強力な抗腫よう活性アルカロイドのエクチナサイジン７４３の全合成

• 菅 敏幸

  東京大学大学院薬学系研究科

書誌事項

タイトル別名

• Total Synthesis of Potent Antitumor Alkaloid Ecteinascidin 743

抄録

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.<BR>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 AgNO₃, was successfully converted to ecteinascidin 743 (1).

収録刊行物

• 有機合成化学協会誌

  有機合成化学協会誌 61 (10), 949-960, 2003

  公益社団法人 有機合成化学協会

キーワード

• ecteinascidin 743
• potent antitumor alkaloid
• phase II and III clinical trials
• chiral template
• DuPHOS
• Ugi's 4 CC reaction
• intramolecular Heck reaction
• phenol-aldehyde cyclization
• tetrahydroisoquinoline
• Pictet-Spengler reaction

詳細情報

• CRID: 1390282680287688832
• NII論文ID: 10011907956
• NII書誌ID: AN0024521X
• DOI: 10.5059/yukigoseikyokaishi.61.949
• ISSN: 18836526
• ISSN: 00379980
• 本文言語コード: ja
• データソース種別:
  • JaLC
  • Crossref
  • CiNii Articles
• 抄録ライセンスフラグ: 使用不可