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Development of viable synthetic route to the furaquinocins and its application to creating new antitumor agents

Research Project

Project/Area Number 09554045
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field 物質変換
Research InstitutionTokyo Institute of Technology

Principal Investigator

SUZUKI Keisuke  Professor, Tokyo Institute of Technology, 大学院・理工学研究科, 教授 (90162940)

Co-Investigator(Kenkyū-buntansha) FUJIMOTO Katsumi  Sankyo Co., 活性物質研究所, 副主任研究員
OHMORI Ken  Assistant Professor, Tokyo Institute of Technology, 理工学研究科, 助手 (50282819)
MATSUMOTO Takashi  Associate Professor, Tokyo Institute of Technology, 理工学研究科, 助教授 (70212222)
藤本 克巳  三共(株), 活性物質研究所, 副主任研究員
Project Period (FY) 1997 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥10,200,000 (Direct Cost: ¥10,200,000)
Fiscal Year 1999: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1998: ¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1997: ¥4,900,000 (Direct Cost: ¥4,900,000)
Keywordsfuraquinocin / antitumor compound / chemical synthesis / 抗生物質 / 全合成 / 転位反応 / 立体選択的反応
Research Abstract

An efficient and flexible synthetic route to the furaquinocins, a new class of antibiotics which show cytotoxic activity against HeLa S3 and B16 melanoma cells but no antimicrobial activity, was developed. These compounds pose new synthetic challenges due to their unique hybrid structure composed of the polyketide-derived naphthoquinone and the isoprenoid side chain, including (1) stereocontrol of three contiguous stereogenic centers at C-2, C-3 (quaternary), and C-10, (2) selective construction of the densely functionalized naphthoquinone, and (3) establishment of the sterically congested aromatic-isoprenoid hybrid structure.
Stereocontrolled construction of two of the three contiguous stereogenic centers, including a quaternary chiral center, was effected by the 1,2-rearrangement of optically active epoxy alcohol armed with the cobalt-complexed alkyne as the migrating group. The alkyne in the resulting homopropargyl alcohol, after decoordination of the cobalt, effectively worked as the C2 unit for constructing the naphthofuran skeleton by an electrocyclic benzannulation. The third chiral center was constructed by stereoselective methylenation of the aldehyde, adjacent to the quaternary chiral center, by a sulfur ylide. Through the resulting epoxide as the common intermediate, total syntheses of furaquinocin D, furaquinocin A, furaquinocin B, and furaquinocin H were achieved in a convergent manner.
Biological activity test revealed that some of the synthetic intermediates exhibit potent cyctocidal activities comparable to natural furaquinocins, which provides a valuable information for designing new synthetic antitumor agents.

Report

(4 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] T. Saito, T. Matsumoto, K, Suzuki: "Stereocontrolled Convergent Total Synthesis of dl-Furaquinocin D"J. Am. Chem. Soc.. 117. 10757-10758 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T. Nagasawa, K. Suzuki: "Novel Migrating Group in 1,2-Anionotropic Reactions : Cobalt-Complexation Facilities 1,2-Shift of Aklynyl Groups"J. Am. Chem. Soc.. 118. 8949-8950 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] K. Taya, K. Suzuki: "Enantiopure Acetals of α-Alkynyl Carbonyl Compounds : Organoaluminum-Medidated 1,2-Shift of Cobalt-Complexed Alkynyl Group with Concomitant Capture by a Nucleophile"Synlett. 1997. 304-306 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T. Saito, T. Matsumoto, K, Suzuki: "Implication and Improvement of Stereoselective Methylenetion of a Chiral Aldehyde Related to Total Synthesis of Furaquinocins"Tetrahedron Lett.. 38. 3755-3758 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T. Saito, T. Matsumoto, K, Suzuki: "Total Synthesis of the Fraquinocins"J. Am. Chem. Soc.. 120. 11633-11644 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T. Saito, T. Matsumoto, K. Suzuki: "Stereocontroled Convergent Total Synthesis of dl-Furaquinocin D"J. Am. Chem. Soc.. 117. 10757-10758 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T. Nakagawa, K. Suzuki: "Novel Migrating Group in 1,2-Anionotropic Reactions : Cobalt-Complexation Facilitates 1,2-Shift of Alkynyl Groups"J. Am. Chem. Soc.. 118. 8949-8950 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] K. Taya, K. Suzuki: "Enantiopure Acetals of a-Alkynyl Carbonyl Compounds : Organoaluminum-Mediated 1,2-Shift of Cobalt-Complexed Alkynyl Group with Concomitant Capture by a Nucleophile"Synlett. 304-306 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T. Saito, T. Matsumoto, K. Suzuki: "Implication and Improvement of Stereoselective Methylenetion of a Chiral Aldehyde Related to Total Synthesis of Furaquinocins"Tetrahedron Lett. 38. 3755-3758 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T. Saito, T. Matsumoto, K. Suzuki: "Total Synthesis of the Fraquinocins"J. Am. Chem. Soc.. 120. 11633-11644 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 斉藤 丈: "Total Synthesis of the F aquinocins" Journal of the American chemical Society. 120・45. 11633-11644 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 斉藤 丈: "Impication and Improvement of Selective Methylenation of a Chiral Aldehycle Related to Total Synthesis of the Fraquinoctns" Te+rahedron Letters. 38・21. 3755-3759 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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