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Research of development and application of the synthesis of fluoroolefins for dipeptide isosteres

Research Project

Project/Area Number 14572010
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Chemical pharmacy
Research InstitutionTokyo Women's Medical University

Principal Investigator

OKADA Midori  Tokyo Women's Medical University, School of Medicine, Lecturer, 医学部, 講師 (20147391)

Co-Investigator(Kenkyū-buntansha) SATO Azusa  Tokyo Women's Medical University, School of Medicine, Research Assistant, 医学部, 助手 (10338965)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 2003: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2002: ¥1,100,000 (Direct Cost: ¥1,100,000)
Keywordspeptide isostere / fluoroolefin / alkylaluminum -copper(I) / S_N2'-type reaction / imine / allylzirconium species / carbocyclization reaction / difluoroalkenyl methine / アルキルアルミニウム-銅(I) / 分子内カルボスタニル化 / ヨードカルボ還化 / アルキルアルミニウムー銅(I)
Research Abstract

Fluoroolefins (-CF=CH-) are considered to be ideal mimics for amide bonds (-CO-NH-) owing to the close similarity of the steric and electric properties. Therefore we researched the synthesis of (Z)-fluoroolefins which attract much attention as nonhydrolyzable and/or conformationally restricted dipeptide or depsipeptide isosteres.
Reaction of (E)-γ,γ-difluoro-α,β-enoates having a δ-hydroxyl group with trialkyl-aluminum (R_3Al) in the presence of CuI・2LiCl proceeded in SN2'-type manner to give α-alkylated (Z)-γ-fluoro-β,γ-enoates, while reductive defluorination with Me_2CuLi followed by reaction with alkyl halides provided the same products. Although both reactions proceed with complete Z-selectivity, low diastereoselectivity on chiral centers (2-and 5-positions) of each reaction is a problem to he solved. Then we examined Cu(I)-mediated alkyl-transfer reaction of R_3Al with (E)-or (Z)-4,4-difluoro-5-hydroxyallylic alcohols, which proceeded in similar manner mentioned above to give the co … More rresponding 2-alkylated (Z)-4-fluoro-5-hydroxyhomoallylic alcohols with 2,5-syn or 2,5-anti selectivity, respectively. As the reaction with R_3Al-Cu(I) of the substrates lacking of hydroxyl group on 5-position didn't proceed, 5-hydroxyl group seemed to be essential for Cu(I)-mediated alkyl-transfer reaction. It is likely that formation of a five-membered complex involving fluorine-aluminum coordination should be the first step in the present reaction. Oxidation of the primary hydroxyl group of the product to carboxylic acid was achieved without epimerization on the chiral centers and 5-hydroxyl group was converted to amino group via sulfonylation, followed by azidation in one-pot manner. We also found the preparation of 4-fluorohomoallylic alcohols via regioselective hydride reduction of 4,4-difluoroallylic alcohols. These reactions provide the stereoselective synthesis or depsipeptide and peptide isosteres.
Furthermore, we examined carbocyclization reaction of the terminally difluorinated alkenyl active methine compounds.
In addition, copper-catalyzed reactions of γ,γ-dialkoxyallylic zirconium species with imines proceeded at γ-position of zirconium species to give homoallylic amines. This result provides the possibility of the preparation of peptide isosteres using zirconium species. Less

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (11 results)

All Other

All Publications (11 results)

  • [Publications] 岡田 みどり: "Synthesis of α-Alkylated(Z)-γ-Fluoro-β,γ-enoates through Organocopper Mediated Reaction of γ,γ-Difluoro-α,β-enoates : A Different Reactivity of R_3Al-Cu(l) and Me2CuLi"Chemistry Letters. 31. 28-29 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 中村 裕子: "Preparation of 6-fluorinated homoallylic alcohol derivatives via regioselective hydride reduction of altytic alcohol derivatives"J.Fluorine Chem.. 117. 143-148 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 岡田 みどり: "Stereoselective construction of functionalized (Z)-fluoroalkene directed to depsipeptide isosteres"Tetrahedron Letters. 43. 5845-5847 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 齋藤 亜紀夫: "Carbocyclization reactions of terminally difluorinated alkenyl active methine compounds mediated by SnCl_4 and amine"J.Fluorine Chem.. 123. 75-80 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Midori Okada: "Synthesis of α-Alkylated (Z)-γ-Fluoro-β,γ-enoates through Organocopper Mediated Reaction of γ,γ-Difluoro-α,β-enoates : A Different Reactivity of R_3Al-Cu(I) and Me_2CuLi"Chemistry Letters. 31. 28-29 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yuko Nakamura: "Preparation of δ-fluorinated homoallylic alcohol derivatives via regioselective hydride reduction of allylic alcohol derivatives"J.Fluorine Chem.. 117. 143-148 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Midori Okada: "Stereoselective construction of functionalized (Z)-fluoroalkene directed to depsipeptide isosteres"Tetrahedron Letters. 43. 5845-5847 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Akio Saito: "Carbocyclization reactions of terminally difluorinated alkenyl active methine compounds mediated by SnCl_4 and amine"J.Fluorine Chem.. 123. 75-80 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 齋藤 亜紀夫: "Carbocyclization reactions of terminally difluorinated alkenyl active methine compounds mediated by SnCl4 and amine"J Fluorine Chem.. 123・1. 75-80 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 岡田 みどり: "Synthesis of α-Alkylated (Z)-γ-Fluoro-β,γ-enoates through Organocopper Mediated Reaction of γ,γ-Difluoro-α,β-enoates : A Different Reactivity of R_3Al-Cu(I) and Me_2CuLi"Chemistry Letters. 28-29 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 岡田 みどり: "Stereoselective construction of functionalized (Z)-fluoroalkenes directed to depsipeptide isosteres-"Tetrahedron Letters. 43. 5845-5847 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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