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2003 Fiscal Year Final Research Report Summary

Total Synthesis of Antifungal Substances Based on a Combination of Biocatalytic and Organometalic Methods

Research Project

Project/Area Number 14572016
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Chemical pharmacy
Research InstitutionToho University

Principal Investigator

AKITA Hiroyuki  Toho University, School of Pharmaceutical Sciences, Professor, 薬学部, 教授 (60087525)

Co-Investigator(Kenkyū-buntansha) KINOSITA Masako  Toho University, School of Pharmaceutical Sciences, Assistant Professor, 薬学部, 助手 (10277345)
KATO Keisuke  Toho University, School of Pharmaceutical Sciences, Lecturer, 薬学部, 講師 (80276609)
ONO Machiko  Toho University, School of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (80104149)
Project Period (FY) 2002 – 2003
Keywordscystothiazole / melithiazole / antibiotic / total synthesis / lipase / palladium
Research Abstract

Total Synthesis of Antifungal Substances Based on a Combination of Biocatalytic and Organometalic Methods
Antifungal substances, cystothiazoles and melithiazoles, were isolated from different strains of myxobacterium Cystobacter fuscus and Melittangium lichenicola, respectively. They are related to the oudemansins and myxothiazole which are naturally occurring congeners of β-methoxyacrylic acid. These antibiotics possessing a bis-thiazole skeleton as well as a β-methoxyacrylate moiety have indicated potent antifungal activity against the phytopathogenic fungus, and have shown activity against a broad range of additional fungi with no effect on bacterial growth. The fungicidal activity of these β-methoxyacrylate (MOA) inhibitors has been shown to be due to their ability to inhibit mitochondrial respiration by blocking electron transfer between cytochrome b and cytochrome c. We describe total synthesis of (+)-cystothiazoles A, B, F and (4R, 5S)-melithiazoles B, F, H, I based on a catalytic synthesis of the β-methoxyacrylate moiety including the adjacent chiral centers. Retrosynthetically, the synthesis of cystothiazoles and melithiazoles can be achieved by Wittig condensation of the left-half aldehyde 1 and the right-half phosphonium iodide 2. Palladium-catalyzed cyclization-methoxycarbonylation of (2R, 3S)-3-methylpenta-4-yne-1, 2-diol 3 derived from (2R, 3S)-epoxy butanoate 4 followed by methylation gave the tetrahydro-2-furylidene acetate 7, which was converted to the left-half aldehyde 1. A Wittig reaction between 1 and the phosphoranylide derived from the bithiazole-type phosphonium iodide 2 using lithium bis(trimethylsilyl)amide afforded the (+)-cystothiazoles A, B, F and (4R, 5S-melithiazoles B, F, H, I.

  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] 秋田弘幸 他3名: "New total synthesis of(±)-,(-)-and(+)-Chuangxinmycins."Tetrahedron. 57. 10055-10062 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 秋田弘幸 他3名: "Improved method for the synthesis of(E)-cyclic-β-alkoxy-acrylates under mild conditions."Tetrahedron Letters. 42. 4203-4205 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 秋田弘幸 他3名: "New total synthesis of(+)-cystothiazole A"Tetrahedron Letters. 43. 643-645 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 秋田弘幸 他3名: "New total synthesis of(+)-cystothiazole A based on palladium-catalyzed cyclization-methoxycarbonylation"Tetrahedron. 59. 2679-2685 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 秋田弘幸 他9名: "(+)-cystothiazole G : Isolation and Structural Elicidation"Tetrahedron. 60. 4735-4738 (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 秋田弘幸 他2名: "Determination of Absolute Structure of (+)-cystothiazole B"Chem.Pharm.Bull.. 52(印刷中). (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kato, K., Ono, M., Akita, H.: "New total synthesis of (±)-, (-)-and (+)-Chuangxinmycins."Tetrahedron. 57. 10055-10062 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kato, K., Nishimura, A., Yamamoto, Y., Akita, H.: "Improved method for the synthesis of (E)-cyclic-β-alkoxy-acrylates under mild conditions."Tetrahedron Letters. 42. 4203-4205 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kato, K., Nishimura, A., Yamamoto, Y., Akita, H.: "New total synthesis of (+)-cystothiazole A"Tetrahedron Letters. 43. 643-645 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kato, K., Sasaki, T., Takayama, H., Akita, H.: "New total synthesis of (+)-cystothiazole A based on palladium-catalyzed cyclization-methoxycarbonylation"Tetrahedron.. 59. 2679-2685 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Akita, H., Sasaki, T., Kato, K., Suzuki, Y., Kondo, K., Sakagami, Y., Ojika, M., Fudou, R., Yamanaka, S.: "(+)-cystothiazole G: Isolation and Structural Elicidation"Tetrahedron.. 60. 4735-4738 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sasaki, T., Kato, K., Akita, H.: "Determination of Absolute Structure of (+)-cystothiazole B"Chem.Pharm.Bull.. 52(in press). (2004)

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

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Published: 2005-04-19  

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