Total synthesis of siphonazole and its O-methyl derivative, structurally unusual bis-oxazole natural products?

Organic & Biomolecular Chemistry Pub Date: 2008-09-02 DOI: 10.1039/B810855B

Abstract

The details of the first syntheses of the unusual bis-oxazole natural products siphonazole and its O-methyl derivative are reported. The cinnamyl substituted oxazole was constructed using diazocarbonyl chemistry, whereby the cinnamamide was reacted with the rhodium carbene derived from methyl 2-diazo-3-oxobutanoate to give a β-ketoamide that was cyclodehydrated to the corresponding oxazole-4-ester. Reduction to the corresponding aldehyde was followed by coupling with a zinc reagent derived from methyl 2-iodomethyl-5-methyloxazole-4-carboxylate, also prepared using rhodium carbene chemistry, to give, after oxidation of the resulting secondary alcohol, the desired bis-oxazole ketone. The syntheses were completed by hydrolysis of the ester and coupling of the 2,4-pentadienylamine side chain.

Graphical abstract: Total synthesis of siphonazole and its O-methyl derivative, structurally unusual bis-oxazole natural products
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