DAPHNIPHYLLUM ALKALOIDS .15. TOTAL SYNTHESES OF (+/-)-METHYL HOMODAPHNIPHYLLATE AND (+/-)-DAPHNILACTONE-A

Biomimetic total syntheses of (+/-)-daphnilactone A (6) and (+/-)-methyl homodaphniphyllate (4) have been carried out. The syntheses began with the preparation of tricyclic lactone ether 18d, which was reduced to diol 19d with LiAlH4. Oxidation of 19d gave a sensitive dialdehyde (20d), which was treated sequentially with ammonia and warm acetic acid to obtain the hexacyclic amino ether 22d. The tetracyclization process leading from 19d to 22d proceeded in 47% yield and resulted in the formation of five new sigma-bonds and four new rings. After hydrogenation of the double bond, the saturated amino ether 7 was fragmented by treatment with diisobutylaluminum hydride in refluxing toluene. Unsaturated amino alcohol 23 was obtained in 71% yield, accompanied by a smaller amount of the simple elimination product 24. Compound 23 was converted into (+/-)-daphnilactone A (6) by oxidation to the unsaturated amino acid, which was cyclized by treatment with aqueous formaldehyde at pH 7. For the preparation of 4, compound 23 was oxidized and the resulting amino acid esterified to obtain 26. Treatment of this compound with phenyl isocyanate gave a urea derivative (27) that underwent smooth cyclization to (+/-)-methyl homodaphniphyllate (4) in refluxing formic acid. From homogeranyl iodide, the limiting starting material, compound 6 was obtained in 11 steps and 8% overall yield and compound 4 was obtained in 13 steps and 11% overall yield.