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New Synthetic Method of Cyclic Peroxide toward the Development of Effective Antimalarial Drugs

Research Project

Project/Area Number 07555583
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section試験
Research Field 有機工業化学
Research InstitutionOsaka University

Principal Investigator

NOJIMA Masatomo  Department of Materials Chemistry, Faculty of Engineering, Osaka University, Full Professor, 工学部, 教授 (80029181)

Project Period (FY) 1995 – 1996
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 1996: ¥4,100,000 (Direct Cost: ¥4,100,000)
Keywordsantimalarial drugs / ozonolysis / carbonyl oxide / cyclic peroxides / trioxepane / pentoxocane / tetroxazocine / hexoxecane / 環状過酸化物 / 1,2,4-トリオキサン / 溶媒捕獲生成物
Research Abstract

To develop new synthetic methods of cyclic peroxides, we used two methodologies. (1) Cycloaddition of carbonyl oxide intermediates, generated from alkene ozonolysis, and (2) cyclizations of the solvent-derived ozonolysis products, prepared by capture of the carbonyl oxide intermediate by protic solvent.
As the important examples of the first methodology, we discovered that (1) [3+3+2] cycloaddition between a carbonyl oxide, a nitrone, and an aldehyde provides a new 8-membered cyclic peroxide 3,4-dihydro-1,2,5,7,4-tetroxazocine derivative and (2) [3+2] cycloadditions of carbonyl oxides to imines lead to the formation of 1,2,4-dioxazolidines ; This is the most general method for the synthesis of this type of cyclic peroxides.
As the examples of the second methodology, we found that (1) ozonolysis of indene derivatives in trifluoroacetic acid provides the alpha-alkoxy-alpha'-hydroperoxy ethers, derived from partial capture of the carbonyl oxide by the adjacent aldehyde group, (2) acid-catalyzed cyclization of the derived ozonolysis product leads to the formation of 10-membered hexoxecane derivatives, while capture of the solvent-derived ozonolysis product by formaldehyde oxide, followed by acidcatalyzed cyclization results in the formation of the 8-membered pentoxocane derivative. (3) By the ozonolysis of vinyl ether in the presence of unsaturated alcohol the corresponding unsaturated hydroperoxy acetal is obtained ; Depending on the structure of the acetals, subsequent N-halosuccinimide-mediated cyclization gives the halogeno-substituted 1,2,4-trioxanes and/or 1,2,4-trioxepanes.
Using owl monkey (Aotus trivirgatus), Professor Mamoru Suzuki of Gumma University is kindly investigating the effectiveness of the prepared cyclic peroxides as the antimalarial drugs.

Report

(3 results)
  • 1996 Annual Research Report   Final Research Report Summary
  • 1995 Annual Research Report
  • Research Products

    (36 results)

All Other

All Publications (36 results)

  • [Publications] K. J. McCullough: "[3+2] Cycloadditions of Carbonyl Oxides to Imines : An Alternative Approach to the Synthesis of 1, 2, 4-Dioxazolidines" J. Chem. Soc., Perkin Trans. 1. -(1). 41-48 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Y. Ushigoe: "New Synthetic Approaches to 1, 2, 4, 5, 7-Pentoxocan Drivatives" Chem. Lett.-(8). 705-706 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] K. Teshima: "Ozonolysis of Indene and of 1-Alkyl-and 1, 1-Dialkyl-Substituted Indenes in Protic Solvents" J. Org. Chem.60(15). 4755-4763 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] S. Satake: "The Synthesis of Novel 3, 4-Dihydro-1, 2, 5, 7, 4-tetroxazocine Derivatives via Extended [3+3+2] Cycloaddition Reactions between a Carbonyl Oxide" J. Chem. Soc., Chem. Commun.-(14). 1469-1470 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Y. Ushigoe: "Transformation of 1-Alkyl-Substituted Indene Ozonides and the Corresponding Solvent-Derived Ozonolysis Products to Tricyclic Peroxides" Tetrahedron Lett.37(12). 2093-2096 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] H. Kuwabara: "Synthesis and Reaction of Cyano-Substituted 1, 2, 4-Trioxolanes" J. Chem. Soc., Perkin Trans. 1. -(9). 871-874 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] H. Yamakoshi: "Ozonolysis of Highly Methylated 1, 2-Bis (methylene) cycloalkanes. Influence of the Methyl Substituents on the Course of the Reaction" J. Org. Chem.61(17). 5939-5943 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] S. Kawamura: "Ozonolyses of 4, 4-Dimethyl-2-cyclohexen-1-yl Acetate and 4, 4-Dimethyl-2-cyclopenten-1-yl Acetate" J. Org. Chem.61(17). 5953-5958 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Y. Ushigoe: "Synthesis of 1, 2, 4-Trioxanes and 1, 2, 4-Trioxepanes by N-Halogenosuccinemide-Mediated Cyclizations of Unsaturated Hydroperoxy Acetals" J. Chem. Soc., Perkin Trans. 1. -(1). 5-10 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] K.J.McCullough, M.Mori, T.Tabuchi, H.Yamakoshi, S.Kusabayashi, and M.Nojima: "[3+2] Cycloadditions of Carbonyl Oxides to Imines : An Alternative Approach to the Synthesis of 1,2,4-Dioxazolidines" J.Chem.Soc., Perkin Trans.1. 1995(1). 41-48

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Y.Ushigoe, M.Nojima, and K.J.McCullough: "New Synthetic Approaches to 1,2,4,5,7-Pentoxocan Derivatives" Chem.Lett.1995(8). 705-706

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] K.Teshima, S.Kawamura, Y.Ushigoe , M.Nojima, and K.J.McCullough: "Ozonolysis of Indene and of 1-Alkyl-and 1,1-Dialkyl-Substituted Indenes in Protic Solvents. Remarkable Effects of the Substituent Steric Bulk and the Solvent Nucleophilicity on the Direction of Cleavage of the Primary Ozonides and on the Mode of Capture of the Carbonyl Oxide Intermediates by the Solvents" J.Org.Chem.60(15). 4755-4763 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] S.Satake, Y.Ushigoe, M.Nojima, and K.J.McCullough: "The Synthesis of Novel 3,4-Dihydro-1,2,5,7,4-tetroxazocine Derivatives via Extended [3+3+2] Cycloaddition Reactions between a Carbonyl Oxide, a Nitrone and an Aldehyde" J.Chem.Soc.Chem.Commun.1995(14). 1469-1470

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Y.Ushigoe, S.Kawamura, K.Teshima, M.Nojima, and K.J.McCullough: "Transformation of 1-Alkyl-Substituted Indene Ozonides and the Corresponding Solvent-Derived Ozonolysis Products to Tricyclic Peroxides ; Isolation and Characterization of Novel Hexoxecane Derivatives" Tetrahedron Lett.37(12). 2093-2096 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] H.Kuwabara, Y.Ushigoe, and M.Nojima: "Synthesis and Reaction of Cyano-Substituted 1,2,4-Trioxolanes" J.Chem.Soc., Perkin Trans 1. 1996(9). 871-874

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] H.Yamakoshi, S.Kawamura, M.Nojima, H.Mayr, and J.Baran: "Ozonolysis of Highly Methylated 1,2-Bis (methylene) cycloalkanes. Influence of the Methyl Substituents on the Course of the Reaction" J.Org.Chem.61(17). 5939-5943 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] S.Kawamura, H.Yamakoshi, and M.Nojima: "Ozonolyses of 4,4-Dimethyl-2-cyclohexen-1-yl Acetate and 4,4-Dimethyl-2-cyclopenten-1-yl Acetate. Competition between the Steric Effects of the Allylic Methyl Groups and the Electronic Effects of the Acetoxy Group on the Direction of Cleavage of the Primary Ozonides" J.Org.Chem.61(17). 5953-5958 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Y.Ushigoe, Y.Kano, and M.Nojima: "Synthesis of 1,2,4-Trioxanes and 1,2,4-Trioxepanes by N-Halogenosuccinimide-Mediated Cyclizations of Unsaturated Hydroperoxy Acetals" J.Chem.Soc., Perkin Trans 1. 1997(1). 5-10

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] K.J.McCullough: "[3+2]Cycloadditions of Carbonyl Oxides to Imines : An Alternative Approach to the Synthesis of 1,2,4-Dioxazolidines" J.Chem.Soc.,Perkin Trans.1. (1). 41-48 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Y.Ushigoe: "New Synthetic Approaches to 1,2,4,5,7-Petoxocan Drivatives" Chem.Lett.(8). 705-706 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] K.Teshima: "Ozonolysis of Indene and of 1-Alkyl-and 1,1-Dialkyl-Substituted Indenes in Protic Solvents" J.Org.Chem.60(15). 4755-4763 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] S.Satake: "The Synthesis of Novel 3,4-Dihydro-1,2,5,7,4-tetroxazocine Derivatives via Extended [3+3+2] Cycloaddition Reactions between a Carbonyl Oxide." J.Chem.Soc.,Chem.Commun.(14). 1469-1470 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Y.Ushigoe: "Transformation of 1-Alkyl-Substituted Indene Ozonides and the Corresponding Solvent-Derived Ozonolysis Products to Tricyclic Peroxides" Tetrahedron Lett.37(12). 2093-2096 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] H.Kuwabara: "Synthesis and Reaction of Cyano-Substituted 1,2,4-Trioxolanes" J.Chem.Soc.,Perkin Trans.1. (9). 871-874 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] K.Tashiro: "First Success in Direct Analysis of Microscopic Deformation Mechamism of Polydiacetylere Single Crystal by the X-ray Imaging-Plate System" Macrowolecules. 29. 8188-8196 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] K.Tashiro: "Stouctural Inves tigation of Orthohon Gic -To -Henagonal Plare Transition in Palyethyleve Cuystal : The Erperimental Corfimation・・・・" Macromolecules. 29. 7460-7469 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] K.Tashiro: "Molecular Fheonatical Study on the Intimate Relationshi P between Structure and Mechauical Propertiss of Polymer Crystals" Polymer. 37. 1775-1786 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] K.Tashiro: "Development of a New Software for the X-ray Stuctural Analysis of Polymer Crystals by Utilizcuy the X-ray Imaging Plate System" J.Polym.Sci : Part B : Polym.Phys. (印刷中).

    • Related Report
      1996 Annual Research Report
  • [Publications] K.Tashiro: "First Application of an X-ray Imaging Plate for the Accurate Evaluation of the Cuystallite Medulus of Polymers" Macromol.Rapid Commun.17. 633-638 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] K.Tashiro: "Cnystal Stuctural change in Poly (3-A/Ky/ Thiophene) s Jrduced by Ipdine Doping" Polymer. (印刷中).

    • Related Report
      1996 Annual Research Report
  • [Publications] K.Tashiro: "Ferroelectric Polymers (Structural Phese Transiton)" CRC Press,Jnc., 2312-2320 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] K.Tashiro: "Crgstalline Polymers (Structural Aspects)" CRC Press,Jnc, 4322-4330 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Y.Ushigoe: "New Synthetic Approaches to 1,2,4,5,7-Pentoxocan Derivatives" Chemistry Letters. 705-706 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] K.Teshima: "Ozonolysis of Indene and of 1-Alkyl-and 1,1-Dialkyl-Substituted Indenes in Protic Solvents" Journal of Organic Chemistry. 60. 4755-4763 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] S.Satake: "The Synthesis of Novel 3.4-Dihydro-1,2,5,7,4-tetroxazocine Derivatives via Extended [3+3+2] Cycloaddition Reactions" J.Chem.Soc.,Chemical Communications. 1469-1470 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] K.J.McCullough: "[3+2] Cycloadditions of Carbonyl Oxides to Imines:An Alternative Approach to the Synthesis of 1,2,4-Dioxazolidines" J.Chem.Soc., Perkin Transactions 1. 41-48 (1995)

    • Related Report
      1995 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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