臺灣博碩士論文加值系統

　　本論文分成兩大部分，分別為多取代基呋喃化合物之合成，和以L-脯胺酸為架構之有機催化劑的開發及其在有機催化反應上的探討：

　　第一部分：具有多取代基的呋喃化合物在有機合成中佔有很重要的角色，因此本實驗室以新穎的合成方法製備具有四個取基之呋喃化合物。反應由起始物88做為Michael的受體，依序加入三丁基膦、三乙基胺與醯氯89，於室溫下反應1.5小時到36小時，可得具四個取代基之呋喃化合物92，產率在32% ~ 98%之間。我們推測合成路徑為三丁基膦先進行Michael加成反應到化合物88，形成兩性離子分子90，接著醯氯89與化合物90進行醯化反應後，形成的中間化合物93進行去質子化反應，生成的化合物91經過分子內Wittig反應，即可得呋喃產物92。

第二部分：自2000年以來，以L-脯胺酸為架構設計的有機催化劑被用在許多不對稱有機反應中。依此概念，本實驗室以L-脯胺酸為架構，結合硫與砜設計新式有機催化劑，以催化Michael加成反應和aldol反應。我們以環己酮與β-硝基苯乙烯為起始物，仔細的篩選催化劑以及溶劑種類和反應溫度，探討不同反應條件下對產物鏡像選擇性的影響，結果發現最佳的催化劑為化合物141 (產率98%，非鏡像超越值大於99/1，鏡像超越值98%)。之後我們改用不同種類的β-硝基乙烯試劑，最終產率為40%或90%，非鏡像超越值為74/26或88/12，鏡像超越值為30%或94%。接著我們改用丙酮或異丁醛搭配β-硝基苯乙烯為起始物，進行Michael加成反應，但兩者的鏡像選擇性均不佳。我們也將催化劑應用在aldol反應，我們以環己酮與4-硝基苯甲醛為起始物，產率最高可達99%，但無較佳的立體選擇性(非鏡像超越值為56/44-70/30，anti 構型之鏡像超越值為9-51%)。

　　The dissertation is divided into two parts : synthesis of fully substituted furans (part I), and other development of new type of organocatalysts and their application in asymmetric catalysis (part II).

　　Part I: Multi substituted furans are great importance for organic synthesis. Novel preparation of tetrasubstituted furans strating from the Michael acceptors 88, tributylphosphine, triethylamine and acyl chlorides 89, is realized according to our protocol. Various highly functional furans cab be prepared in very mild condition (RT) within 1.5-36 h in moderate to yields (32-98%). The reaction mechanism is proposed to undergo the Michael reaction of Bu3P and 88 followed by acylation with 90, deprotonation of the corresponding intermediate 93, and finally an intramolecular Wittig reaction of 91.

Part II: Since 2000, the L-proline derivatives are one of the most well-known organocatalysts used in asymmetric reactions. The described new type of organocatalysts , bearing a pyrrolidine and a sulfone or sulfide moiety, are successfully prepared and applied in the asymmetric Michael addition and aldo reactions. After carefully screening the reaction condition (solvent, temperature), the organocatalyst 141 turned out to be the best one for the direct asymmetric Michael addition of cyclohexanone and β-nitrostyrene (98% yield, >99/1 dr, 98% ee). The other two aryl-substituted nitroolefins were examined with our designed catalyst in 40% or 90% yield and with 74/26 dr (30% ee) or 88/12 dr (94% ee), respectively. The reaction acetone or isobutyraldehyde withβ-nitrostyrene gave poor result (76% ee or 52% ee). The application of our catalysts in asymmetric aldol reaction of cyclohexanone and 4-nitrobenzaldehyde gave good chemical yield (up to 99%), albeit poor stereoselectivity (56/44-70/30 dr, anti form: 9-51% ee).

第一章 有機膦試劑經過分子內Wittig反應合成四取代呋喃化合物
1-1前言 1
1-2 呋喃的歷史背景與文獻介紹 2
1-2-1 呋喃分子直接進行官能基化反應之探討 2
1-2-2 Paal-Knorr 呋喃合成反應之探討 4
1-2-3 Feist-Bénary 呋喃合成反應之探討 6
1-2-4 過渡金屬催化呋喃合成反應之探討 8
1-2-5 其它呋喃合成反應之探討 13
1-3 研究動機 15
1-4 實驗結果與討論 18
1-4-1 對位具硝基取代基之起始物與不同醯氯反應之探討 18
1-4-2 反應機構之探討 21
1-4-3 對位具拉電子取代基之起始物與醯氯反應之探討 23
1-4-4 鄰位具拉電子取代基之起始物與醯氯反應之探討 25
1-4-5 立體效應之探討 27
1-4-6 其它芳香官能基起始物與不同醯氯反應之探討 28
1-4-7 雜環取代基之起始物與醯氯反應之探討 30
1-4-8 特殊呋喃分子之合成 32
1-4-9 具雙呋喃官能基之化合物 36
1-4-10 結論 39
1-5 實驗部分 40
1-5-1 分析儀器及基本實驗操作 40
1-5-2 實驗步驟及光譜數據 42
1-6 參考文獻 71
第二章 以L-脯胺酸為架構設計新式有機催化劑及其在Michael與aldol反應 上的應用及探討
2-1 前言 73
2-2 L-脯胺酸及其衍生物之有機催化劑的發展與探討 73
2-3 研究動機 80
2-4 實驗結果與討論 82
2-4-1 製備L-脯胺酸衍生之有機催化劑 82
2-4-2 L-脯胺酸衍生之有機催化劑在Michael加成反應上的應用 84
2-4-2-1 催化劑效應 84
2-4-2-2 溶劑效應 85
2-4-2-3 反應機構之探討 88
2-4-2-4 取代基效應 88
2-4-2-5 丙酮和β-硝基苯乙烯之Michael加成反應探討 90
2-4-2-6 異丁醛和β-硝基苯乙烯之Michael加成反應探討 91
2-4-3 L-脯胺酸衍生之有機催化劑在aldol加成反應上的應用 91
2-4-3-1 催化劑效應 91
2-4-3-2 溶劑效應 93
2-4-4 結論 94
2-5 實驗部分 96
2-5-1 分析儀器及基本實驗操作 96
2-5-2 實驗步驟及光譜數據 98
2-6 參考文獻 108

附錄一、 1H-NMR、13C-NMR、31P-NMR之光譜 109
附錄二、 X-ray單晶繞射結構解析與數據 243
附錄三、 論文發表 312

[1] C.-L. Kao, J.-W. Chern, J. Org. Chem. 2002, 67, 6772.
[2] R. Acheson, An introduction to the chemistry of heterocyclic compounds, 2 ed., Interscience Publishers, New York, 1967.
[3] http://en.wikipedia.org/wiki/Furan.
[4] L. Melzig, C. B. Rauhut, P. Knochel, Chem. Commun. 2009, 3536.
[5] a) L. Knorr, Chem. Ber. 1884, 17, 2863; b) C. Paal, Chem. Ber. 1884, 17, 2756.
[6] V. Amarnath, K. Amarnath, J. Org. Chem. 1995, 60, 301.
[7] G. Wang, Z. Guan, R. Tang, Y. He, Synth. Commun. 2010, 40, 370.
[8] M. Ceylan, M. Gurdere, Y. Budak, C. Kazaz, H. Secen, Synthesis 2004, 1750.
[9] F. Feist, Chem. Ber. 1902, 35, 1545.
[10] L. Kürti, B. Czakó, Strategic applications of named reactions in organic synthesis, Elsevier, Amsterdam, 2005.
[11] G. Mross, E. Holtz, P. Langer, J. Org. Chem. 2006, 71, 8045.
[12] J. Marshall, E. Robinson, J. Org. Chem. 1990, 55, 3450.
[13] A. W. Sromek, M. Rubina, V. Gevorgyan, J. Am. Chem. Soc. 2005, 127, 10500.
[14] X. Du, F. Song, Y. Lu, H. Chen, Y. Liu, Tetrahedron 2009, 65, 1839.
[15] J. Zhang, H. Schmalz, Angew. Chem. Int. Ed. 2006, 45, 6704.
[16] K. Y. Lee, M. J. Lee, J. N. Kim, Tetrahedron 2005, 61, 8705.
[17] R. Brown, Angew. Chem. Int. Ed. 2005, 44, 850.
[18] S. Palimkar, V. More, K. Srinivasan, Ultrason. Sonochem. 2008, 15, 853.
[19] Y. Hu, K. Nawoschik, Y. Liao, J. Ma, R. Fathi, Z. Yang, J. Org. Chem . 2004, 69, 2235.
[20] J. Zhang, X. Zhao, L. Lu, Tetrahedron Lett.2007, 48, 1911.
[21] B. Trost, M. McIntosh, J. Am. Chem. Soc.1995, 117, 7255.
[22] C. Lo, H. Guo, J. Lian, F. Shen, R. Liu, J. Org. Chem. 2002, 67, 3930.
[23] A. Hashmi, P. Sinha, Adv. Synth. Catal. 2004, 346, 432.
[24] J. Aurrecoechea, E. Perez, Tetrahedron 2004, 60, 4139.
[25] M. Yoshida, M. Al-Amin, K. Matsuda, K. Shishido, Tetrahedron Lett. 2008, 49, 5021.
[26] A. Dudnik, A. Sromek, M. Rubina, J. Kim, V. Gevorgyan, J. Am. Chem. Soc. 2008, 130, 1440.
[27] S. Ma, J. Zhang, L. Lu, Chem. Eur. J. 2003, 9, 2447.
[28] J. Marshall, X. WANG, J. Org. Chem. 1991, 56, 960.
[29] H. Ghasemnejad-Bosra, M. Faraje, S. Habibzadeh, Helv. Chim. Acta 2009, 92, 575.
[30] A. Alizadeh, S. Rostamnia, L. Zhu, Synthesis 2008, 1788.
[31] J. C. Trisler, J. K. Doty, J. M. Robinson, J. Org. Chem. 1969, 34, 3421.
[32] Y. Gololobov, N. Kardanov, V. Khroustalyov, P. Petrovskii, Tetrahedron Lett. 1997, 38, 7437.
[33] X. Zhu, C. Henry, O. Kwon, J. Am. Chem. Soc. 2007, 129, 6722.
[34] R. Tanikaga, N. Konya, K. Hamamura, A. Kaji, Bull. Chem. Soc. Jpn. 1988, 61, 3211.
[35] C.-S. Chao, J. H. Chen, H.-L. Hsu, H.-R. Tsai, K. Chen, Chemistry (The Chinese Chem. Soc. Taipei) 2004, 62, 239.
[36] V. U. Eder, G. Sauer, R. Wiechert, Angew. Chem. 1971, 83, 492.
[37] Z. Hajos, D. Parrish, J. Org. Chem. 1974, 39, 1615.
[38] A. Erkkilä, I. Majander, P. M. Pihko, Chem. Rev. 2007, 107, 5416.
[39] S. Mukherjee, J. W. Yang, S. Hoffmann, B. List, Chem. Rev. 2007, 107, 5471.
[40] B. List, R. A. Lerner, C. F. Barbas III, J. Am. Chem. Soc. 2000, 122, 2395.
[41] B. List, P. Pojarliev, H. J. Martin, Org. Lett. 2001, 3, 2423.
[42] J. Wang, H. Li, B. Lou, L. Zu, H. Guo, W. Wang, Chem. Eur. J. 2006, 12, 4321.
[43] S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb, K. B. Sharpless, Angew. Chem. Int. Ed. 2005, 44, 3275.
[44] Y. Hayashi, T. Sumiya, J. Takahashi, H. Gotoh, T. Urushima, M. Shoji, Angew. Chem. Int. Ed. 2006, 45, 958.
[45] C. J. Rogers, T. J. Dickerson, K. D. Janda, Tetrahedron 2006, 62, 352.
[46] P. M. Pihko, K. M. Laurikainen, A. Usano, A. I. Nyberg, J. A. Kaavi, Tetrahedron 2006, 62, 317.
[47] D. G. Blackmond, A. Armstrong, V. Coombe, A. Wells, Angew. Chem. Int. Ed. 2007, 46, 3798.
[48] B. Tan, X. Zeng, Y. Lu, P. J. Chua, G. Zhong, Org. Lett. 2009, 11, 1927.