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

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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.