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

强效稀有抗肿瘤天然产物Ecteinascidin 743的合成研究

• 批准号: 12307052
• 负责人: FUKUYAMA Tohru
• 金额: $ 16.83万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12307052/
• 关键词: Ecteinascidin 743; antitumor; anticancer drug; total synthesis; natural scarcity; tetrahydroisoquinoline; Ugi's 4CC reaction; Heck reaction; 抗ガン剤; 立体選択的; セグメント; UGIの連結反応; 類縁体; 10員環チオエーテル化; 大量供給; ピペラジン; テトラヒドロイソキノリン; 光学活性イミノエステル; 不斉アミノヒドロ

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.

Ecteinascidin 743（Et 743）是一种从海洋被囊动物Ecteinascidia turbinata中分离得到的高效抗肿瘤药物。基于II期临床试验的良好结果，Et 743可能成为海洋天然产物中的第一个抗癌药物。其新奇的结构、显著的生物活性和天然的稀缺性使其成为全合成的一个有吸引力的目标。我们完成了Et 743的有效全合成，这将潜在地导致开发这种重要化合物的实际合成。合成从左片段和右片段的大规模制备开始。这两个片段通过Ugi的4CC反应有效地偶联，并通过二酮哌嗪转化为环烯酰胺。烯酰胺的分子内Heck反应顺利进行，得到双环[3.3.1]骨架。通过苯酚-醛环化进行B环的构建，得到所需的五环化合物。在转化为含硫的十元内酯后，构建四氢异喹啉部分，得到海鞘素743。

项目成果

T.Fukuyama: "Highy Versatile Synthesis of Polyamines by the Ns-strategy on a Novel Trityl Chloride Resin"synlett. 1338-1340 (2002)

T.Fukuyama：“在新型三苯甲基氯树脂上通过 Ns 策略高度通用地合成多胺”synlett。

T.Fukuyama: "Facile Construction of N-Hydroxybenzazocine : Enantioselective Total Synthesis of (+)-FR900482"Angew.Chem.Int.Ed.. 41. 4686-4687 (2002)

T.Fukuyama：“N-羟基苯并佐辛的简便构建：( )-FR900482的对映选择性全合成”Angew.Chem.Int.Ed.. 41. 4686-4687 (2002)

Tetsuji Itho, Manabu Watanabe, Tohru Fukuyama: "Synthetic Approach to Tetrodotoxin"Synlett. 1323 (2002)

Tetsuji Itho、Manabu Watanabe、Tohru Fukuyama：“河豚毒素的合成方法”Synlett。

T.Fukuyama: "Total Synthesis of Ecteinascidin 743"J.Am.Chem.Soc.. 124. 6552-6555 (2002)

T.Fukuyama：“Ecteinascidin 743 的全合成”J.Am.Chem.Soc.. 124. 6552-6555 (2002)

Toshiyuki Kan, Akiko Fujiwara, Hideki Kobayashi, Tohru Fukuyama: "Efficient Macrocyclization by Means of 2-Nitrobenzenesulfonamide and Total Synthesis of Lipogrammistin-A"Tetrahedron. 58. 6267 (2002)

Toshiyuki Kan、Akiko Fujiwara、Hideki Kobayashi、Tohru Fukuyama：“通过 2-硝基苯磺酰胺进行高效大环化和 Lipogrammistin-A 的全合成”四面体。