臺灣博碩士論文加值系統

本文描述合成探討主要分成兩部分，第一部分是天然物Asperjinone，此天然物首次由Wen-Ying Liao與他的工作團隊在2012年從土麴黴(A. terreus)分離出來並建立結構。 隔年,2013年由Mikhail Elyashberg等人藉由電腦輔助結構解析法重新確立其結構；第二部分是全合成牛樟芝衍生物的前驅物，我們採用不同策略做出牛樟芝相關衍生物，利用Suzuki coupling來完成，不僅操作較方便相對的產率也提升，對於牛樟芝衍生物的研究更為快速。
合成策略上，我們希望建立簡單的合成路徑，將目標物Asperjinone分成三部分,由市售的4-bromophenol出發,分成兩條路徑修飾，而中心架構五元環則是由succinic anhydride開始，加成上鹵素後，接著運用Suzuki及Grignard或Kumada cross coupling，前後兩者皆利用鈀金屬催化試劑，而結構上Asperjinone與牛樟芝(Antrodia camphorate)菌絲體萃取馬來酸衍生物有相同的中心骨架，加上實驗室對於製備及使用零價鈀金屬試劑已累積有一定的程度與資料，預期可以得到目標產物Asperjinone及牛樟芝的前驅物，隨後經過一連串修飾,應該可以成功完成目標物。

Asperjinone, a natural product first isolated from thermophilic Aspergillus terreus in 2012 and its structure was revised using the computer-assisted structure elucidation (CASE) in 2013. But, we still devoted ourself in accomplishing the original structure, that we called it is precursor of Asperjinone, 3-(3-((3,3-dimethy
loxiran-2-yl)methyl)-4-hydroxybenzyl)-4-4(4-hydroxyphenyl) maleic anhydride.
In our lab, we’re trying to design a concise strategy and make a usage of palladium-catalyst couplings that we have been studied for a long time in Suzuki and Kumada coupling.
On the other hand, we found that the core structure of Asperjinone is quite similar with hepasim and himanimides analogues.
Hence,we divide our target to three portions : N-Benzyl-2,3-dibromomaleimide (3) and two side chains. In addition to this one, we hope to fully utilize the same route on other natural produc

中文摘要 I
英文摘要 II
第一章 : 緒論
1-1前言 1
1-2馬來酸及其衍生物的介紹 2
1-3 Asperjinone的介紹 3
1-3-1土麴黴( Aspergillus terreus )的介紹 4
1-4 Asperjinone的結構鑑定 6
1-5前人合成類似結構文獻 7
1-6逆合成分析 9
第二章 : 結果與討論
2-1製備N-Benzyl-2,3-dibromomaleimide (3) 10
2-2製備Suzuki coupling 所需的片段 11
2-(4-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4)
2-3製備1-(benzyloxy)-4-(bromomethyl)-2-(3-methylbut-2-en-1-yl) 12
benzene (5)
2-3-1製備1-Bromo-3-methyl-2-butene (12) 12
2-3-2製備1-(benzyloxy)-4-(bromomethyl)-2-(3-methylbut-2-en-1-yl)
benzene (5) 12
2-3-3製備1-benzyl-3-(4-(benzyloxy)phenyl)-4-bromo-1H-
pyrrole-2,5-dione (18) 18
2-4 Grignard coupling及Suzuki coupling合成牛樟芝衍生物 19
2-4-1利用Grignard coupling得到1-benzyl-3-bromo-4-isobutyl-1H-
pyrrole-2,5-dione (24) 19

2-4-2利用鈀金屬催化Suzuki coupling得到牛樟芝衍生物之前驅物
1-benzyl-3-(4-(benzyloxy)phenyl)-4-isobutyl-1H- pyrrole-2,5-dione(25) 19
2-5製備Grignard reagent及Kumada cross coupling的應用 21
第三章 結論與未來展望 23
第四章 實驗部分 24
4-1一般實驗 24
4-2儀器與設備 24
4-3實驗藥品 25
4-4化合物的合成與鑑定 26
第五章 參考文獻 45
附件 化合物光譜圖 s-1


List of Figures
Figure 1. Asperjinone的結構 1
Figure 2. 牛樟芝(Antrodia camphorata)菌絲體萃取馬來酸及琥珀酸衍生物 2
Figure 3. 各類馬來醯亞胺衍生物 3
Figure 4. 土麴黴( Aspergillus terreus )之二次代謝物 5
Figure 5. Asperjinone初發現時判定之結構與解析後之真實結構 6
Figure6. 化合物N-Benzyl-2,3-dibromomaleimide(3)的X-ray結構圖 10
Figure 7. 化合物2-(4-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane(4)的X-ray結構圖 11
Figure 8. 化合1-(benzyloxy)-4-(bromomethyl)-2-(3-methylbut-2-en-1-yl)benzene
(5)的X-ray結構圖 15



List of tables
Table 1.碘化的條件測試 16
Table 2.溴化的條件測試 17


List of schemes
Scheme 1. 瑞士學者Patrice Sellès合成 1-Himanimide C之方法 7
Scheme 2. 印度學者Narshinha P. Argade合成Aspergillus acid A-D之方法 8
Scheme 3. 印度學者Narshinha P. Argade合成Antrodin A-C之方法 8
Scheme 4. Retrosynthesis analysis of 3-(3-((3,3-dimethyloxiran-2-yl)methyl)
-4-hydroxybenzyl)-4-(4-hydrophenyl) maleic anhydride 9
Scheme 5. 牛樟芝衍生物之回溯合成 9
Scheme 6. N-Benzyl-2,3-dibromomaleimide(3)的合成方法 10
Scheme 7. 2-(4-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4)的
合成方法 11
Scheme 8. 製備1-Bromo-3-methyl-2-butene (12) 12
Scheme 9. 製備開岔醚類(19)的方法 12
Scheme 10. 測試利用重排反應未得到預期產物(13) 13
Scheme 11. 嘗試先保護後加成的方法 13
Scheme 12. 先加成後保護得到鄰位加成的產物 (14) 13
Scheme 13. 更換起始物為4-hydroxybenzaldehyde套用步驟 14
Scheme 14. (4-(benzyloxy)-3-(3-methylbut-2-en-1-yl)phenyl)methanol (16)的合成
方法 15
Scheme 15. Iodination from 16 to 17 in 2 steps 16
Scheme 16. Bromination with high yield 17
Scheme 17. 1-benzyl-3-(4-(benzyloxy)phenyl)-4-bromo-1H-pyrrole-2,5-dione (18)
的合成方法 18
Scheme 18. 1-benzyl-3-bromo-4-isobutyl-1H-pyrrole-2,5-dione (24)的合成方法 19
Scheme 19. 牛樟芝衍生物之前驅物(25)合成方法 20
Scheme 20. Pinacolborane (27)的合成方法 20
Scheme 21. 將側鍊換成PinB (27)得到另一衍生物(28) 20
Scheme 22. Epoxidation of compound (28) 21
Scheme 23.以Benzyl chloride當起始物，測試製備Grignard reagent的條件，
並進行1,2-addition 22
Scheme 24.製備具有官能基的苯環側鍊(23) 22

1. Kuo, S. C.; Wu, S. H.;Liaw, C. C. J. Nat. Prod. 2012, 75, 630-635.
2. Williams, A. J. J. Nat. Prod. 2013, 76, 113-116.
3. (a) Nakamura, N.; Hirakawa, A.; Gao, J. J.;Kakuda, H.; Shiro, M.;Komatsu, Y.;Sheu, C. C.; Hattori, M. J. Nat. Prod. 2004, 67, 46-48.
4. Lee, Y. L.; Lai, C. Z.; Cheng, C. F. Tetrahedron 2008, 64, 4347-4353.
5. (a) Hattori M., Yasukawa, A. 第一屆中日樟芝研討會，九月，臺灣，民國九十四年. (b) Lin, S. Y.; Chen, C. L.; Lee, Y. J. J. Org. Chem. 2003, 68, 2968-2970.
6. Tsai, Z. T.; Liaw, L. S. The use and the effect of Ganoderma; Sheng-Yun Publisher Inc.; Taichung, Taiwan, 1982; p116.
7. (a) Kaneko, T.; Wong, H. Tetrahedron Lett. 1985, 26, 4015-4018. (b) Davis, P. D.; Hill, C. H.; Lawton, G.; Nixon, J. S.; Wilkinson, S. E.; Hurst, S. A.; Keech, E.; Turner, S. E. J. Med. Chem. 1992, 35, 177-184. (c) Kalgutkar, S. A.; Crews, C. B.; Marneet, J. L. J. Med. Chem. 1996, 39, 1692-1703. (d) Marminon, C.; Anizon, F.; Moreau, P.; Lèonce, S.; Pierrè, A.; Pfeiffer, B.; Renard, P.; Prudhomme, M. J. Med. Chem. 2002, 45, 1330-1339. (e) Marminon, C.; Pierrè, A.; Pfeiffer, B.; Pèrez, B, V.; Lèonce, S.; Renard, P. and Prudhommea, M. Bioorg. Med. Chem. 2003, 11, 679-687.
8. Xie, G.; Lown, J. W. Tetrahedron Lett. 1994, 31, 5555-5558.
9. (a) Faul, M. M.; Winneroski, L. L.; Krunrich, C. A.; Sullivan, K. A.; Gillig, J. R.; Neel, D. A.; Rito, C. J.; Jirousek, M. R. J. Org. Chem. 1990, 63, 1961-1973. (b) Mangaleswarane, S.; Argade, N. P. J. Org. Chem. 2001, 66, 5259-5261.
10. Choi, D. S.; Huang, S.; Huang, M.; Barnard, T. S.; Adams, R. D.; Seminario, J. M.; Tour, J. M. J. Org. Chem. 1998, 63, 2646-2655.
11. Chiang, C. H.; Antagonism of Aspergillus terreus Yua-6 to Botrytis cinerea and
Colletotrichum gloeosporioides.
12. Hajjaj, H.; Niederberger, P.; and Duboc, P. Lovastatin biosynthesis by Aspergillus terreus in a chemically defined medium. Appl Environ Microbiol. 2001, 67, 2596-2602.
13. Melo, I.S.; Faull, J.L.; and Nascimento, R.S. Antagonism of Aspergillus terreus to
Sclerotinia Sclerotiorum. Brazilian Journal of Microbiology. 2006, 37, 417-419.
14. Sellès, P. Org. Lett. 2005, 7, 605-608.
15. Easwar, S.; Argade, N. P. Synthesis. 2006, 831-838.
16. Baag, M. M.; Argade, N. P. Synthesis. 2006, 1005-1008.
17. Lin, S. Y.; Chen, C. L.; Lee, Y. J. J. Org. Chem. 2003, 68, 2968-2970.
18. Creemers, A. F. L.; Lugtenburg, J. J. Am. Chem. Soc. 2002, 124, 6324-6334.
19. Altamura, M.; Perrotta, E. J. Org. Chem. 1993,58, 272-274.
20. Denton, R. M. Chem. Commun., 2010, 46, 3025–3027.
21. (a) Guo Z.X., Cammidge, A. N. Tetrahedron. 2000, 56, 5169-5175. (b) Breton, G. W. Molecules. 2011, 16, 9553-9561. (c) Chavasiri, W. Tetrahedron Lett. 2012, 53, 674–677. (d) Yus, M.; Alonso, F. Eur. J. Org. Chem. Wittig-Type Olefination of Alcohols Promoted by Nickel Nanoparticles.
22. (a) Molander, G. A. J. Org. Chem. 2006, 71, 9198-9202. (b) Wu, H. Y. J. Phys. Chem. C 2010, 114, 22221–22229.
23. (a) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling, U. H.; Grabowski, E. J.J. Tetrahedron Lett. 1995, 36, 5461–5464. (b) Faul, M. M.; Winneroski, L. L.; Krumrich, C. A.; Sullivan, K. A.; Gillig, J. R.; Neel, D. A.; Rito, C. J.; Jirousek, M. R. J. Org. Chem. 1998, 63, 1961-1973. (c) Va, P.; Roush, W. R. J. Am. Chem. Soc. 2006, 128, 15960-15961.
24. (a) Liebeskind, L. S.; Fengl, R. W. J. Org. Chem. 1990, 55, 5359-5364. (b) Kim, W. S.; Kim, H. J.; Cho, C. G. J. Am. Chem. Soc. 2003, 125, 14288-14289. (c) Wang, Y.; Burton, D. Org. Lett. 2006, 6, 1109-1111.
25. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.
26. Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5518. Riviews.