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Development of a method for the asymmetric construction of substituted citric acid structures and synthesis of natural products as leading compounds for drug discovery

Research Project

Project/Area Number 15390008
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Chemical pharmacy
Research InstitutionNagasaki University

Principal Investigator

HATAKEYAMA Susumi  Nagasaki University, Graduate School of Biomedical Sciences, Professor, 大学院・医歯薬学総合研究科, 教授 (20143000)

Project Period (FY) 2003 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥15,300,000 (Direct Cost: ¥15,300,000)
Fiscal Year 2005: ¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 2004: ¥4,600,000 (Direct Cost: ¥4,600,000)
Fiscal Year 2003: ¥8,100,000 (Direct Cost: ¥8,100,000)
Keywordsalkylcitrate natural product / Baylis-Hillman reaction / Mukaiyama aldol reaction / asymmetric reaction / trachyspic acid / virifiofungin / total synthesis / 不斉Bayis-Hillman反応 / 不斉向山アルドール反応 / 不斉Baylis-Hillman反応
Research Abstract

Alkylcitrate family of natural products such as viridiofungin and trachyspic acid have attracted so much attention due to their potent inhibitory activities against biologically important enzymes (e.g. serine-palmitoyl transferase, phospholipase A2, heparanase, squalene synthase) as well as synthetically intriguing structures. However, a general method for the construction of highly functionalized citric acid structures containing a quaternary center has not been developed yet. In this research, we focused on developing a general and efficient method for the asymmetric synthesis of such citric acid structures, and aimed to achieve total syntheses of alkylcitrate family of natural products.
In the former research, we developed a highly efficient asymmetric Baylis-Hillman reaction using dried β-isocupreidine (β-ICD). In addition, we succeeded in synthesizing two enantio-complementary catalysts to β-ICD starting from quinine. We found that β-ICD-catalyzed Baylis-Hillman reaction of γ-(p-methoxybenzyl)oxy-α-ketobutanoate proceeded with high enantioselectivity in good yield. We also examined asymmetric Mukaiyama aldol reaction of γ-(p-methoxybenzyl)oxy-α-ketobutanoate with the ketne silyl ether drived from S-tert-butyl pent-4-enethioate using several BOX-Cu catalysts but the encouraging results were not obtained.
In the latter research, we achieved the first total synthesis of (+)-trachyspic acid as well as (±)-trachyspic acid based on Nozaki-Hiyama-Kishi reaction, therby determining its absolute structure. Furthermore, we accomplished the first total synthesis of (-)-virifiofungin A employing olefin cross metathesis as a key step.

Report

(4 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (18 results)

All 2006 2005 2004 2003 Other

All Journal Article (17 results) Publications (1 results)

  • [Journal Article] β-Isocupreidine-hexafluoroisopropyl acrylate method for asymmetric Baylis-Hillman reactions2006

    • Author(s)
      中野 綾子
    • Journal Title

      Tetrahedron 62・2-3

      Pages: 381-389

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] β-Isocupreidine-hexafluoroisopropyl acrylate method for asymmetric Baylis-Hillman reactions2006

    • Author(s)
      Ayako Nakano
    • Journal Title

      Tetrahedron, 66・2-3

      Pages: 381-389

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] β-Isocupreidine-hexafluoroisopropyl acrylate method for asymmetric Baylis-Hillman reactions2006

    • Author(s)
      中野綾子
    • Journal Title

      Tetrahedron 62・2-3

      Pages: 381-389

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Total synthesis of viridiofungin A2005

    • Author(s)
      諸熊 賢治
    • Journal Title

      Chemical Communications 17

      Pages: 2265-2267

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Synthesis of an Enantio-complementarl Catalyst of β-Isocupreidine(β-ICD)from Quinine2005

    • Author(s)
      中野 綾子
    • Journal Title

      Advanced Synthesis&Catalysis 347・14

      Pages: 1790-1796

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Synthesis of a pseudoenantiomer of β-isocupreidine(β-ICD), a chiral amine catalyst for asymmetric Baylis-Hillman reactions2005

    • Author(s)
      中野 綾子
    • Journal Title

      Heterocycles 66・1

      Pages: 371-383

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Total synthesis of viridiofungin A2005

    • Author(s)
      Kenji Morokuma
    • Journal Title

      Chemical Communications, 17

      Pages: 2265-2267

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Synthesis of an Enantio-complementary Catalyst of β-Isocupreidine (β-ICD) from Quinine2005

    • Author(s)
      Ayako Nakano
    • Journal Title

      Advanced Synthesis & Catalysis, 347-14

      Pages: 1790-1796

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Synthesis of a pseudoenantiomer of β-isocupreidine (β-ICD), a chiral amine catalyst for asymmetric Baylis-Hillman reactions2005

    • Author(s)
      Ayako Nakano
    • Journal Title

      Heterocycles, 66-1

      Pages: 371-383

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Synthesis of an Enantio-complementary Catalyst of β-Isocupreidine (β-ICD) from Quinine2005

    • Author(s)
      中野綾子
    • Journal Title

      Advanced Synthesis & Catalysis 347・14

      Pages: 1790-1796

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Synthesis of a pseudoenantiomer of βisocupreidine (β-ICD), a chiral amine catalyst for asymmetric Baylis-Hillman reactions2005

    • Author(s)
      中野綾子
    • Journal Title

      Heterocycles 66・1

      Pages: 371-383

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Total synthesis of viridiofungin A2005

    • Author(s)
      諸熊賢治
    • Journal Title

      Chemical Communications (印刷中)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 不斉求核触媒-シンコナアルカイドを中心にした化学2004

    • Author(s)
      畑山 範
    • Journal Title

      化学と工業 57・7

      Pages: 716-719

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Chemistry focusing on asymmetric nucleophilic catalyst, cinchona alkaloids2004

    • Author(s)
      Susumi Hatakeyama
    • Journal Title

      Chemistry & Chemical Industry, 57-7

      Pages: 716-719

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] 不斉求核触媒-シンコナアルカロイドを中心にした化学2004

    • Author(s)
      畑山 範
    • Journal Title

      化学と工業 577

      Pages: 716-719

    • NAID

      10013281818

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Total Synthesis of (±)-Trachyspic Acid and Determination of the Relative Configuration2003

    • Author(s)
      平井 加奈子
    • Journal Title

      Organic letters 5・6

      Pages: 857-859

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Total Synthesis of (±)-Trachyspic Acid and Determination of the Relative Configuration2003

    • Author(s)
      Kanako Hirai
    • Journal Title

      Organic letters, 5-6

      Pages: 857-859

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Publications] 平井加奈子: "Total Synthesis of (±)-Trachyspic Acid and Determination of the Relative Configuration"Organic letters. 5・6. 857-859 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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