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

生物催化和有机金属相结合的抗真菌物质的全合成分别从粘杆菌、青霉菌和地衣霉菌中分离得到抗真菌物质--胱噻唑类和美的噻唑类化合物。它们与天然存在的β-甲氧基丙烯酸的同系物--尿囊素和霉唑有关。这些具有双噻唑骨架和β-甲氧基丙烯酸酯部分的抗生素对植物病原真菌显示了强大的抗真菌活性，并对广泛的其他真菌显示出活性，而对细菌生长没有影响。这些β-甲氧基丙烯酸酯(MOA)抑制剂的杀菌活性是由于它们通过阻止细胞色素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。我们描述了基于催化合成β-甲氧基丙烯酸酯部分包括相邻的手性中心的(+)-胱噻唑A，B，F和(4R，5S)-Melithiazoles B，F，H，I的全合成。以(2R，3S)-环氧丁酸酯4为原料，经钯催化的环化-甲氧羰化反应，再甲基化得到(2R，3S)-环氧丁酸酯4，2-二醇3，再经甲基化得到四氢-2-呋喃乙酸酯7，转化为左半醛1。在钯的催化下，双(2R，3S)-3-甲基戊烷-4-炔-1，2-二醇3在钯的催化下环合-甲氧基羰基化，得到四氢-2-呋喃乙酸酯7，转化为左半醛1。5S-美利噻唑B、F、H、I。

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.