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

海鞘杀菌素743(ET743)是从海洋毛囊藻类Eteinascidia turbinata中分离得到的一种非常有效的抗肿瘤药物。基于第二阶段临床试验的良好结果，ET 743很可能成为海洋天然产物中的第一个抗癌药物。其结构新颖，具有显著的生物活性，天然稀缺性使其成为一种极具吸引力的全合成目标。我们完成了ET 743的高效全合成，这可能会导致这一重要化合物的实用合成的发展。该合成是从左、右段的大规模制备开始的。这两个链段通过UGI的4CC反应有效地偶联，并通过二酮基哌嗪转化为环烯酰胺。烯胺的分子内Heck反应顺利进行，得到了双环[3.3.1]骨架。通过酚醛环合反应合成了B环，得到了所需的五环化合物。在转化为含硫十元内酯后，构建了四氢异喹啉结构基团，得到了内酯743。

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.