Synthetic Studies on Zanamivir (Relenza)｜國立清華大學博碩士論文庫

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研究生：	李彥君 Lee, Yen-Chun
論文名稱：	Synthetic Studies on Zanamivir (Relenza)
指導教授：	磯部稔 Minoru Isobe
口試委員:
學位類別：	碩士 Master
系所名稱：	理學院 - 化學系 Department of Chemistry
論文出版年：	2010
畢業學年度：	98
語文別：	英文
論文頁數：	118
中文關鍵詞：	瑞樂沙、C-糖苷化反應、光學異構化反應
外文關鍵詞：	Relenza, C-glycosidation, epimerization
相關次數：	點閱：2 下載：0
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在抗流感藥物瑞樂沙之活性物質Zanamivir合成研究中，我們以tri-O-acetyl-D-glucal (57)為起始物進行C-糖苷化反應(C-glycosidation)，得到具有 Zanamivir 基本骨架之加成產物48。我們首先進行光學異構化反應(epimerization)的研究。將加成產物48與Co2(CO)8進行錯合反應後，得到具有兩個活性中心之鈷錯合物63。在路易士酸及醋酸的環境下，化合物63 成功地進行光學異構化反應，且同時進行保護基轉換得到產物67。
在取得加成產物67後，經由七步合成，可成功地引入含氮之官能基並合成氮丙環化合物73與53。應用先前所發展的方法，進行光學異構化反應之研究：發現化合物73在光學異構化反應中矽醚基被水解，並攻擊至為路易士酸活化 之氮丙環，得到開環產物，接著進行hydrosilation得到化合物89；而化合物53，在光學異構化反應中得到了保護基轉換之產物80，並在hydrosilation完後取得化合物83，經NOESY實驗鑑定，發現其 未進行光學異構化反應。

    Contents

中文摘要    i
Abstract    ii
Acknowledgements    iii
Index    v
Figure index    viii
Table index    ix
Scheme index    x
Abbreviations    xii

Chapter 1 Introduction    1
1 General introduction    1
2 Synthetic approaches to Zanamivir    2
2.1 von Itzstein group - first design and synthesis of Zanamivir    2
2.2 Merck Frosst Centre - synthesis of Zanamivir from sialic acid    3
2.3 Glaxo - scalable route to Zanamivir    4
2.4 Yao’s group - synthesis of Zanamivir from D-glucono-δ-lactone    5
3 Methodologies developed by our group    7
3.1 C-glycosidation with silylacetylenes to D-glucals    7
3.2 Cobalt mediated C-1 alkynyl pyranose ring system functionalization    8
3.3 Strategies for the removal of cobalt complex     10
4 Retrosynthetic plan    11

Chapter 2 Results and Discussion    14
1 Construction of basic carbon skeleton    14
1.1 Nucleophile preparation    14
1.2 C-glycosidation of tri-O-acetyl-D-glucal    15
2 Model study of cobalt mediated epimerization    15
3 Synthesize the aziridine intermediate    20
4 Epimerization of the alkynyl aziridine    23


Chapter 3 Conclusion    30

Chapter 4 Proposal of Next Generation Zanamivir Synthesis    32
1 Proposal A: epimerization and aziridine formation as key steps    32
2 Proposal B: reductive amination and aziridine formation as key steps 34

Chapter 5 Experimental Section    36
1 General method    36
2 Experimental section of chapter 2    38
2.1 Methylalcohol formation YCL02023 (60)    38
2.2 OTBDPS protection YCL02024 (58)    39
2.3 C-glycosidation YCL02104 (48)    40
2.4 Cobalt complexation YCL02013 (64)    41
2.5 Epimerization YCL02077 (67)    42
2.6 Hydrolysis of diacetate YCL02076 (69)     43
2.7 Selective OTBS protection YCL03006 (70)    44
2.8 Preparation of trichloriacetimidate YCL03038 (56)    45
2.9 Iodo-oxazoline formation YCL03012 (55)    46
2.10 Oxazoline ring opening YCL03063 (54)    47
2.11 O-acetylation YCL03026 (72)    48
2.12 Aziridine formation YCL03094 (53)    49
2.13 Aziridine formation YCL03112 (73)    50
2.14 Oxazoline formation YCL03088 (74)    51
2.15 Cobalt complexation YCL03096 (78)    52
2.16 Aziridine opening YCL03136 (79)    52
2.17 Hydrosilation YCL03136 (80)    53
2.18 Cobalt complexation YCL03096 (52)    54
2.19 Cobalt mediated epimerization YCL03098 (81, 82)    54
2.20 Hydrosilation YCL03150 (83)    55
2.21 Hydrosilation YCL03122 (84)    56
2.22 Hydrolysis of trichloracetamide YCL03124 (85)    57
2.23 Hydrolysis of trichloracetamide YCL03128 (85)    58
3 Reference     59

Supporting information I: crystal data of compound YCL03136 (80)    61
Supporting information II: NMR spectra of synthesized compounds    65
Supporting information III: the PPT slides of final defence    101

                                

(1) Shibasaki, M.; Kanai, M. Eur. J. Org. Chem. 2008, 1839.
(2) Vargese, J. N.; Laver, W. G.; Colman, P. M. Nature 1983, 303, 41.
(3) Vargese, J. N.; Colman, P. M. J. Mol. Biol. 1991, 221, 473.
(4) Burmeister, W. P.; Ruigrok, R. W. H.; Cusack, S. EMBO J. 1992, 11, 49.
(5) von Itzstein, M.; Wu, W.-Y.; Kok, G. B.; Pegg, M. S.; Dyason, J. C.; Jin, B.; Phan, T. V.; Smythe, M. L.; White, H. F.; Woods, J. M.; Bethell, R. C.; Hotham, V. J.; Cameron, J. M.; Penn, C. R. Nature 1993, 363, 418.
(6) Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.; Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai, C. Y.; Laver, W. G.; Stevens, R. C. J. Am. Chem. Soc. 1997, 119, 681.
(7) Magano, J. Chem. Rev. 2009, 109, 4398.
(8) Jong, M. D. d.; Thanh, T. T.; Khanh, T. H.; Hien, V. M.; Smith, G. J. D.; Chau, N. V.; Cam, B. V.; Qui, P. T.; Ha, D. Q.; Guan, Y.; Peiris, J. S. M.; Hien, T. T.; Farrar, J. N. Engl. J. Med. 2005, 25, 2633.
(9) Ohyabu, N.; Nishikawa, T.; Isobe, M. J. Am. Chem. Soc. 2003, 125, 8798.
(10) Hamajima, A.; Isobe, M. Angew. Chem. Int. Ed. 2009, 48, 2941.
(11) von Itzstein, M.; Wu, W.-Y.; Jin, B. Carbohydr. Res. 1994, 259, 301.
(12) Scheigetz, J.; Zamboni, R.; Bernstein, M. A.; Roy, B. Org. Prep. Proc. Int. 1995, 27, 637
(13) Chandler, M.; Bamford, M. J.; Conroy, R.; Lamont, B.; Patel, b. B.; Patel, V. K.; Steeples, I. P.; Storer, R.; Weir, a. N. G.; Wright, M.; Williamson, C. J. Chem. Soc., Perkin Trans. 1 1995, 1173.
(14) Schreuner, E.; Zbiral, E.; Kleineidam, R. G.; Schauer, R. Liebigs. Ann. Chem. 1991, 129.
(15) Liu, K.-G.; Yan, S.; Wu, Y.-L.; Yao, Z.-J. Org. Lett. 2004, 6, 2269.
(16) Liu, K.-G.; Zhou, H.-B.; Wu, Y.-L.; Yao, Z.-J. J. Org. Chem. 2003, 68, 9528.
(17) Tsukiyama, T.; Isobe, M. Tetrahedron Lett. 1992, 33, 7911.
(18) Saeeng, R.; Isobe, M. Chem. Lett. 2006, 35, 552.
(19) Isobe, M.; Saeeng, R.; Nishizawa, R.; Konobe, M.; Nishikawa, T. Chem. Lett. 1999, 467.
(20) Teobald, B. J. Tetrahedron 2002, 58, 4133.
(21) Tanaka, S.; Tsukiyama, T.; Isobe, M. Tetrahedron Lett. 1993, 34, 5757.
(22) Tanaka, S.; Isobe, M. Tetrahedron 1994, 50, 5633.
(23) Tanaka, S.; Isobe, M. Tetrahedron Lett. 1994, 35, 7801.
(24) Tanaka, S.; N. Tatsuta; O. Yamashita; Isobe, M. Tetrahedron 1994, 50, 12883.
(25) Tanaka, S.; Isobe, M. Synthesis 1995, 859.
(26) Takai, S.; Ploypradith, P.; Hamajima, A.; Kira, K.; Isobe, M. Synlett 2002, 4, 588.
(27) Hosokawa, S.; Isobe, M. Tetrahedron Lett. 1998, 39, 2609.
(28) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron Lett. 1983, 24, 3943.
(29) Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron 1984, 40, 2247.
(30) DeNinno, M. P.; Danishefsky, S. J.; Schulte, G. J. Am. Chem. Soc. 1988, 110, 3925.
(31) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
(32) Banwell, M. G.; Hungerford, N. L.; Jolliffe, K. A. Org. Lett. 2004, 6, 2737.
(33) Jones, T. K.; Denmark, S. E. Org. Synth. 1986, 64, 182.
(34) Toshima, K.; Ohta, K.; Ohashi, A.; Nakamura, T.; Nakata, M.; Tatsuta, K.; Matsumura, S. J. Am. Chem. Soc. 1995, 117, 4822.
(35) Takimoto, M.; Usami, S.; Hou, Z. J. Am. Chem. Soc. 2009, 131, 18266.
(36) Saeeng, R.; Sirion, U.; Sahakitpichan, P.; Isobe, M. Tetrahedron 2003, 44, 6211.
(37) Nishikawa, T.; Asai, M.; Ohyabu, N.; Isobe, M. J. Org. Chem. 1998, 63, 188.
(38) Nishikawa, T.; Asai, M.; Ohyabu, N.; Yamamoto, N.; Isobe, M. Angew. Chem. Int. Ed. 1999, 38, 3081.
(39) Yeung, Y.-Y.; Gao, X.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 9644.
(40) Takai, S.; Isobe, M. Org. Lett. 2002, 4, 1183.

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