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Total Synthesis of Alkaloids usingAsymmetric Catalysts

Research Project

Project/Area Number 18590016
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

ITOH Takashi  Showa University, Pharmaceutical Sciences, Professor (40159885)

Co-Investigator(Kenkyū-buntansha) NAGATA Kazuhiro  Showa University, Pharmaceutical Sciences, Associate Professor (20208010)
KANEMITSU Takuya  Showa University, Pharmaceutical Sceinces, Assistant Professor (10372913)
MIYAZAKI Michiko  Showa University, Pharmaceutical Sceinces, Assistant Professor (00266165)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsOrganocatalvst / Asymmetric allulation / Proline Catalyst / Thiourea Catalyst / Indole Alkaloid / Isoauinoline Alkaloid / イソキノリンアルカロイト / 不斉アリル化反応 / アリル銅 / プロリン / エメチン
Research Abstract

We have investigated new methods for the introduction of a chiral center at C-1 position of isoquinolines and β-carbolines. In the case of isoquinolines as substrates, allylcopper reagents which have diphosphine ligands afforded moderate enantioselectivity to give 1-aIly1-1, 2, 3, 4-tetrahydroisoquinol ne derivatives. This is the fast example that the addition reaction to cyclic imines proceeded in an enantioselective manner in the presence of a chiral catalyst. The product thus obtained was used as a starting material for the enantioselective total synthesis of emetine.
The reaction system was further applied to the total synthesis of α-schulzeine, which is a natural product having a high α-glucosidase inhibitory activity. By using DTBM-segphos as a bidentate ligand, a high enantioselectivity was accomplished for the crucial asymmetric addition of allylcopper to the starting material. The allyl adduct thus obtained was transformed to the core structure of schulzeine in a stereoselectiv … More e manner. In addition, inhibition of a-glucosidase activity was planned to measure using bioassay.
In order to introduce an electron-deficient Cl unit at Cl position of isoquinoline derivative in an enantioselective manner, Jacobsen thiourea catalyst was applied to 3, 4-dihydroisoquinoline, and 1-cyano-1, 2, 3, 4-tetrahydroisoquinoline derivatives were abtained in a highly enantioselective manner. The product thus obtained was applied to the synthesis of several isoquinoline alkaloids such as trolline and crispine.
In the cases of 3, 4-dihydro β3-carboline derivatives, proline-catalyzed Mannich reaction proceeded to give chiral 1-substituted 1, 2, 3, 4-tetrahydro-β-carbol ne derivatives in good yields and a high enantioselectivity. In the process of the optimization of reaction conditions, it was revealed that the small amount of water in the reaction system was crucial for obtaining the high stereoselectivity. This is the fast example that the contribution of water to the stereochemistry was suggested in organocatalytic chemistry of proline. The reaction products were used as a starling material for theasymmetric total synthesis of dihydrocorynantheol and yohimbine Less

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (23 results)

All 2008 2007 2006

All Journal Article (19 results) (of which Peer Reviewed: 6 results) Presentation (4 results)

  • [Journal Article] Catalytic Asymmetric Hydroxylation of Oxindoles by Molecular Oxygen Using a Phase-Transfer Catalyst2008

    • Author(s)
      Sano, D.; Nagata, K.; Itoh, T.
    • Journal Title

      Organic Letters 10

      Pages: 1593-1595

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Catalytic Asymmetric Hydroxylation of Oxindoles by Molecular Oxygen Using a Phase-Transfer Catalyst2008

    • Author(s)
      Sano, D., Nagata, K, Itoh, T
    • Journal Title

      Org. Lett 10

      Pages: 1593-1595

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Catalytic Asymmetric Hydroxylation of Oxindoles by Molecular Oxygen Using a Phase-Transfer Catalyst2008

    • Author(s)
      Sano, D.;Nagata, K.;Itoh, T.
    • Journal Title

      Organic Letters 10

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Catalytic Asymmetric Alkylation of a-Cyanocarboxylate Using a Phase-transfer Catalyst2007

    • Author(s)
      Nagata, K.; Sano, D.; Itoh, T.
    • Journal Title

      Synlett

      Pages: 547-550

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Synthesis of(-)-Trolline,(-)-Crispine A and(-)-Crispine E2007

    • Author(s)
      Kanemitsu, T.; Yamashita, Y.; Nagata, K.; Itoh, T.
    • Journal Title

      Heterocycles 74

      Pages: 199-203

    • NAID

      40015919577

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Synthesis of(-)-TroRine,(-)-Crispine A and(-)-Crispine E2007

    • Author(s)
      Kanemitsu, T., Yamashita, Y., Nagata, K., Itoh, T
    • Journal Title

      Heterocycles 74

      Pages: 199-203

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Diastereoselective Construction of Indolo[2, 3-a]quinolizidine Skeleton by Cycloaddition Reaction of 3, 4-Dihydro-β-carbolines with γ, δ-Unsaturated-β-ketoesters2007

    • Author(s)
      Nagata, K., Sekishiro, Y., Itoh, T
    • Journal Title

      Heterocycles 72

      Pages: 175-179

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Catalytic Asymmetric Alkylation of a-Cyanocarboxylate Using a Phase- transfer Catalyst2007

    • Author(s)
      Nagata, K., Sano, D, Itoh, T
    • Journal Title

      Synlett

      Pages: 547-550

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Catalytic Asymmetric Alkylation of a-Cyanocarboxylate Using a Phase-transfer Catalyst2007

    • Author(s)
      Nagata, K.;Sano, D.;Itoh, T.
    • Journal Title

      Synlett 2007

      Pages: 547-550

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Synthesis of (-)-Trolline,(-)-Crispine A and(-)-Crispine E.2007

    • Author(s)
      Kanemitsu, T.;Yamashita, Y.;Nagata, K.;Itoh, T.
    • Journal Title

      Heterocycles 74

      Pages: 199-203

    • NAID

      40015919577

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Diastereoselective Construction of Indolo[2,3-a]quinolizidine Skeleton by Cycloaddition reaction of 3,4-Dihydro-β-carbolines with γ,δ-Unsaturated-β-ketoesters.2007

    • Author(s)
      Itoh, T 他
    • Journal Title

      Heterocycles 72 (in press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Enantioselective Syntheses of ent-Sedridine and(+)-Coniine via Proline-Catalyzed Mannich Reaction2006

    • Author(s)
      Nagata, K., Nishimura, K., Yokoya, M., Itoh, T
    • Journal Title

      Heterocycles 70

      Pages: 335-344

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Total Synthesis of ent-Sedridine Using Proline Catalyzed Asymmetric Addition as a Key Step2006

    • Author(s)
      Itoh, T., Nishimura, K., Nagata, K., Yokoya, M
    • Journal Title

      Synlett

      Pages: 2207-2210

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Catalytic Asymmetric Synthesis of(R)-(-)-Calycotomine,(S-(-)-Salsolidine and(R)-(-)-Carnegine2006

    • Author(s)
      Kanemitsu, T., Yamashita, Y., Nagata, K., Itoh, T
    • Journal Title

      Synlett

      Pages: 1595-1597

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Formal Total Synthesis of (-)-Emetine Using Catalytic Asymmetric Allylation of Cyclic Imines as a Key Steps.2006

    • Author(s)
      Itoh, T 他
    • Journal Title

      Organic Letters 8

      Pages: 1295-1297

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Total Synthesis of ent-Dihydrocorynantheol Using a Proline-Catalyzed Asymmetric Addition Reaction.2006

    • Author(s)
      Itoh, T 他
    • Journal Title

      Organic Letters 8

      Pages: 1533-1535

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Catalytic Asymmetric Synthesis of (R)-(-)-Calycotomine, (S)-(-)-Salsolidine and (R)-(-)-Carnegine.2006

    • Author(s)
      Itoh, T 他
    • Journal Title

      Synlett

      Pages: 1595-1597

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Total Synthesis of ent-Sedridine Using Proline Catalyzed Asymmetric Addition as a Key Step.2006

    • Author(s)
      Itoh, T 他
    • Journal Title

      Synlett

      Pages: 2207-2210

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Enantioselective Syntheses of ent-Sedridine and (+)-Coniine via Proline-Catalyzed Mannich Reaction.2006

    • Author(s)
      Itoh, T 他
    • Journal Title

      Heterocycles 70

      Pages: 335-344

    • Related Report
      2006 Annual Research Report
  • [Presentation] Asymmetric Total Synthesis of Corynanthe Alkaloids Using Proline-catalyzed Mannich Cyclization2008

    • Organizer
      The 128th Annual Meeting of the Pharmaceutical Society of Japan
    • Place of Presentation
      Yokohama, Japan
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] チオ尿素触媒の開発と不斉反応への応用2007

    • Author(s)
      豊島 英輔, 金光 卓也, 永田 和弘, 伊藤 喬
    • Organizer
      第33回反応と合成の進歩シンポジウム
    • Place of Presentation
      長崎
    • Year and Date
      2007-11-06
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Presentation] Development of New Thiourea Catalyst and Its Application to Asymmetric Syntheses2007

    • Author(s)
      E., Toyoshima, T., Kanemitsu, T., Itoh
    • Organizer
      33rd Symposium on Progress in Organic Reactions and Syntheses-Applications in the Life Sciences
    • Place of Presentation
      Nagasaki, Japan
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Total Synthesis of Schulzeine A Using Catalytic Asymmetric Allylation of Cyclic Imines as a Key Step2007

    • Author(s)
      K., Sugai, N., Ando, M., Miyazaki, K., Nagata, T., Itoh
    • Organizer
      The 127th Annual Meeting of the Pharmaceutical Society of Japan
    • Place of Presentation
      Toyama, Japan
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary

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Published: 2006-04-01   Modified: 2016-04-21  

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