16 エクチナサイジン743の全合成(口頭発表の部)

• 遠藤 篤史

  東大院薬

• 柳沢 新

  東大院薬:(現)協和発酵工業(株)堺研究所

• 阿部 昌尚

  東大院薬

• 當間 重光

  東大院薬

• 菅 敏幸

  東大院薬

• 福山 透

  東大院薬

書誌事項

タイトル別名

• 16 Total Synthesis of Ecteinascidin 743

抄録

Ecteinascidin 743 (Et 743, 1) is an extremely potent antitumor agent isolated from a marine tunicate, Ecteinascidia turbinata. Based on promising results in phase II 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. We describe herein an efficient total synthesis of 1 that would potentially lead to the development of a practical synthesis of this important compound. Synthesis of the left segment 23, a highly functionalized (R)-phenylglycinol derivative, involves a Mannich-type reaction of phenol 19 with the chiral template 16 developed recently in our laboratories. The right segment 32, (S)-iodophenylalanine derivative, was synthesized in 13 steps from 3-methylcatechol (24) by employing DuPHOS-mediated asymmetric hydrogenation as the key step. These two segments were efficiently coupled by the Ugi's 4CC reaction, and transformed into the cyclic enamide 38 via diketopiperazine 37. Intramolecular Heck reaction of the enamide 38 proceeded smoothly to give 39, containing the bicyclo[3.3.1] skeleton, in high yield. The stereochemistry at C-3 position was controlled by stereoselective reduction of the acyliminium intermediate to give the key intermediate 42. Construction of B-ring was performed by the phenol-aldehyde cyclization of 44, which was invoked by hydrogenolysis of the benzyl groups, giving the desired pentacycle 45 with requisite oxidation state at C-4 position. An acid-induced intramolecular sulfide formation provided the sulfur-containing ten-membered lactone 48. Finally, construction of tetrahydroisoquinoline moiety by means of the Pictet-Spengler reaction with 4 afforded Et 770 (2), which, upon treatment with AgNO_3, was successfully converted to ecteinascidin 743 (1). The present synthetic route is convergent, high-yielding, and exhibiting high selectivities throughout the process. Furthermore, it would also be applicable to the synthesis of a variety of the analogues.

収録刊行物

• 天然有機化合物討論会講演要旨集

  天然有機化合物討論会講演要旨集 44 (0), 91-96, 2002

  天然有機化合物討論会実行委員会

詳細情報

• CRID: 1390282681056984320
• NII論文ID: 110006682169
• DOI: 10.24496/tennenyuki.44.0_91
• ISSN: 24331856
• 本文言語コード: ja
• データソース種別:
  • JaLC
  • CiNii Articles
• 抄録ライセンスフラグ: 使用不可