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2006 Fiscal Year Final Research Report Summary

Development of synthesis and applications of fluoroolefins directed to peptide mimetics.

Research Project

Project/Area Number 16590014
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, Associate Professor, 医学部, 准教授 (20147391)

Co-Investigator(Kenkyū-buntansha) SATO Azusa  Tokyo Women's Medical University, School of Medicine, Assistant Professor, 医学部, 助教 (10338965)
NAKAMURA Yuko  Tokyo Women's Medical University, School of Medicine, Assistant Professor, 医学部, 助教 (00161216)
Project Period (FY) 2004 – 2006
Keywordspeptide isostere / fluoroalkenes / organofluorine compounds / copper(I) mediated reaction / γ,γ-dialkoxyallylic zirconium species / carbon-carbon bond forming reaction
Research Abstract

(Z)-fluoroolefins attracts much attention as a no hydrolysable dipeptide isostere. For the construction of fluorinated dipeptide isosteres, stereocontrol of the fluoroolefin part and relative stereochemistry of two chiral centers at C2 and C5 should be major issues to be solved. We developed reductive defluorination of γ,γ-difluoro-α,β-enoates with lithiocuprate followed by reaction with alkyl halides to give the corresponding (Z)-a-alkylated products in high yields. This reaction was applied to the preparation of dipeptide (Z)-fluoroalkene isostere of Sta-Ala, which is the central dipeptide unit in Pepstatin, a natural inhibitor of aspartate proteases. Optically pure γ,γ-difluoro-α,β-enoate derived from N-Boc leucinol was converted to the desired α-methylated product in excellent yield in moderate Z selectivity (Z/E=6.4:1), but without diasteroselectivity. Fortunately, separation of the product mixture could be carried out to give N-Boc-Sta-Ψ[CF=CH]-Ala ethyl ester. This reaction was … More also applicable to construction of fluorinated Bestatin analogues which is a protease inhibitor and has been used as an anticancer drug.
As a new strategy, defluorinative allylic alkylation of 4,4-difluoro-3-hydroxy-5-alkenol derivatives were achieved using Grignard reagent and a catalytic amount of CuI (20 mol%) to afford 6-alkylated 4-fluoro-3-hydroxy-4-alkenols 1. Then, 1 was converted to 5-amino-4-fluoro-3-alkenol derivatives through Overman reaction or one-pot mesylation-azidation reaction in 2,5-syn or 2,5-anti selectivity, respectively. These reactions are useful methods for the diastereoselective construction of fluorinated peptide isosteres.
We have developed carbon-carbon bond-forming reaction using γ,γ-dialkoxyallylic zirconium species 2. Without an additive, 2 reacts with carbonyl compounds at the γ-position of 2. Under Lewis acid prompted conditions, 2 reacts with carbonyl compounds at the β-position followed by the cyclopropanation or cyclobutanation reaction.
In the presence of CuCN, reaction of 2 with imines proceeded at the γ-position to give gem-dialkoxyhomoallylic amines in high yield. The product could be changed to the vinyl ketones. Less

  • Research Products

    (12 results)

All 2007 2006 2005

All Journal Article (12 results)

  • [Journal Article] γ,γ-ジアルコキシアリルジルコニウム種を用いた炭素・炭素結合形成反応の開発2007

    • Author(s)
      伊藤 久央
    • Journal Title

      有機合成化学協会誌 65・1

      Pages: 54-56

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Development of Carbon-Carbon Bond-Forming Reactions using gamma, gamma-Dialkoxyallylic Zirconium Species.2007

    • Author(s)
      Hisanaka Ito, Azusa Sato, Takeo Taguchi
    • Journal Title

      Journal of Synthetic Organic Chemistry, Japan. 65(1)

      Pages: 54-64

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] An efficient synthetic method for Z-fluoroalkene dipeptide isosteres : Application to the synthesis of the dipeptide isostere of Sta-Ala.2006

    • Author(s)
      中村 裕子
    • Journal Title

      J. Fluorine Chem. 127・4-5

      Pages: 627-636

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] An efficiensynthetic method for Z-fluoroalkene dipeptide isosteres : Application to the synthesis of the dipeptide isostere of Sta-Ala.2006

    • Author(s)
      Y.Nakamura, M.Okada, M.Koura, M.Tojo, A.Saito, A.Sato, T.Taguchi
    • Journal Title

      J.Fluorine Chem. 127(4-5)

      Pages: 627-636

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Copper-catalyzed addition reaction of γ,γ-dialkoxyallylic zirconium species with imines.2005

    • Author(s)
      佐藤 梓
    • Journal Title

      Tetrahedron Lett. 46・48

      Pages: 8381-8383

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Stereoselective synthesis of (Z)-fluoroalkenes directed to peptide isosteres : Copper mediated reaction of trialkylaluminum with 4,4-difluoro-5-hydroxyallylic alcohol derivatives.2005

    • Author(s)
      中村 裕子
    • Journal Title

      Tetrahedron 61・24

      Pages: 5741-5753

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Lewis acid promoted reactions of γ,γ-dialkoxyallylic zirconium species with various carbonyl compounds.2005

    • Author(s)
      伊藤 久央
    • Journal Title

      Tetrahedron 61・46

      Pages: 10868-10879

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Highly Regioselective Coupling Reactions of Allylic and Propargylic Alcohol.2005

    • Author(s)
      佐藤 梓
    • Journal Title

      J. Org. Chem. 70・2

      Pages: 709-712

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Copper-catalyzed addition reaction of γ,γ-dialkoxyallylic zirconium species with imines.2005

    • Author(s)
      A.Sato, H.Ito, M.Okada, Y.Nakamura, T.Taguchi
    • Journal Title

      Tetrahedron Lett. 46(48)

      Pages: 8381-8383

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Stereoselective synthesis of (Z)-fluoroalkenes directed to peptide isosteres : copper mediated reaction of trialkylaluminum with 4,4-difluoro- 5-hydroxyallylic alcohol derivatives.2005

    • Author(s)
      Y.Nakamura, M.Okada, A.Sato, H.Horikawa, M.Koura, A.Saito, T.Taguchi
    • Journal Title

      Tetrahedron 61(24)

      Pages: 5741-5753

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Lewis acid promoted reactions of γ,γ-dialkoxyallylic zirconium species with various carbonyl compounds.2005

    • Author(s)
      H.Ito, A.Sato, T.Taguchi
    • Journal Title

      Tetrahedron 61(46)

      Pages: 10868-10879

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Highly Regioselective Coupling Reactions of Allylic and Propargylic Alcohol.2005

    • Author(s)
      A.Sato, H.Ito, T.Taguchi
    • Journal Title

      J.Org.Chem. 70(2)

      Pages: 709-712

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2008-05-27  

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