臺灣博碩士論文加值系統

中文摘要

　　7-氧基雙環[2.2.1]庚烷的衍生物大多具有生物活性，往往在自然界中扮演著重要的角色。在本論文中，我們以此類化合物為主要骨架，應用於天然物的不對稱合成上，如gibberellic acid (GA3) 和 solanoeclepin A。

　　Gibberellic acid (GA3)是一種調節植物生長的賀爾蒙。其可利用7-氧基雙環[2.2.1]庚烷與鋅錯合物(zincate, Me3ZnLi)試劑進行甲基化反應，得到動力學上的加成產物。更進一步在路易士酸的催化下，經由分子內的內酯化反應以完成左半邊的合成。　

　　另一天然物solanoeclepin A，研究發現其具有刺激馬鈴薯中的囊腫線蟲提早孵化的功能，可運用在農業病蟲害的防治上。其主要合成策略是以(S)-(−)-4-甲氧基-α-甲苄胺為掌性輔助基試劑，經由分子內Diels-Alder反應建構出左半邊7-氧基雙環[2.2.1]庚烷的基本骨架。


Abstract

Derivatives of 7-oxabicyclo[2.2.1]heptanes perform an important role in nature, many of which show biological activities. Herein, these skeletons were employed toward stereoselective synthesis of natural products, gibberellic acid (GA3) and solanoeclepin A.

We focused the left hand segment of gibberellinc acid (GA3), which functions as plant growth regulator. The key steps include: (1) the methylation with “zincate”, Me3ZnLi, reagent to give the conjugate adduct without ring-opening of oxa-bridged, and (2) an intramolecular lactonization with Lewis acid to form the lactone.

In addition, an asymmetric synthesis is also described on the oxa- bicyclo[2.2.1]heptane segment of solanoeclepin A, which shows significant hatch-stimulating activity for the potato cyst nematode. The oxabicyclo framework was constructed through an intramolecular Diels-Alder cycloaddition by treatment with the (S)-(−)-4-methoxy-α- methylbenzylamine as well as the chiral auxiliary.

Contents

中文摘要.........................................................I
Abstract..................................................II
Acknowledgment...........................................III
Abbreviations.............................................IV
Contents...................................................V
Figure index.............................................VII
Table index.............................................VIII

Chapter I. Introduction

I-1. Introduction of 7-Oxabicyclo[2.2.1]heptanes...........1
I-1-1. Synthesis of 7-Oxabicyclo[2.2.1]heptanes........1
I-1-2. Natural 7-Oxabicyclo[2.2.1]heptanes and
Bioactive Analogues...2
I-2. Introduction and Synthetic Strategy of Gibberellic
Acid....6
I-2-1. Introduction of Gibbrellic Acid................6
I-2-2. Synthetic Strategy of Gibberellic Acid (GA3)....7
I-3. Organozinc Mediated Reactions.........................8
I-3-1. Organozinc Reagent, RCu(CN)ZnI..................8
I-3-2. Ate Complexes and Organozincate Reagent,
Me3ZnLi.........9
I-3-3. The Applications of Organozincate Reagent,
Me3ZnLi........10
I-4. Introduction and Synthetic Strategy of
Solanoeclepin A..........11
I-4-1. Introduction of Solanoeclepin A................11
I-4-2. Synthetic Strategy of Solanoeclepin A..........12
I-5. Intramolecular Diels-Alder Cycloaddition of Furan....13
I-5-1. Literature Review of IMDA Cycloaddition of
Furan.......13
I-5-2. Synthetic Applications of IMDA Cycloaddition of
Furan.......15

Chapter II. Result and Discussion

II-1. Synthesis of Left Hand Side of Gibberellic Acid
(GA3)......17
II-1-1. Research Motif................................17
II-1-2. Synthetic Route...............................18
II-1-3. Methylation of 7-Oxabicyclo[2.2.1]hepta-2,5-
diene 21 with Organozincate Me3ZnLi...........19
II-1-4. The Reactivity of 7-Oxanorbornadiene 21 with
Organozinc and Organoaluminium Reagents......24
II-1-5. Lactone Formation Activate by Lewis Acid....27
II-2. Synthesis of Left Hand Side of Solanoeclepin A......35
II-2-1. Research Motif of Asymmetric 7-
Oxanorbornadienes.....35
II-2-2. Synthetic Route of Solanoeclepin A............36
II-2-3. 7-Oxabicyclo[2.2.1]heptene 93 Formation via
IMDA Cycloaddition......37
II-2-4. Reduction of the Diels-Alder Cycloadduct 93...40
II-2-5. Formation of γ-Lactam 104 and Further
Synthesis.......42
II-3. Conclusion..........................................44

Chapter III. Experimental and Reference

III-1. General............................................47
III-2. Experimental Procedure.............................49
III-3. Reference..........................................70

Appendix..................................................75

Reference

1.Vogel, P.; Cossy, J.; Plumet, J.; Arjona, O. Tetrahedron 1999, 55, 13521.

2.(a) Lipshutz, B. H. Chem. Rev. 1986, 86, 795. (b) Oliver Kappe, C.; Shaun Murphree, S.; Padwa, A. Tetrahedron 1997, 53, 14179. (c) Woo, S.; Keay, B. A. Synthesis 1996, 669. (d) Hudlicky, T.; Entwistle, D. A.; Pitzer, K. K.; Thorpe, A. J. Chem. Rev. 1996, 96, 1195. (e) Jiang, S.; Singh, G. Tetrahedron 1998, 54, 4697.

3.(a) Garside, P.; Halsall, T. G.; Hornby, G. M. J. Chem. Soc. (C) 1969, 716. (b) Frank, W. C. Tetrahedron: Asymmetry 1998, 9, 3745.

4.Warrener, R. N.; Russell, R. A.; Tan, R. Y. S. Tetrahedron Lett. 1978, 19, 1585.

5.Eggelte, T. A.; De Koning, H.; Huisman, H. O. J. Chem. Soc., Perkin Trans. 1 1978, 980.

6.Hall, S. E.; Han, W. C.; Haslanger, M. F.; Harris, D. N.; Ogletree, M. L. J. Med. Chem. 1986, 29, 2335.

7.Eggelte, T. A.; De Koning, H.; Huisman, H. O. Tetrahedron 1973, 29, 2491.

8.Sprague, P. W.; Heikes, J. E.; Gougoutas, J. Z.; Malley, M. F.; Harris, D. N.; Greenberg, R. J. Med. Chem. 1985, 28, 1580.

9.Aziz, M.; Rouessac, F. Tetrahedron 1988, 44, 101.

10.(a) Demnitz, F. W. J.; Philippini, C.; Raphael, R. A. J. Org. Chem. 1995, 60, 5114. (b) Mukaiyama, T.; Iwasawa, N. Chem. Lett. 1981, 29.

11.(a) Fukuzawa, A.; Furusaki, A.; Ikura, M.; Masamune, T. J. Chem. Soc., Chem. Commun. 1985, 222. (b) Masamune, T.; Fukuzawa, A.; Furusaki, A.; Ikura, M.; Matsue, H.; Kaneko, T.; Abiko, A.; Sakamoto, N.; Tanimoto, N.; Murai A. Bull. Chem. Soc. Jpn. 1987, 60, 1001.

12.(a) Benningshof, J. C. J.; Blaauw, R. H.; van Ginkel, A. E.; Rutjes, F. P. J. T.; Fraanje, J.; Goubitz, K.; Schenk, H.; Hiemstra, H. Chem. Commun. 2000, 1465. (b) Buu Hue, B. T.; Dijkink, J.; Kuiper, S.; van Schaik, S.; van Maarseveen, J. H.; Hiemstra, H. Eur. J. Org. Chem. 2006, 127. (c) Benningshof, J. C. J.; Blaauw, R. H.; van Ginkel, A. E.; van Maarseveen, J. H.; Rutjes, F. P. J. T.; Hiemstra, H. J. Chem. Soc., Perkin Trans. 1 2002, 1693.

13.Matsuno, T.; Tani, Y.; Matsuo, K.; Komori, T. Phytochemistry 1986, 25, 2837.

14.Estrada, D. M.; Ravelo, J. L.; Ruiz-Pérez, C.; Martín, J. D.; Solans, X. Tetrahedron Lett. 1989, 30, 6219.

15.(a) Mander, L. N. Chem. Rev. 1992, 92, 573. (b) Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S.; Keck, G. E.; Gopalan, B.; Larsen, S. D.; Siret, P.; Gras, J. L. J. Am. Chem. Soc. 1978, 100, 8034. (c) Lombardo, L.; Mander, L. N.; Turner, J. V. J. Am. Chem. Soc. 1980, 102, 6626. (d) Hook, J. M.; Mander, L. N.; Urech, R. J. Am. Chem. Soc. 1980, 102, 6628. (e) Phuoc, L. T.; Mander, L. N.; Koshioka, M.; Oyama-Okubo, N.; Nakayama, M.; Ito, A. Tetrahedron 2008, 64, 4835.

16.(a) Kappe, C. O.; Padwa, A. J. Org. Chem. 1996, 61, 6166. (b) Best, W. M.; Wege, D. Tetrahedron Lett. 1981, 22, 4877. (c) Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J. Org. Chem. 1997, 62, 4088. (d) Cella, J. A. J. Org. Chem. 1988, 53, 2099.

17.Sanchez, A. J.; Konopelski, J. P. J. Org. Chem. 1994, 59, 5445.

18.Arjona, O.; De Dios, A.; Plumet, J.; Saez, B. Tetrahedron Lett. 1995, 36, 1319.

19.Macmillan, J.; Takahashi, N. Nature 1968, 217, 170.

20.Isobe, M.; Kondo, S.; Nagasawa, N.; Goto, T. Chem. Lett. 1977, 679.

21.(a) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117. (b) Knochel, P.; Almena Perea, J. J.; Jones, P. Tetrahedron 1998, 54, 8275.

22.Simmons, H. E.; Cairns, T. L.; Vladuchick, A.; Hoiness, C. M. Org. React. 1972, 20, 1.

23.Furstner, A. Synthesis 1989, 571.

24.Hatano, M.; Suzuki, S.; Ishihara, K. J. Am. Chem. Soc. 2006, 128, 9998.

25.Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135.

26.Weidmann, B.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1983, 22, 31.

27.(a) Negishi, E. Acc. Chem. Res. 1982, 15, 340. (b) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem. 1988, 53, 2390.

28.Uchiyama, M.; Kameda, M.; Mishima, O.; Yokoyama, N.; Koike, M.; Kondo, Y.; Sakamoto, T. J. Am. Chem. Soc. 1998, 120, 4934.

29.(a) Kondo, Y.; Takazawa, N.; Yamazaki, C.; Sakamoto, T. J. Org. Chem. 1994, 59, 4717. (b) Kondo, Y.; Matsudaira, T.; Sato, J.; Murata, N.; Sakamoto, T. Angew. Chem., Int. Ed. Engl. 1996, 35, 736. (c) Kondo, Y.; Fujinami, M.; Uchiyama, M.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1997, 799.

30.(a) Harada, T.; Katsuhira, T.; Hattori, K.; Oku, A. J. Org. Chem. 1993, 58, 2958. (b) Harada, T.; Katsuhira, T.; Hara, D.; Kotani, Y.; Maejima, K.; Kaji, R.; Oku, A. J. Org. Chem. 1993, 58, 4897.

31.Uchiyama, M.; Furumoto, S.; Saito, M.; Kondo, Y.; Sakamoto, T. J. Am. Chem. Soc. 1997, 119, 11425.

32.(a) Hirao, T.; Takada, T.; Sakurai, H. Org. Lett. 2000, 2, 3659. (b) Hatano, M.; Ito, O.; Suzuki, S.; Ishihara, K. J. Org. Chem. 2010, 75, 5008.

33.Equey, O.; Vrancken, E.; Alexakis, A. Eur. J. Org. Chem. 2004, 2151.

34.Dieter, R. K.; Guo, F. J. Org. Chem. 2009, 74, 3843.

35.Mulder, J. G.; Dipenhorst, P.; Bruggemann-Rotgans, I. E. M. PCT Int. Appl WO 9302083, 1993, Chem. Abstr. 1993, 118, 185844.

36.Schenk. H.; Driessen, R. A. J.; de Gelder, R.; Goubitz, K.; Nieboer, H.; Bruggemann-Rotgans, I. E. M.; Diepenhorst, P. Croat. Chem. Acta 1999, 72, 593.

37.Tanino, K.; Takahashi, M.; Tomata, Y.; Tokura, H.; Uehara, T.; Narabu, T.; Miyashita, M. Nature Chem. 2011, 484.

38.Tojo, S.; Isobe, M. Synthesis 2005, 1237.

39.Parker, K. A.; Adamchuk, M. R. Tetrahedron Lett. 1978, 1689.

40.Prajapati, D.; Sandhu, J. S. Heterocycles 1985, 23, 17.

41.Pelter, A.; Singaram, B. J. Chem. Soc., Perkin Trans. 1 1983, 1383.

42.Wright, D. L.; Robotham, C. V.; Aboud, K. Tetrahedron Lett. 2002, 43, 943.

43.Mukaiyama, T.; Iwasawa, N. Chem. Lett. 1981, 29.

44.Passaro; Linda, C.; Pollack; Steve, K. U.S. Pat. Appl. Publ. 2006, 20060094888.

45.Ladjel, C.; Fuchs, N.; Zhao, J.; Bernardinelli, G.; Alexakis, A. Eur. J. Org.Chem. 2009, 4949.

46.Che, C.; Liu, L.; Gong, J.; Yang, Y.; Wang, G.; Quan, J.; Yang, Z. Org. Lett. 2010, 12, 488.

47.Krasovskiy, A.; Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 3333.

48.Hamada, M.; Inami, Y.; Nagai, Y.; Higashi, T.; Shoji, M.; Ogawa, S.; Umezawa, K.; Sugai, T. Tetrahedron: Asymmetry 2009, 20, 2105.

49.Koshimizu, H.; Baba, T.; Yoshimitsu, T.; Nagaoka, H. Tetrahedron Lett. 1999, 40, 2777.

50.Rickborn, B. The Retro–Diels–Alder Reaction Part I. C-C Dienophiles. In Organic Reactions, John Wiley & Sons, Inc.: 2004.

51.Zubkov, F. I.; Ershova, J. D.; Orlova, A. A.; Zaytsev, V. P.; Nikitina, E. V.; Peregudov, A. S.; Gurbanov, A. V.; Borisov, R. S.; Khrustalev, V. N.; Maharramov, A. M.; Varlamov, A. V. Tetrahedron 2009, 65, 3789.

52.(a) Zumbrunn, A.; Uebelhart, P.; Eugster, C. H. Helv. Chim. Acta 1985, 68, 1519. (b) Wolff, M.; Seemann, M.; Grosdemange-Billiard, C.; Tritsch, D.; Campos, N.; RodrIguez-Concepción, M.; Boronat, A.; Rohmer, M. Tetrahedron Lett. 2002, 43, 2555. (c) Jordan, M.; Humam, M.; Bieri, S.; Christen, P.; Poblete, E.; Muñoz, O. Phytochemistry 2006, 570.