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2012 , Vol. 70 >Issue 21: 2232 - 2235

DOI: https://doi.org/10.6023/A12090626

研究论文

8-epi-Liphagal的合成研究

  • 彭金宝 ,
  • 后小军 ,
  • 张书宇 ,
  • 涂永强
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  • 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

收稿日期: 2012-09-04

  网络出版日期: 2012-10-11

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.

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Studies on the Total Synthesis of 8-epi-Liphagal

  • Peng Jinbao ,
  • Hou Xiaojun ,
  • Zhang Shuyu ,
  • Tu Yongqiang
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  • State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000

Received date: 2012-09-04

  Online 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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摘要

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

本文引用格式

彭金宝 , 后小军 , 张书宇 , 涂永强 . 8-epi-Liphagal的合成研究[J]. 化学学报, 2012 , 70(21) : 2232 -2235 . DOI: 10.6023/A12090626

Abstract

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

参考文献

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[6] For a recent synthetic study of 5-epi-liphagal, see: Zhang, J.; Li, L.; Wang, Y.; Wang, W.; Xue, J.; Li, Y. Org. Lett. 2012, 14, 4528.

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[8] Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R.; Meneses, R. Synlett 1999, 10, 1663. For additional studies directed toward the total synthesis of liphagal, see: (a) Deore, V.; Lohar, M. K.; Mundada, R.; Roychowdhury, A.; Vishwakarma, R.; Kumar, S. Synth. Commun. 2011, 41, 177; (b) Zhang, Y.; Oblak, E. Z.; Bolstad, E. S. D.; Anderson, A. C.; Jasinski, J. P.; Butcher, R. J.; Wright, D. L. Tetrahedron Lett. 2010, 51, 6120; (c) Mehta, G.; Likhite, N. S.; Kumar, C. S. A. Tetrahedron Lett. 2009, 50, 5260.
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