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Development of New Method for Construction of Chiral, Non-Racemic Quaternary Carbon Center by Enzymatic Acylation of Alcohols and Application Thereof

Research Project

Project/Area Number 13672214
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) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2001: ¥2,500,000 (Direct Cost: ¥2,500,000)
Keywordslipase / ethoxyvinyl ester / chiral, non-racemic quaternary carbon center / cycloaddition / asymmetric desymmetrization / oxindole / domino reaction / nitrone / 双極子付加環化反応 / ジオール / タンデム不斉合成 / 分子内 Diels-Alder反応
Research Abstract

Construction of chiral, non-racemic quaternary carbon center via enzymatic acylation of alcohols is believed to be an effective environmentally benign process because of its high enantioselectiviry and safe and easy operation; however, the successful examples have been limited. This is mainly due to the problems of the currently-best method using vinyl esters, which involve inactivation of the enzymes and easy racemication via intramolecular acyl group migration. Recently, we have disclosed their resolution by using 1-ethoxyvinyl esters (EVEs), leading to the discovery of the first effective enzymatic desymmetrization of symmetric diols and the first domino asymmetric reactions. This project has aimed at the expansion of these methods for the construction of chiral, non-racemic quaternary carbon centers and also their application for asymmetric synthesis of leading compounds for new drug discovery. The followings are summary of the results:
1. The enzymatic desymmetrization method was e … More ffective for wide range of 1,2- and 1,3-diols, and a new general method for the construcntion of chiral, non-racemic quaternary carbon centers has been established. This protocol was successfully applied for asymmetric synthesis of either enantiomer of the ABCDE-analog of antitumor antibiotic fredericamycin A and also for asymmetric preparation of the various oxindoles (86- 98% ee) with a chiral, non-racemic quaternary carbon center at the C-3 position and a variety of N-1 protective group.
2. The lipase-catalyzed domino asymmetric synthesis was applied to various furfuryl alcohol to provide a one-pot synthesis of 7-oxabicycloheptenes (91- 99% ee) with a chiral quaternary carbon center. Especially, useful chiral synthons bearing a vinyl bromide moiety were prepared from the 3-bromofurfuryl alcohols. The first domino process involving dynamic kinetic resolution was achieved by the similar reaction of α-hydroxynitrones to give aza-polycyclic products in good yields. The asymmetric total synthesis of a natural pyrrolizidine alkaloid, rosmarinecine, was attained in 3 steps from a readily available racemic hydroxynitrone and a maleic acid. Less

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (16 results)

All Other

All Publications (16 results)

  • [Publications] AKAI, Shuji: "Lipase-Catalyzed Enantioselective Desymmetrization of Prochiral 3,3-Bis(hydroxymethl)oxindoles"Tetrahedron Letters. 42. 7315-7317 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 赤井, 周司: "リパーゼの不斉識別能を活用する新規不斉合成反応の開発研究"生産技術誌. 53. 57-60 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] AKAI, Shuji: "Enantiodivergent Synthesis of Either Enantiomer of ABCDE-Ring Analog of Antitumor Antibiotic, Fredericamycin A via Intramolecular [4+2] Cycloaddition Approach"Organic Letters. 3. 4015-4018 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] AKAI, Shuji: "An Efficient Lipase-Catalyzed Enantioselective Desymmetrization of Prochiral 2,2-Disubstituted 1,3-Propanediols and Meso 1,2-Diols Using 1-Ethoxyvinyl 2-Furoate"Journal of Organic Chemistry. 67. 411-419 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] AKAI, Shuji: "Lipase-Catalyzed Domino Kinetic Resolution/Intramolecular Diels-Alder Reaction : One-Pot Synthesis of Optically Active 7-Oxabicyclo[2.2.1]heptenes from Furfuryl Alcohols and β-Substituted Acrylic Acids"Chemistry-A European Journal. 8. 4255-4264 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] AKAI, Shuji: "Lipase-Catalyzed Enantioselective Desymmetrization of Prochiral 3, 3-Bis(hydroxymethyl)oxindoles"Tetrahedron Letters. 42. 7315-7317 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] AKAI, Shuji: "Development of Lipase-Catalyzed Novel Asymmetric Synthesis"The Production & Technique. 53. 57-60 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] AKAI, Shuji: "Enantiodivergent Synthesis of Either Enantiomer of ABCDE-Ring Analog of Antitumor Antibiotic, Fredericamycin A via Intramolecular [4+2] Cycloaddition Approach"Organic Letters. 3. 4015-4018 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] AKAI, Shuji: "An Efficient Lipase-Catalyzed Enantioselective Desymmetrization of Prochiral 2,2-Disubstituted 1,3-Propanediols and Meso 1,2-Diols Using 1-Ethoxyvinyl 2-Furoate"Journal of Organic Chemistry. 67. 411-419 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] AKAI, Shuji: "Lipase-Gatalyzed Domino Kinetic Resolution/Intramolecular Diels-Alder Reaction: One-Pot Synthesis of Optically Active 7-Oxabicyclo[2.2.1]heptenes from Furfuryl Alcohols and β-Substituted Acrylic Acids"Chemistry-A European Journal. 8. 4255-4264 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] AKAI.SHUJI: "An Efficient Lipase-Catalyzed Enantioselective Desymmetrization of Prochiral 2, 2-Disubstituted 1, 3-Propanediols and Meso 1, 2-Diols Using 1-Ethoxyvinyl 2-Furoate"Journal of Organic Chemistry. 67. 411-419 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] AKAI.Sshuji: "Lipase-Catalyzed Domino Kinetic Resolution/Intramolecular Diels-Alder Reaction : One-Pot Synthesis of Optically Active 7-Oxabicyclo[2.2.1]heptenes from Furfuryl Alcohols and β-Substituted Acrylic Acids"Chemistry-A European Journal. 8. 4255-4264 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 赤井, 周司: "リパーゼの不斉識別能を活用する新規不斉合成反応の開発研究"生産技術誌. 53. 57-60 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] AKAI, Shuji: "Lipase-Catalyzed Enantioselective Desymmetrization of Prochiral 3,3-Bis(hydroxymethyl)oxindoles"Tetrahedron Letters. 42. 7315-7317 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] AKAI, Shuji: "Enantiodivergent Synthesis of Either Enantiomer of ABCDE-Ring Analog of Antitumor Antibiotic, Fredericamycin A via Intramolecular [4+2] Cycloaddition Approach"Organic Letters. 3. 4015-4018 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] AKAI, Shuji: "An Efficient Lipase-Catalyzed Enantioselective Desymmetrization of Prochiral 2,2-Disubstituted 1,3-Propanediols and Meso 1,2-Diols Using 1-Ethoxyvinyl 2-Furoate"Journal of Organic Chemistry. 67. 411-419 (2002)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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