Synthesis of Fluoroalkene Dipeptide Isosteres Using Organocopper Reagents

• Project/Area Number: 13672210
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Chemical pharmacy
• Research Institution: KYOTO UNIVERSITY
• Principal Investigator: OTAKA Akira Graduate School of Pharmaceutical Sciences, Kyoto University, Associate Professor, 薬学研究科, 助教授 (20201973)
• Co-Investigator(Kenkyū-buntansha): TAMAMURA Hirokazu Graduate School of Pharmaceutical Sciences, Kyoto University, Assistant Professor, 薬学研究科, 講師 (80217182)
• Project Period (FY): 2001 – 2002
• Project Status: Completed (Fiscal Year 2002)
• Budget Amount: ¥3,400,000 (Direct Cost: ¥3,400,000); Fiscal Year 2002: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 2001: ¥2,000,000 (Direct Cost: ¥2,000,000)
• Keywords: organocopper reagents / fluoroalkene / dipeptide isosteres / samarium diiodide / one-electron reducing agent / samarium dienolate / ジペプチドイスター / ヨウ価サマリウム / ペプチドミメティック

Research Abstract

During the course of our synthetic study of nonhydrolyzabk phosphoamino acid mimetics, we found that γ,γ-difluoro-α,β-enoates were reduced to the corresponding γ-fluoro-β,γ-enoates by organocopper reagents. This reduction was successfully applied to the synthesis of fluoroalkene dipeptide isosteres. During the term of the project, we found several finding as shown below
1. Organocoppermediated reduction seems to proceed via single electron transfer mechanism
2. Based on the above mechanism, reductionoxidative alkylation procedure for the synthesis of α-substituted fluoroalkene dipeptide isosteres
3. SmI_2, representative one-electron reducing agent, is also applicable to the synthesis of fluoroalkene dipeptide isosteres
4. In the SmI_2mediated reduction of γ,γ-difluoro-α,β-enoates, Sm(III)dienolate spicies are likely to be involved Based on formation of this plausible intermediate, kinetitic trapping of the intermediate by aldehydes or ketones were attempted. And this kinetic trapping procedure is proved to be useful for the synthesis of α-substituted fluoroalkene dipeptide isosteres

Research Products

• [Publications] Akira Otaka et al.: "Regio-and Stereoselective Synthesis of (E)-Alkene trans-Xaa-Pro Dipeptide Mimetics Utilizing Organocopper-Mediated Anti-SN2´ Reactions"J. Org. Chem.. 67. 6152-6161 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Akira Otaka et al.: "Remodeling of gp41-C34 Peptide Leads to Highly Effective Inhibitors of the Fusion of HIV-1 with Target Cells"Angew. Chem. Int. Ed.. 41. 2937-2940 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Shinya Oishi et al.: "Diastereoselective Synthesis of New ψ[(E)-CH=CMe]-and ψ[(Z)-CH=CMe]-type Alkene Dipeptide Isosteres by Organocopper Reagents and Application to Conformationally Restricted Cyclic RGD Peptidomimetics"J. Org Chem.. 67. 6162-6173 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Akira Otaka et al.: "Application of samarium diiodide (SmI_2)-induced reduction of γ-acetoxy-α, β-enoates with α-specific kinetic electrophilic trapping for the synthesis of amino acid derivatives"Chem Commun.. (印刷中).
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Akira Otaka et al.: "Synthesis of (Z)-Fluoroalkene Dipeptide Isosteres Utilizing Organocopper-mediated Reduction of γ, γ-Difluoro-α, β-enoates"Tetrahedron Lett.. 42. 285-287 (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Akira Otaka et al.: "New Access to α-Substituted (Z)-Fluoroalkene Dipeptide Isosteres Utilizing Organocopper Reagents under "Reduction-Oxidative Alkylation (R-OA)" Conditions"Tetrahedron Lett.. 42. 5443-5446 (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] A. Otaka, F. Katagiri, T. Kinoshita, Y. Odagaki, S. Oishi, H. Tamamura, N. Hamanaka, and N. Fujii: "Regio and Stereoselective Synthesis of (E)-Alkene trans-Xaa-Pro Dipqptide Mimetics Utilizing Oiganocopper-Mediated Anti-S_N2' Reactions"J. Org. Chem. 67. 6152-6161 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] A. Otaka, M. Nakamura, D. Nameki, E. Kodama, S. Uchiyama, S. Nakamura, H. Nakano, H. Tamamura, Y. Kobayashi, M. Masuoka, and N. Fujii: "Remodeling of gp41-C34 Peptide Leads to Highly Effective Inhibitors of the Fusion of HIV-1 wim Target Cells"Angew. Chem. Int. Ed.. 41. 2937-2940 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] S. Oishi, T. Kamano, A. Niida, Y. Odagaki, N. Hamaaaka, M. Yamamoto, K. Ajito, H. Tamamura, A. Otak, and N. Fujii: "Diastereoselective Synthesis of New Ψ[(E)-CH=Cme]- and Ψ[(Z)-CH=Cme]-type Alkene Dipeptide Isosteres by Organocopper Reagents and Applicatioa to Conformationally Restricted Cyclic RGD Peptidomimetics"J. Org. Chem.. 67. 6162-6173 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] A. Otaka, A. Yukimasa, J. Watanabe, Y. Sasaki, S. Oishi, H. Tamamura, and N. Fujii: "Application of samarium diiodide (SmI_2)-induced reduction of γ-acetoxy-α,β-enoates with α-specific kinetic electrophilic trapping for the synthesis of amino acid derivatives"Chem. Commun.. (in press).
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] A. Otaka, H. Watanabe, E. Mitsuyama, A. Yukimasa, H. Tamamura, and N. Fujii: "Synthesis of (Z)-Fhioroalkene Dipeptide Isosteres Utilizing Organocopper-mediated Reduction of γ,γ-Difluoro-α,β-eaoates"Tetrahedron Lett.. 42. 285-287 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] A. Otaka, H. Watanabe, A. Yukimasa, S. Oishi, H. Tamamura, and N. Fujii: "New Access to α-Substituted (Z)-Fluoroalkene Dipeptide Isosteres Utilizing Organocopper Reagents under "Reduction-Oxidative Alkylation (R-OA)" Conditions"Tetrahedron Lett.. 42. 5443-5446 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Akira Otaka et al.: "Regio-and Stereoselective Synthesis of (E)-Alkene trans-Xaa-Pro Dipeptide Mimetics Utilizing Organocopper-Mediated Anti-SN2' Reactions"J Org. Chem.. 67. 6152-6161 (2002)
• [Publications] Akira Otaka et al.: "Remodeling of gp4l-C34 Peptide Leads to Highly Effective Inhibitors of the Fusion of HIV-1 with Target Cells"Angew. Chem. Int. Ed.. 41. 2937-2940 (2002)
• [Publications] Shinya Oishi et al.: "Diastereoselective Synthesis of New Ψ[(E)-CH=CMe]-and Ψ[(Z)-CH=CMe]-type Alkene Dipeptide Isosteres by Organocopper Reagents and Application to Conformationally Restricted Cyclic RGD Peptidomimetics"J Org. Chem.. 67. 6162-6173 (2002)
• [Publications] Akira Otaka: "Synthesis of (Z)-Fluoroalkene Dipepiide Isosteres Utilizing Organocopper-mediated Reduction of γ,γ-Difluoro-α, β-enoates"Tetrahedron Lett.. 42. 285-287 (2001)
• [Publications] Akira Otaka: "New Access to α-Substituted (Z)-Fluoroalkene Dipeptide Isosteres Utilizing Organocopper Reagents under "Reduction-Oxidative Alkylation (R-OA)" Conditions"Tetrahedron Lett.. 42. 5443-5446 (2001)