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

基于生物催化和有机金属方法相结合的抗真菌物质的全合成

• 批准号: 14572016
• 负责人: AKITA Hiroyuki
• 金额: $ 2.11万
• 依托单位: Toho University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14572016/
• 关键词: cystothiazole; melithiazole; antibiotic; total synthesis; lipase; palladium; cystothiazole; リバーゼ; biocatalyst; lipase; palladium; chiral syuthesis; antibiotic

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

基于生物催化和有机合成相结合的抗真菌活性物质的全合成从不同的粘细菌Cystophylusfuscus和Melittangiumlichenicola中分离得到了抗真菌活性物质，分别为cystothiazoles和melithiazoles。它们与Oudemansins和Myxothiazole有关，后者是β-甲氧基丙烯酸的天然同系物。这些具有双噻唑骨架以及β-甲氧基丙烯酸酯部分的抗生素已经显示出对植物病原性真菌的有效抗真菌活性，并且已经显示出对广泛的其他真菌的活性，而对细菌生长没有影响。这些β-甲氧基丙烯酸酯（MOA）抑制剂的杀真菌活性已被证明是由于它们通过阻断细胞色素B和细胞色素c之间的电子转移来抑制线粒体呼吸的能力。本文报道了（+）-硫代噻唑A、B、F和（4 R，5S）-甲基噻唑B、F、H、I的全合成，其基础是催化合成含有相邻手性中心的β-甲氧基丙烯酸酯部分。通过逆合成，可以通过左半醛1和右半碘化磷鎓 2的Wittig缩合来实现硫代噻唑和甲基噻唑的合成。由（2 R，3S）-环氧丁酸酯4衍生的（2 R，3S）-3-甲基戊-4-炔-1，2-二醇3经钯催化的环化-甲氧基羰基化，然后甲基化，得到四氢-2-呋喃亚基乙酸酯7，将其转化为左半醛1。1与衍生自双噻唑型碘化磷鎓 2的正膦酰基之间使用双（三甲基甲硅烷基）氨基锂进行Wittig反应，得到（+）-硫代噻唑A、B、F和（4 R，5 S）-甲基噻唑B、F、H、I。

项目成果

秋田弘幸 他9名: "(+)-cystothiazole G : Isolation and Structural Elicidation"Tetrahedron. 60. 4735-4738 (2004)

Hiroyuki Akita 和其他 9 人：“(+)-cystothiilla G：分离和结构消除”Tetrahedron 60. 4735-4738 (2004)。

K.Kato, A.Nishimura, Y.Yamamoto, H.Akita: "Improved method for the synthesis of (E)-cyclic-β-alkoxyacrylates under mild conditions"Tetrahedron Letters. 42. 4203-4205 (2001)

K. Kato、A. Nishimura、Y. Yamamoto、H. Akita：“在温和条件下合成 (E)-环状-β-烷氧基丙烯酸酯的改进方法”Tetrahedron Letters 42. 4203-4205 (2001)。

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)

秋田 H.、佐佐木 T.、加藤 K.、铃木 Y.、近藤 K.、坂上 Y.、小鹿 M.、福藤 R.、山中 S.：“( )-胱噻唑

Sasaki, T., Kato, K., Akita, H.: "Determination of Absolute Structure of (+)-cystothiazole B"Chem.Pharm.Bull.. 52(in press). (2004)

Sasaki, T.、Kato, K.、Akita, H.：“( )-胱噻唑 B 绝对结构的测定”Chem.Pharm.Bull.. 52（印刷中）。

秋田弘幸他9名: "(+)-cystothiazole G : Isolation and Structural Elicidation"Tetrahedron. 60巻(印刷中). (2004)

Hiroyuki Akita 和其他 9 人：“(+)-胱噻唑 G：分离和结构消除”四面体第 60 卷（印刷中）。