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

• Published in: Organic & biomolecular chemistry Vol. 6; no. 21; pp. 3908 - 3916
• Main Authors: Linder, Joerg, Blake, Alexander J., Moody, Christopher J.
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 01.01.2008
• Subjects: Biological Products - chemical synthesis; Biological Products - chemistry; Chemistry; Chemistry, Organic; Oxazoles - chemical synthesis; Oxazoles - chemistry; Physical Sciences; Science & Technology; NUDIBRANCH HEXABRANCHUS-SANGUINEUS; SPONGE PHORBAS SP; PHORBOXAZOLE-B; DIAZONAMIDE-A; CYANOBACTERIUM NOSTOC-MUSCORUM; 1ST TOTAL-SYNTHESIS; THIAZOLE ALKALOIDS; FUNCTIONALIZED OXAZOLES; N-H INSERTION; MARINE SPONGE
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/b810855b

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 beta-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.