diazonamide-a and 2-oxindole

A short formal total synthesis of the marine natural product diazonamide A is described. The route is based on indole oxidative rearrangement, and a number of options were investigated involving migration of tyrosine or oxazole fragments upon oxidation of open chain or macrocyclic precursors. The final route proceeds from 7-bromoindole by sequential palladium-catalysed couplings of an oxazole fragment at C-2, followed by a tyrosine fragment at C-3. With the key 2,3-disubstituted indole readily in hand, formation of a macrocyclic lactam set the stage for the crucial oxidative rearrangement to a 3,3-disubstituted oxindole. Notwithstanding the concomitant formation of the unwanted indoxyl isomer, the synthesis successfully delivered, after deprotection, the key oxindole intermediate, thereby completing a formal total synthesis of diazonamide A.

Topics: Biological Products; Heterocyclic Compounds, 4 or More Rings; Indoles; Molecular Structure; Oxazoles; Oxidation-Reduction; Oxindoles; Stereoisomerism

The synthesis of both the AEFG macrolactam and the CDEFG bis-indole/tyrosine units found in the marine natural product diazonamide A is presented. Key to the success of the synthesis is the highly stereoselective direct C-arylation of an oxindole by an aryllead(IV) reagent derived from tyrosine.

Topics: Benzofurans; Heterocyclic Compounds, 4 or More Rings; Indoles; Oxazoles; Oxindoles; Stereoisomerism; Substrate Specificity; Tyrosine