Synthetic Study on Ecteinascidin 743, Potent and Scarcity Antitumor Natural Product

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Ecteinascidin 743 (Et 743) is an extremely potent antitumor agent isolated from a marine tunicate, Ecteinascidia turbinata. Based on promising results in phase II clinical trials, Et 743 is likely to become the first anticancer drug among marine natural products. The novelty of its structure, the remarkable biological activities, and its natural scarcity have made it an attractive target for total synthesis. We accomplished an efficient total synthesis of Et 743 that would potentially lead to the development of a practical synthesis of this important compound. The synthesis was started from a large scale preparation of left and right segment. These two segments were efficiently coupled by the Ugi's 4CC reaction, and transformed into the cyclic enamide via diketopiperazine. Intramolecular Heck reaction of the enamide proceeded smoothly to give the bicyclo[3.3.1] skeleton. Construction of B-ring was performed by the phenol-aldehyde cyclization, giving the desired pentacyclic compound. After conversion to the sulfur-containing ten-membered lactone, construction of tetrahydroisoquinoline moiety was afforded ecteinascidin 743.