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Development of Lipase-Catalyzed Domino-Type Asymmetric Syntheses

Research Project

Project/Area Number 15590005
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

AKAI Shuji  Osaka University, Graduate School of Pharmaceutical Sciences, Research Associate, 薬学研究科, 助手 (60192457)

Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2003: ¥2,100,000 (Direct Cost: ¥2,100,000)
Keywordslipase / ethoxyvinyl ester / domino-type reaction / asymmetric synthesis / dynamic kinetic resolution / ruthenium complex / Diels-Alder reaction / dipolar cycloaddition / ラセミ化 / ニトロン / アルカロイド / 不斉全合成 / ルテニウム触媒
Research Abstract

The lipase catalyzed organic syntheses have been gaining increased attention as environmentally benign processes. However, their application has been limited mainly to the preparation of optically active compounds via the kinetic resolution of racemic carboxylic acid derivatives or the alcohols. Recently, we disclosed the first domino type asymmetric synthesis, in which the lipase catalyzed kinetic resolution of racemic alcohols with ethoxyvinyl esters (EVEs) bearing reactive functional moieties was followed by the intramolecular Diels-Alder reaction of the resulting optically active esters to directly give polycyclic compounds. This project has aimed at the practical expansion of this domino type synthesis methodology. The followings are summary of the results :
1. Some ruthenium complexes were discovered to effectively catalyze the racemization of optically active alcohols at room temperature and have no inhibition of the lipase-catalyzed reactions. By the combined use of these comple … More xes and lipases, we have achieved the first domino-type synthesis accompanied by a dynamic kinetic resolution. Thus, in this process, the kinetic resolution of 3-vinylcyclohexen-1-ols, the racemization of the remaining optically active alcohols, and the intramolecular Diels-Alder reaction concurrently took place to directly afford multi-substituted decalines (90-95% ee, 69.83% yields).
2. The lipase catalyzed domino type synthesis was applied to racemic acyclic and cyclicα-hydroxynitrones, and the kinetic resolution and the intramolecular dipolar cycloaddition reactions continuously proceeded to give isoxazolidine derivatives (>90% ee) as a single diastereomer in each case. This protocol was used for the first catalytic asymmetric total synthesis of (-)-rosmarinecine, a natural pyrrolizidine alkaloid, from commercially available racemic 3-hydroxypyrrolidine.
3. Systematic investigation on the ruthenium-catalyzed racemization of optically active alcohols has found that the substituents of the benzene-ligands of the ruthenium complexes had significant affect on their catalytic reactivity. Less

Report

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

    (14 results)

All 2005 2004 2003 Other

All Journal Article (12 results) Publications (2 results)

  • [Journal Article] Lipase-catalyzed domino kinetic resolution of α-hydroxynitrones/intramolecular 1,3-dipolar cycloaddition : A concise asymmetric total synthesis of (-)- rosmarinecine2005

    • Author(s)
      Akai, Shuji et al.
    • Journal Title

      Chem.Commun.

      Pages: 2369-2371

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Lipase-Catalyzed Domino Kinetic Resolution of α-Hydroxy-nitrones/Intramolecular 1,3-Dipolar Cycloaddition : A Concise Asymmetric Total Synthesis of (-)-Rosmarinecine2005

    • Author(s)
      S.Akai, K.Tanimoto, Y.Kanao, S.Omura, Y.Kita
    • Journal Title

      Chem.Commun.

      Pages: 2369-2371

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Lipase-catalyzed domino kinetic resolution of α-hydroxynitrones/intramolecular 1,3-dipolar cycloaddition : A concise asymmetric total synthesis of (-)- rosmarinecine2005

    • Author(s)
      Akai, Shuji et al.
    • Journal Title

      Chem.Commun. (印刷中)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Lipase-Catalyzed Domino Dynamic-Kinetic-Resolution of Racemic 3-Vinylcyclohex-2-en-1-ols/Intramolecular Diels-Alder Reaction2004

    • Author(s)
      Akai, Shuji et al.
    • Journal Title

      Angew.Chem.Int.Ed. 43

      Pages: 1407-1410

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Enantiodivergent Preparation of Optically Active Oxindoles Having a Stereo-genic Quaternary Carbon Center at the C3 Position via the Lipase-Catalyzed Desymmetrization Protocol : Effective Use of 2-Furoates for Either Enzymatic Esterification or Hydrolysis2004

    • Author(s)
      Akai, Shuji et al.
    • Journal Title

      J.Org.Chem. 69

      Pages: 2478-2486

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 1-Alkoxyvinyl Esters : Renaissance of Half-Century-Old Acyl Donors with Potential Applicability2004

    • Author(s)
      Kita, Yasuyuki, Akai, Shuji
    • Journal Title

      Chemical Record 4

      Pages: 363-372

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Lipase-Catalyzed Domino Dynamic-Kinetic-Resolution of Racemic 3-Vinylcyclohex-2-en-1-ols/Intramolecular Diels-Alder Reaction2004

    • Author(s)
      S.Akai, K.Tanimoto, Y.Kita
    • Journal Title

      Angew.Chem.Int.Ed. 43

      Pages: 1407-1410

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Enantiodivergent Preparation of Optically Active Oxindoles Having a Stereogenic Quaternary Carbon Center at the C3 Position via the Lipase-Catalyzed Desymmetrization Protocol : Effective Use of 2-Furoates for Either Enzymatic Esterification or Hydrolysis2004

    • Author(s)
      S.Akai, T.Tsujino, E.Akiyama, K.Tanimoto, T.Naka, Y.Kita
    • Journal Title

      J.Org.Chem 69

      Pages: 2478-2486

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 1-Alkoxyvinyl Esters Renaissance of Half-Century-Old Acyl Donors with Potential Applicability2004

    • Author(s)
      Y.Kita, S.Akai
    • Journal Title

      Chemical Record 4

      Pages: 363-372

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Enantiodivergent Preparation of Optically Active Oxindoles Having a Stereogenic Quaternary Carbon Center at the C3 Position via the Lipase-Catalyzed Desymmetrization Protocol : Effective Use of 2-Furoates for Either Enzymatic Esterification or Hydrolysis2004

    • Author(s)
      Akai, Shuji et al.
    • Journal Title

      J.Org.Chem. 69

      Pages: 2478-2486

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 次世代型酵素触媒反応を志向する不斉合成反応の開発研究2003

    • Author(s)
      赤井 周司
    • Journal Title

      薬学雑誌 123

      Pages: 919-931

    • NAID

      110003614856

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Development of Novel Asymmetric Reactions Oriented to Next-Generation Enzymatic Organic Syntheses2003

    • Author(s)
      S.Akai
    • Journal Title

      Yakugaku Zasshi 123

      Pages: 919-931

    • NAID

      110003614856

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Akai, Shuji: "Lipase-Catalyzed Domino Dynamic-Kinetic-Resolution of Racemic 3-Vinyl-cyclohex-2-en-1-ols/Intramolecular Diels-Alder Reaction"Angew.Chem.Int.Ed.. 43. 1407-1410 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 赤井 周司: "次世代型酵素触媒反応を志向する不斉合成反応の開発研究(日本薬学会学術振興賞受賞記念総説)"薬学雑誌. 123. 919-931 (2003)

    • Related Report
      2003 Annual Research Report

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

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