Summarized in this article are our total syntheses of Ecteinascidin 743 (Et 743, 1) which is an extremely potent antitumor alkaloid isolated from a marine tunicate,
Ecteinascidia turbinata. Based on promising results in phase II and III clinical trials, Et 743 (1) 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. In 2002, we accomplished a convergent and stereocontrolled total synthesis of 1 that would potentially lead to the development of a practical synthesis of this important compound.
Synthesis of the left segment 77, a highly functionalized (
R) -arylglycinol derivative, involves a Mannich-type reaction of phenol 73 with the chiral template 65 developed recently in our laboratories. The right segment 81, (
S) -iodophenylalanine derivative, was synthesized by employing DuPHOS-Rh mediated asymmetric hydrogenation as the key step. These two segments were efficiently coupled by the Ugi's 4 CC reaction, and transformed into the cyclic enamide 87
via diketopiperazine 86. Intramolecular Heck reaction of the enamide 87 proceeded smoothly to give 88, containing the bicyclo [3.3.1] skeleton, in high yield. Construction of B-ring was performed by the phenol-aldehyde cyclization of 95, which was invoked by hydrogenolysis of the benzyl groups, giving the desired pentacycle 96 with requisite oxidation state at C-4 position. An acid-induced intramolecular sulfide formation provided the sulfur-containing ten-membered lactone 100. Finally, construction of tetrahydroisoquinoline moiety by the Pictet-Spengler reaction and treatment with AgNO
3, was successfully converted to ecteinascidin 743 (1).
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