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2012 , Vol. 70 >Issue 22: 2323 - 2336

DOI: https://doi.org/10.6023/A12090668

研究论文

含有二氟亚甲基的Fostriecin类似物的设计和合成研究

  • 杨义 ,
  • 游正伟 ,
  • 卿凤翎
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  • a 中国科学院上海有机化学研究所 有机氟化学重点实验室 上海 200032;
    b 四川理工学院 化学与制药工程学院 自贡 643000;
    c 东华大学 化学化工与生物工程学院 上海 201620

收稿日期: 2012-09-16

  网络出版日期: 2012-10-25

基金资助

项目受国家自然科学基金(Nos. 21072028, 20832008, 21272036)和国家基础研究重点项目(No. 2012CB21600)资助.

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Design and Synthetic Investigation toward gem-difluoromethylenated Fostriecin Analogue

  • Yang Yi ,
  • You Zhengwei ,
  • Qing Fengling
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  • a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032;
    b School of Chemistry and Pharmaceutical Engineering, Sichuan University of Science & Engineering, Zigong 643000;
    c College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620

Received date: 2012-09-16

  Online published: 2012-10-25

Supported by

Project supported by the National Natural Science Foundation of China (Nos. 21072028, 20832008, 21272036) and the National Basic Research Program of China (No. 2012CB21600).

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摘要

Fostriecin是近年来备受瞩目的新型抗肿瘤天然产物. 根据构效关系分析, 设计了具有潜在更高活性的含有二氟亚甲基的Fostriecin类似物4, 并进行了合成研究. 目标分子的骨架结构由片段a, b, c经螯合控制的加成反应和Stille偶联反应汇聚合成. 在含氟片段a的合成中应用了以下关键反应: (Z)-烯基碘8与溴二氟乙酸乙酯在铜粉作用下的偶联反应; 酶动力学拆分构建C-5位的手性中心. 合成甲基酮片段b的关键步骤包括: 酶动力学拆分构建C-11位的手性中心和CBS不对称还原α,β-不饱和酮23. 从商业可得的原料出发, 经最长线性步骤18步以1.28%的总产率成功地得到未脱保护的含有二氟亚甲基的Fostriecin类似物42. 但在对42脱除保护基时, 没有得到目标分子4. 这可能是由于偕二氟亚甲基的强吸电子作用使内酯环极化程度增大, 从而导致内酯环易发生水解开环反应.

关键词： Fostriecin; 偕二氟亚甲基; α,β-不饱和δ-内酯; 酶动力学拆分; 1,5-氧化关环反应; 含氟内酯的水解

本文引用格式

杨义 , 游正伟 , 卿凤翎 . 含有二氟亚甲基的Fostriecin类似物的设计和合成研究[J]. 化学学报, 2012 , 70(22) : 2323 -2336 . DOI: 10.6023/A12090668

Abstract

Fostriecin is a promising leading anticancer compound. The α,β-unsaturated lactone in Fostriecin is believed to be the critical pharmacophore, which can covalently bind to the Cys269 residue of the PP2A subunit via a Michael 1,4-conjugate addition. We reasoned that the introduction of strong electron-withdrawing gem-difluoromethylene to replace the methylene group at the γ position of the lactone ring would lead to fostriecin analogue 4 with enhanced enzymatic binding affinity. Accordingly, the synthesis of fostriecin analogue 4 was investigated. The skeleton of target molecule 4 was established convergently from fragments a, b and c via an magnesium mediated chelation-controlled addition and Stille coupling using Pd(CH3CN)Cl2 as catalyst. The key steps of synthesizing fragment a included the coupling between alkenyl iodide 8 and ethyl bromodifluoroacetate in the presence of copper powder and the establishment of C-5 stereocenter via lipase AK catalyzed kinetic resolution. The construction of C-11 and C-9 stereocenters in fragment b were realized by the lipase AK catalyzed kinetic resolution and CBS asymmetric reduction of α,β-unsaturated ketone 23 (BH3·PhNEt2 as reductive agent), respectively. The connection of fragments a and b proceeded through the magnesium mediated chelation-controlled addition procedures: fragment a (vinyl stannane) was firstly converted to vinyl lithium reagent 27 by the treatment of BuLi (1.05 equiv.) at -78 ℃, then the i-PrMgCl (2.0 equiv.) solution in THF was added dropwise to produce the critical magnesium-ate complex intermediate A, finally the addition of fragment b solution in THF to the magnesium-ate complex A gave the coupled product 29. The Stille coupling of fragment c with vinyl iodide 39 prepared from 29 in the presence of Pd(CH3CN)Cl2 gave target molecule skeleton 40 in 85% yield. Finally, the protected fostriecin analogue 42 was successfully synthesized by a longest linear steps of 18 steps in 1.28% overall yield. However, the deprotection of compound 42 failed to give the target molecular 4. This could be caused by the instability of the fluorinated lactone in which the strong electron- withdrawing gem-difluoromethylene group enhanced the polarization of the lactone function.

Key words： Fostriecin; difluoromethylene; α,β-unsaturated δ-lactone; enzymatic kinetic resolution; 1,5-oxidative cyclization; hydrolysis of fluorinated lactone

参考文献

[1] (a) Tunac, J. B.; Graham, B. D.; Dobson, W. E. J. Antibiot. 1983, 36, 1595; (b) Stampwala, S. S.; Bunge, R. H.; Hurley, T. R.; Willmer, N. E.; Brankiewicz, A. J.; Steinman, C. E.; Smitka, T. A.; French, J. C. J. Antibiot. 1983, 36, 1600.
[2] Boger, D. L.; Hikota, M.; Lewis, B. M. J. Org. Chem. 1997, 62, 1748.
[3] Lewy, D. S.; Gauss, C.-M.; Soenen, D. R.; Boger, D. L. Curr. Med. Chem. 2002, 9, 2005.
[4] (a) Walsh, A. H.; Cheng, A.; Honkanen, R. E. FEBS Lett. 1997, 416, 230; (b) Hastie, C. J.; Cohen, P. T. W. FEBS Lett. 1998, 431, 357.
[5] Lê, L. H.; Erlichman, C.; Pillon, L.; Thiessen, J. J.; Day, A.; Wainman, N.; Eisenhauer, E. A.; Moore, M. J. Invest. New Drugs 2004, 22, 159.
[6] Buck, S. B.; Hardouin, C.; Ichikawa, S.; Soenen, D. R.; Gauss, C. M.; Hwang, I.; Swingle, M. R.; Bonness, K. M.; Honkanen, R. E.; Boger, D. L. J. Am. Chem. Soc. 2003, 125, 15694.
[7] Takeuchi, T.; Takahashi, N.; Ishi, K.; Kusayanagi, T.; Kuramochi, K.; Sugawara, F. Bioorg. Med. Chem. 2009, 17, 8113.
[8] For review, see: (a) Shibasaki, M.; Kanai, M. Heterocycles 2005, 66, 727. For examples, see: (b) Boger, D. L.; Ichikawa, S.; Zhong, W. J. Am. Chem. Soc. 2001, 123, 4161; (c) Cossy, J.; Pradaux, F.; BouzBouz, S. Org. Lett. 2001, 3, 2233; (d) David, E. C.; Eric, N. J. Angew. Chem., Int. Ed. 2001, 40, 3667; (e) Esumi, T.; Okamoto, N.; Hatakeyama, S. Chem. Commun. 2002, 3042; (f) Falck, J. R. Org. Lett. 2002, 4, 969; (g) Kiyotsuka, Y.; Igarashi, J.; Kobayashi, Y. Tetrahedron Lett. 2002, 43, 2725; (h) Miyashita, K.; Ikejiri, M.; Kawasaki, H.; Maemura, S.; Imanishi, T. Chem. Commun. 2002, 742; (i) Wang, Y.-G.; Kobayashi, Y. Org. Lett. 2002, 4, 4615; (j) FujⅡ, K.; Maki, K.; Kanai, M.; Shibasaki, M. Org. Lett. 2003, 5, 733; (k) Miyashita, K.; Ikejiri, M.; Kawasaki, H.; Maemura, S.; Imanishi, T. J. Am. Chem. Soc. 2003, 125, 8238; (l) Ramachandran, P. V.; Liu, H.; Ram Reddy, M. V.; Brown, H. C. Org. Lett. 2003, 5, 3755; (m) Trost, B. M.; Frederiksen, M. U.; Papillon, J. P. N.; Harrington, P. E.; Shin, S.; Shireman, B. T. J. Am. Chem. Soc. 2005, 127, 3666; (n) Takeuchi, T.; Kuramochi, K.; Kobayashi, S.; Sugawara, F. Org. Lett. 2006, 8, 5307; (o) Yadav, J. S.; Prathap, I.; Tadi, B. P. Tetrahedron Lett. 2006, 47, 3773; (p) Hayashi, Y.; Yamaguchi, H.; Toyoshima, M.; Okado, K.; Toyo, T.; Shoji, M. Org. Lett. 2008, 10, 1405; (q) Robles, O.; McDonald, F. E. Org. Lett. 2009, 11, 5498; (r) Sarkar, S. M.; Wanzala, E. N.; Shibahara, S.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. Chem. Commun. 2009, 5907; (s) Gao, D.; O’Doherty, G. A. Org. Lett. 2010, 12, 3752; (t) Li, D.; Zhao, Y.; Ye, L.; Chen, C.; Zhang, J. Synthesis 2010, 3325.
[9] Maki, K.; Motoki, R.; FujⅡ, K.; Kanai, M.; Kobayashi, T.; Tamura, S.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 17111.
[10] De Jong, R.; Mulder, N.; Uges, D.; Sleijfer, D. T.; Höppener, F.;

Groen, H.; Willemse, P.; Van der Graaf, W.; De Vries, E. Br. J. Cancer 1999, 79, 882.
[11] (a) Yamazaki, T.; Taguchi, T.; Ojima, I. In Fluorine in Medicinal Chemistry and Chemical Biology, Ed.: Ojima, I., Wiley-Blackwell, Chichester, U.K., 2009, p. 3; (b) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881; (c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320; (d) Wang, J.; Liu, H. Chin. J. Org. Chem. 2011, 31, 1785. (王江, 柳红, 有机化学, 2011, 31, 1785.)
[12] (a)You, Z.-W.; Wu, Y.-Y.; Qing, F.-L. Tetrahedron Lett. 2004, 45, 9479-9481; (b) You, Z.-W.; Jiang, Z.-X.; Wang, B.-L.; Qing, F.-L. J. Org. Chem. 2006, 71, 7261; (c) You, Z.-W.; Zhang, X.; Qing, F.-L. Synthesis 2006, 2535; (d) Lin, J.; Qiu, X.-L.; Qing, F.-L. J. Fluorine Chem. 2010, 131, 684; (e) Lin, J.; Qiu, X.-L.; Qing, F.-L. Beilstein J. Org. Chem. 2010, 6, 37; (f) Lin, J.; Yue, X.; Huang, P.; Cui, D.; Qing, F.-L. Synthesis 2010, 267; (g) Chen, J.-L.; Zheng, F.; Huang, Y.; Qing, F.-L. J. Org. Chem. 2011, 76, 6525.
[13] You, Z.-W. Ph.D. Dissertation, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai, 2007. (游正伟, 博士论文, 中国科学院上海有机化学研究所, 上海, 2007.)
[14] Hansen, T. M.; Florence, G. J.; Lugo-Mas, P.; Chen, J.; Abrams, J. N.; Forsyth, C. J. Tetrahedron Lett. 2003, 44, 57.
[15] (a) Veeraraghavan Ramachandran, P.; Chatterjee, A. Org. Lett. 2008, 10, 1195; (b) Ramachandran, P. V.; Tafelska-Kaczmarek, A.; Sakavuyi, K.; Chatterjee, A. Org. Lett. 2011, 13, 1302; (c) Ramachandran, P. V.; Tafelska-Kaczmarek, A.; Sakavuyi, K. Org. Lett. 2011, 13, 4044.
[16] (a) Sato, K.; Kawata, R.; Ama, F.; Omote, M.; Ando, A.; Kumadaki, I. Chem. Pharm. Bull. 1999, 47, 1013; (b) Sato, K.; Omote, M.; Ando, A.; Kumadaki, I. J. Fluorine Chem. 2004, 125, 509.
[17] (a) Ma, S.; Lu, X.; Li, Z. J. Org. Chem. 1992, 57, 709; (b) Beruben, D.; Marek, I.; Normant, J. F.; Platzer, N. J. Org. Chem. 1995, 60, 2488.
[18] Burgess, K.; Jennings, L. D. J. Am. Chem. Soc. 1991, 113, 6129.
[19] (a) Itoh, T.; Kudo, K.; Tanaka, N.; Sakabe, K.; Takagi, Y.; Kihara, H. Tetrahedron Lett. 2000, 41, 4591; (b) Kirihara, M.; Kawasaki, M.; Katsumata, H.; Kakuda, H.; Shiro, M.; Kawabata, S. Tetrahedron: Asymmetry 2002, 13, 2283; (c) Itoh, T.; Kudo, K.; Yokota, K.; Tanaka, N.; Hayase, S.; Renou, M. Eur. J. Org. Chem. 2004, 2004, 406; (d) Kaneda, T.; Komura, S.; Kitazume, T. J. Fluorine Chem. 2005, 126, 17.
[20] Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143.
[21] Corey, E. J.; Guzman-Perez, A.; Lazerwith, S. E. J. Am. Chem. Soc. 1997, 119, 11769.
[22] Matsuo, J.; Kozai, T.; Nishikawa, O.; Hattori, Y.; Ishibashi, H. J. Org. Chem. 2008, 73, 6902.
[23] (a) Kitagawa, K.; Inoue, A.; Shinokubo, H.; Oshima, K. Angew. Chem., Int. Ed. 2000, 39, 2481; (b) Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K. J. Org. Chem. 2001, 66, 4333; (c) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42, 4302.
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