Total Synthesis of Natural Products utilizing Selective Cross-coupling and the Diels-Alder Reaction of 3,5-dibromo-2-pyrone. 1. Total Synthesis of (∂)-Galanthamine. 2. Total Synthesis of (∂)-Aspidospermidine.

Abstract

Reinvestigation on the regioselective Stille reaction of 3,5-dibromo-2-pyrone disclosed the possibility of a reversible oxidative addition mechanism. The established regioselective cross coupling reactions were applied to the studies of total syntheses of clivonine, 3-demethoxyerythratidinone, galanthamine and aspidospermidine. Despite the incompleteness, some of the persistent problems of our laboratory such as the problems of the Curtius reaction and the retro-Aldol lactone ring opening were addressed and the debromination reaction using zinc successfully replaced the erratic tin hydride reduction. The total synthesis of galanthamine was completed by tandem Stille coupling/IMDA cascade over 15 steps. The identification of the formation of the impurities during the cascade allowed enhancement of yield and reproducibility of the step. Also studies toward the total synthesis of aspidospermidine suggested detours for the ring cyclization tactics and contributed the imino Diels�XAlder reaction route for the successful synthesis of aspidospermidine. Finally, new schemes of the synthesis of morphine and aplykurodinone-1 were proposed and some preliminary experiments were carried out.