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Acta Chimica Sinica >

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

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

Article

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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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

Cite this article

Yang Yi , You Zhengwei , Qing Fengling . Design and Synthetic Investigation toward gem-difluoromethylenated Fostriecin Analogue[J]. Acta Chimica Sinica, 2012 , 70(22) : 2323 -2336 . DOI: 10.6023/A12090668

References

[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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