Araki Hiroshi, Inoue Munenori, Suzuki Takeyuki, Yamori Takao, Kohno Michiaki, Watanabe Kazuhiro, Abe Hideki, Katoh Tadashi
Department of Electronic Chemistry, Tokyo Institute of Technology, Nagatsuta, Yokohama, Japan.
Chemistry. 2007;13(35):9866-81. doi: 10.1002/chem.200700789.
Enantioselective total synthesis of (+)-ottelione A (1) and (-)-ottelione B (2), novel and potent antitumor agents from a freshwater plant, and (+)-3-epi-ottelione A (3), the earlier proposed stereostructure of 1, was efficiently achieved starting from the known tricyclic compound 10. The synthesis involved the following key steps: i) coupling reactions of aldehydes 8 and 9 with the aromatic portion 7 (8+7-->15 and 9+7-->27), ii) base-induced hemiacetal-opening/epimerization reactions of the cyclic hemiacetals 6 and 27 (6-->17 and 27 a-->26 a), and iii) Corey-Winter's reductive olefination of the cyclic thiocarbonates 21 and 36 (21-->22 and 36-->37). The present total synthesis fully established the absolute configuration of these natural products. The cell growth inhibition profile, COMPARE analysis, and tubulin inhibitory assay of (+)-3-epi-ottelione A (3) and its O-acetyl derivative 24 demonstrated that these unnatural substances could be prominent lead compounds for the development of anticancer agents with a novel mode of action.
从一种淡水植物中提取的新型强效抗肿瘤药物（+）-奥特利酮A（1）和（-）-奥特利酮B（2）以及先前提出的1的立体结构（+）-3-表-奥特利酮A（3）的对映选择性全合成，以已知的三环化合物10为起始原料高效完成。合成过程涉及以下关键步骤：i）醛8和9与芳环部分7的偶联反应（8 + 7→15和9 + 7→27）；ii）环状半缩醛6和27的碱诱导半缩醛开环/差向异构化反应（6→17和27a→26a）；iii）环状硫代碳酸酯21和36的Corey-Winter还原烯烃化反应（21→22和36→37）。本次全合成完全确定了这些天然产物的绝对构型。（+）-3-表-奥特利酮A（3）及其O-乙酰基衍生物24的细胞生长抑制谱、COMPARE分析和微管蛋白抑制试验表明，这些非天然物质可能成为开发具有新型作用模式抗癌药物的重要先导化合物。
