Studies on (+)-Strictamine2021

    • Author(s)
      Yoshiyuki Komatsu、Masato Yamanashi、Daisuke Motoki、Hirofumi Ueda、Hidetoshi Tokuyama
    • Organizer
      13th AFMC International Medicinal Chemistry Symposium
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Development of Aerobic Oxidation of Amines with Grubbs Catalyst and Its Application2021

    • Author(s)
      Kenta Noda、Daichi Kawauchi、Tatsuki Utsumi、Hirofumi Ueda、Hidetoshi Tokuyama
    • Organizer
      13th AFMC International Medicinal Chemistry Symposium
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Synthetic Studies on Batzelladines via Gold Catalyzed Cascade Cyclization2021

    • Author(s)
      Hirofumi Ueda、Daichi Itagaki、Kazuya Marumo、Yudai Abe、Hidetoshi Tokuyama
    • Organizer
      13th AFMC International Medicinal Chemistry Symposium
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] 金触媒によるドミノ型連続環化反応を鍵とするBatelladine類の合成研究2021

    • Author(s)
      植田浩史
    • Organizer
      第141回日本薬学会年会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] C-Hアルキル化を伴う新規インドール縮環型中員環構築法の開発2021

    • Author(s)
      岡田 康佑、吉田慶、植田浩史、徳山英利
    • Organizer
      第141回日本薬学会年会
    • Related Report
      2020 Research-status Report
  • [Presentation] (-)-Deoxoapodineの全合成2020

    • Author(s)
      岡田康佑、吉田慶、植田浩史、徳山英利
    • Organizer
      第18回次世代を担う有機化学シンポジウム
    • Related Report
      2020 Research-status Report
  • [Presentation] Nitrile synthesis by aerobic oxidation of primary amines and imines with Grubbs catalyst2020

    • Author(s)
      Kenta Noda, Tastuki Utsumi, Daichi Kawauchi, Hirofumi Ueda, Hidetoshi Tokuyama
    • Organizer
      令和2年度化学系学協会東北大会
    • Related Report
      2020 Research-status Report
  • [Presentation] 金触媒による連続的環化反応を鍵とするBatzelladine類の合成研究2020

    • Author(s)
      阿部祐大、板垣大地、丸茂和哉、植田浩史、徳山英利
    • Organizer
      第49回複素環化学討論会
    • Related Report
      2020 Research-status Report
  • [Presentation] (-)-Deoxoapodineの全合成2020

    • Author(s)
      岡田康佑、吉田慶、植田浩史、徳山英利
    • Organizer
      第31回万有仙台シンポジウム
    • Related Report
      2020 Research-status Report
  • [Presentation] (-)-Deoxoapodineの全合成2020

    • Author(s)
      岡田康佑、吉田慶、植田浩史、徳山英利
    • Organizer
      第32回万有札幌シンポジウム
    • Related Report
      2020 Research-status Report
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Published: 2020-04-28   Modified: 2024-01-30  

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