Synthesis and Biological Activity of Macrocyclic Peroxides

• Project/Area Number: 13650904
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 有機工業化学
• Research Institution: Osaka University
• Principal Investigator: NOJIMA Masatomo Osaka University Graduate School of Engineering, Professor, 大学院・工学研究科, 教授 (80029181)
• Project Period (FY): 2001 – 2002
• Project Status: Completed (Fiscal Year 2002)
• Budget Amount: ¥1,200,000 (Direct Cost: ¥1,200,000); Fiscal Year 2002: ¥1,200,000 (Direct Cost: ¥1,200,000)
• Keywords: Macrocyclic Peroxides / Unsaturated Hvdroperoxides / BCIH-promoted Cyclization / Ozonation / Antimalarial Agents / BCHI プロモータ環化 / 大環状過酸化物 / 求電子的分子内環化反応 / ヨウ素イオン / SCIHメディエータ / 酸素酸化

Research Abstract

Since malaria parasites are rapidly developing resistance to the most commonly used chemo-tnerapeutic alkaloidal drugs, the antimalarial properties of nonalkaloidal compounds such as artemisinin have attracted considerable attention. Based on our original methodologies for the synthesis of medium-sized cyclic peroxides, we tried to develop new synthetic methods of macrocyclic peroxides. The key starting material is unsaturated hydroperoxides, which could be prepared by the mono-alkylation of 1, 1 -bishydroperoxides or selective oxidation of one of the double bonds of dienes. Bis(syn-collidine)iodine(l) hexafluorophosphate-promoted cyclization of the derived unsaturated hydroperoxides was found to give the corresponding 11- to 20-membered cyclic peroxides in excellent yields. Alternatively, ozonolyses of unsaturated hydroperoxides in trifluoroethanol gave the hydroperoxysubstituted cyclic peroxides including the 13-membred one, derived from intramolecular capture of the carbonyl oxide moiety by the hydroperoxy group. We are now investigating the biological activities of these macrocyclic peroxides.

Research Products

• [Publications] T.Tokuyasu et al.: "Yingzhaosu A analogues : synthesis by the ozonolysis of unsaturated hydroperoxides, structural analysis and determination of anti-malarial activity"Tetrahedron. 57. 5979-5989 (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] K.J.McCullough et al.: "The synthesis and crystal structure analysis of novel macrocyclic peroxides"Tetrahedron Letters. 42. 5529-5532 (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] H.-S.Kim et al.: "Synthesis and Antimalarial Activity of Novel Medium-Sized 1,2,4,5-Tetraoxacycloalkanes"Journal of Medicinal Chemistry. 44. 2357-2361 (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] T.Tokuyasu et al.: "Co(III)-Alkyl Complex-and Co(III)-Alkylperoxo Complex-Catalyzed Triethylsilylperoxidation of Alkenes with Molecular Oxygen and Triethylsilane"Organic Letters. 4. 3595-3598 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] H.-S.Kim et al.: "Antimalarial Activity of Yingzhasu A Analogues"Journal of Medicinal Chemistry. 45. 4732-4736 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] T.Ito et al.: "Synthesis of novel macrocyclic peroxides by bis(sym-collidine)iodine(I) hexafluorophosphate-mediated cyclization of unsaturated hydroperoxides and unsaturated alcohols"Tetrahedron. 59. 525-536 (2003)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Takahiro Tokuyasu, Araki Masuyama, Masatomo Nojima, Kevin J. McCullough, Hye-Sook Kim, and Yusuke Wataya: "Yingzhaosu A analogues: synthesis by the ozonolysis of unsaturated hydroperoxides, structural analysis and determination of anti-malarial activity"Tetrahedron. 57 (28). 5979-5989 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kevin J. McCullough, Toyonari Ito, Takahiro Tokuyasu, Araki Masuyama, and Masatomo Nojima: "The synthesis and crystal structure analysis of novel macrocyctic peroxides"Tetrahedron Letters. 42 (32). 5529-5532 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Hye-Sook Kim, Yukiko Nagai, Kanako Ono, Khurshida Begum, Yusuke Wataya, Yoshiaki Hamada, Kaoru Tsuchiya, Araki Masuyama, Masatomo Nojima, and Kevin J. McCullough: "Synthesis and Antimakarial Activity of Novel Medium-Sized 1,2,4,5-Tetraoxacycloalkanes"Journal of Medicinal Chemistry. 44 (14). 2357-2361 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Takahiro Tokuyasu, Shigeki Kunikawa, Araki Masuyama, and Masatomo Nojima: "Co(III)-Alkyl Complex- and Co(III)-Alkylperoxo Complex-Catalyzed Triemylsllyperoxidation of Alkenes with Molecular Oxygen and Triethylsllane"Organic Letters. 4 (21). 3595-3598 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Hye-Sook Kim, Khurshida Begum, Naoki Ogura, Yusuke Wataya, Takahiro Tokuyasu, Araki Masuyama, Masatomo Nojima, and Kevin J. McCutlough: "Antimalarial Activity of Yingzhaosu A Analogues"Journal of Medicinal Chemistry. 45 (21). 4732-4736 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Toyonari Ito, Takahiro Tokuyasu, Araki Masuyama, Masatomo Nojima, and Kevin J. McCutiough: "Synthesis of novel macrocyclic peroxides by bis(sym-coilidine)iodine(l) hexafluorophosphate-mediated cyclization of unsaturated hydroperoxides and unsaturated alcohols"Tetrahedron. 59 (4). 525-536 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] T.Tokuyasu et al.: "Co(III)-Alkyl Complex-and Co(III)-Alkylperoxo Complex-Catalyzed Triethylsilylperoxidation of Alkenes with Molecular Oxygen and Triethylsilane"Organic Letters. 4(21). 3595-3598 (2002)
• [Publications] H.-S.Kim et al.: "Antimalarial Activity of Yingzhaosu A Analogues"Journal of Medicinal Chemistry. 45(21). 4732-4736 (2002)
• [Publications] T.Ito et al.: "Synthesis of novel macrocylic peroxides by bis(sym-collidine)iodine(l) hexafluorophosphate-mediated cyclization of unsaturated hydoroperoxides and unsaturated alcohols"Tetrahedron. 59(4). 525-536 (2003)
• [Publications] T.Kokuyasu et al.: "Yingzhaosu A analogues : synthesis by the ozonolysis of unsaturated hydroeroxides, structural analysis and determination of anti-malarial activity"Tetrahedron. 57(28). 5979-5989 (2001)
• [Publications] K.J.McCullough et al.: "The synthesis and crystal structure analysis of novel macrocyclic peroxides"Tetrahedron Letters. 42(32). 5529-5532 (2001)
• [Publications] H.-S.Kim et al.: "Synthesis and Antimaiarial Activity of Novel Medium-Sized 1, 2, 4, 5-Tetraoxacycloalkanes"Journal of Medicinal Chemistry. 44(14). 2357-2361 (2001)