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化学学报
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化学学报 ›› 2012, Vol. 70 ›› Issue (21): 2232-2235.DOI: 10.6023/A12090626 上一篇    下一篇

研究论文

8-epi-Liphagal的合成研究

彭金宝, 后小军, 张书宇, 涂永强   

  1. 兰州大学化学化工学院 功能有机分子化学国家重点实验室 兰州 730000
  • 投稿日期:2012-09-04 发布日期:2012-10-11
  • 通讯作者: 涂永强 E-mail:tuyq@lzu.edu.cn
  • 基金资助:

    项目受国家自然科学基金(Nos. 21072085, 20921120404, 21102061, 20972059, 21290180)、教育部“111”计划和科技部“973”(No. 2010CB833203)和卫生部重大科技专项(No. 2012ZX09201101-003)资助.

Studies on the Total Synthesis of 8-epi-Liphagal

Peng Jinbao, Hou Xiaojun, Zhang Shuyu, Tu Yongqiang   

  1. State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000
  • Received:2012-09-04 Published:2012-10-11
  • Supported by:

    Project supported by the National Natural Science Foundation of China (Nos. 21072085, 20921120404, 21102061, 20972059, 21290180), 973 program (No. 2010CB833203), the “111” Program of MOE and the Key National S&T Program “Major New Drug Development” of Ministry of Health of China (No. 2012ZX09201101-003).

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补充材料

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四环杂萜类天然产物Liphagal含有新奇的[6-7-5-6]四环骨架, 是磷酸肌醇3-激酶(PI3K)的有效抑制剂之一, 可以选择性抑制细胞增殖和促进细胞死亡, 在治疗炎症、免疫紊乱、癌症以及心血管疾病中有潜在的医用价值. 从廉价的2,4,5-三甲氧基苯甲醛出发, 通过Wittig反应、Cu催化的环化反应、选择性氢化、分子内Friedel-Crafts反应, 以直线步骤最长7步, 8.72%的总收率实现了8-epi-Liphagal高级中间体10的合成.

关键词: 8-epi-Liphagal, 天然产物, 合成, Friedel-Crafts反应, 高级中间体

The tetracyclic meroterpenoid natural product (＋)-liphagal is one of a number of natural inhibitors of phosphatidylinositol 3-kinase (PI3K), which plays a central role in regulation of cell proliferation, cell survival, adhesion, membrane trafficking, glucose transport and neurite growth. Liphagal also shows inhibitory activity against PI3Kα with an IC50 of 100 nmol·L-1 making it as an agent for the treatment of inflammatory and autoimmune disorders as well as cancer and cardiovascular diseases. From a structural point of view, liphagal has an unprecedented [6-7-5-6] tetracyclic skeleton, and has attracted significant attention from the synthetic chemists. Starting from cheap and commercially available 2,4,5-trimethoxylbenzaldehyde and α-ionone, an advanced intermediate 10 for the synthesis of 8-epi-liphagal was achieved in the longest linear 7 steps and 8.72% yield. The key reactions include: Wittig reaction, Cu-catalyzed cyclization, chemoselective hydrogenation and Friedel-Crafts reaction.

Key words: liphagal, natural product, synthesis, Friedel-Crafts reaction, advanced intermediates