研究生: |
鄭祐松 Cheng, You-Song |
---|---|
論文名稱: |
不對稱有機催化之手性藥物合成 Organocatalysis towards the synthesis of chiral drug |
指導教授: |
陳焜銘
Chen, Kwun-Min |
學位類別: |
博士 Doctor |
系所名稱: |
化學系 Department of Chemistry |
論文出版年: | 2019 |
畢業學年度: | 107 |
語文別: | 中文 |
論文頁數: | 383 |
中文關鍵詞: | 不對稱合成 、有機催化 、手性藥物合成 、動力學分割 、連鎖反應 |
英文關鍵詞: | asymmetric synthesis, synthesis of chiral drug, organocatalysis, kinetic resolution, cascade reaction |
DOI URL: | http://doi.org/10.6345/NTNU201900924 |
論文種類: | 學術論文 |
相關次數: | 點閱:126 下載:0 |
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小分子有機催化劑介導的有機催化反應自20世紀萌芽,到了2000年初開始蓬勃發展,透過有機合成所製備因應不同有機合成策略,十餘年的發展能量始終維持高檔,溫和的操作手法與對環境友善的重視,讓有機催化逐漸取代傳統的金屬催化,同時顯示此領域在有機合成的重要性。純手性藥物合成策略開發,長年來熱度不減,製備純手性藥物在於避免另一鏡像異構物於生物體內產生相異的生理表現,使用有機催化策略獲得高光學純度的純手性藥物,替代有潛在污染風險且操作較為複雜的金屬試劑反應,便是個重要課題。
使用L-脯氨酸衍生之三苯基矽醚做為有機催化劑,在反應環境中添加醛類和外消旋硝基苯基丙烯醇分子,進行二級胺催化反應,利用醛類與二級胺縮合形成掌性烯胺中間體,加成至外消旋硝基苯基丙烯醇,過程中進行了不對稱催化連鎖Michael/acetallization反應,生成高鏡像選擇性的多取代四氫吡喃分子,具有五個連續掌性中心,同時反應中伴隨著外消旋化合物的動力學分割現象,也分割了具高光學純度的硝基苯基丙烯醇,所得兩種掌性化合物中,多取代四氫吡喃產物利用官能基轉換可生成艾杜醣醛酸衍生分子,是作為肝素的前驅物,硝基苯基丙烯醇則為高經濟性的氨基羥基丁酸衍生物,亦是氨肽酶和HIV-I蛋白酶抑製劑的主要骨架。
另一方面,使用掌性布忍斯特酸催化含羥基異噁唑分子,產生掌性相對離子中間體,配合吲哚進行親核性Friedel-crafts加成反應,也成功掌性四級α-胺基酸衍生產物,並建構兩個連續四級碳中心,有效結合兩個具活性的芳香化分子,吲哚類四級α-胺基酸是作為HIV反轉錄抑制劑的重要分子,擁有極佳的藥物半效應濃度;因此經由不對稱有機催化劑,反應過程中具活性的掌性中間體能有效地掌控純手性產物的生成,此文兩種合成策略期盼對製備掌性藥物的未來發展也有微薄奉獻。
The utilization of small molecule towards the organocatalysis since the 20th century. Related to the organocatalysis has not only exponentially grown from 2000, but also developed several organosynthetic methods for last decade. The mild operation and environmentally benign methodology in organocatalysis have gradually replaced the conventional metal-mediated reaction, it’s also shown the importance in this field. The development of chiral drug synthetic strategy has really attracted to organic chemist. However, the optically pure enantiomer prevents the additional cytotoxicity which produce by another mirror-imaged isomer in living body. The organocatalyzed reaction applies to the pharmaceutical process to access the highly enantio-pure drug that avoid the potential pollution and complicated operation while using metal-mediated methodology.
Herein we reported the use of L-prolinol trimethylsilyl ether as organocatalyst, and combined with aldehydes and racemic nitro allylic alcohol. The asymmetric synthesis was accessed through the secondary aminocatalysis in cooperation with chiral enamine intermediate condensed from organocatalyst and aldehydes, then followed by the addition of racemic nitro allylic alcohol to afford the desired product. The plausible reaction smoothly proceeded through Michael/acetalization cascade pathway, eventually get the desired multi substituted tetrahydropyrans, simultaneously resolved the less reactive (S)-nitro allylic alcohols with high chemical yields and excellent enantioselectivities. The desired substituted tetrahydropyrans bearing five continuous stereogenic centers were the derivatives of iduronic acid, which was also the important framework of Heparin. It was readily available from the substituted tetrahydropyrans.
On the other hand, the catalytic Friedel-crafts reaction successfully achieved by the chiral counterions and nucleophilic indoles, then the asymmetric counterion intermediate was able to produce by the chiral Bronsted acid and hydroisoxazoles. The chiral quaternary amino acid derived product has two continuous quaternary centers, which could be efficiently constructed from two aromatic molecules. The indole-derived amino acid derivatives were important skeletons of HIV reverse transcriptase inhibitors with excellent EC50 concentration.
Therefore, the organocatalyst mediated chiral intermediate can efficiently control the formation of optical pure compound, we hope that these two asymmetric organic syntheses were respected to have a contribution for the chiral drug synthesis in the future.
1. D. E. Koshland Jr. Science 2002, 295, 2215-2216.
2. L. Kelvin. 1894. The Molecular Tactics of a Crystal. Oxford at the Clarendon Press.
3. L. Kelvin. 1904. Baltimore lectures on molecular dynamics and the wave theory
of light. London: CJ Clay & Sons.
4. D. F. Arago Mem. Inst. 1811, 12, 93-134.
5. J. B. Biot Bull. Soc. Philomath. 1815, 38, 190-192.
6. L. Pasteur C. R. Hebd. Séance Acad. Sci. Paris 1848, 26, 535-538.
7. S. L. Miller, Science, 1953, 117, 528-529
8. M. W. Powner, B. Gerland and J. D. Sutherland Nature, 2009, 459, 239-242.
9. G. F. Joyce, A. W. Schwartz, S. L. Millers, L. E. Orgel Proc. Natl. Acad. Sci. USA, 1987, 84, 4398-4402.
10. F. C. Frank Biochim. Biophys. Acta, 1953, 11, 459-463.
11. R. R. E. Steendam, J. M. M. Verkade, T. J. B. van Benthem, H. Meekes, W. J. P. van Enckevort, J. Raap, F. P. J. T. Rutjes, E. Vlieg Nat. Commun. 2014, 5, 5543.
12. C. Viedma Phys. Rev. Lett. 2005, 94, 065504.
13. W. Ostwald Zeitschrift für Physikalische Chemie. 1897, 22, 289-330.
14. L. C. Sögütoglu, R. R. E. Steendam, H. Meekes, E. Vlieg, F. P. J. T. Rutjes Chem. Soc. Rev. 2015, 44, 6723-6732.
15. J. E. Hein, E. Tse, D. G. Blackmond Nat. Chem. 2011, 3, 704-706.
16. G. F. Joyce, G. M. Visser, C. A. van Boeckel, J. H. van Boom, L. E. Orgel, J. van Westrenen Nature, 1984, 310, 602-604.
17. J. T. Sczepanski, G. F. Joyce Nature, 2014, 515, 440-442.
18. V. Sharma, M. Crne, J. O. Park, M. Srinivasarao Science 2009, 325, 449-451.
19. A. Mendoza-Galván, L. Fernández del Río, K. Järrendahl, H. Arwin Sci. Rep. 2018, 8, 6456.
20. P. Vukusic Science 2009, 325, 398-399.
21. L. Pasteur C. R. Hebd. Séance Acad. Sci. Paris 1857, 45, 1032-1036.
22. L. Pasteur C. R. Hebd. Séance Acad. Sci. Paris 1858, 46, 615-618.
23. J. Gal Chirality 2008, 20, 5-19.
24. A. Piutti L’Orosi-Giornale di Chimica, Farmacia e Scienze Affini 1886, 9, 198-202.
25. J. Gal Chirality 2012, 24, 959-976.
26. I. K. Reddy, R. Mehvar. Chirality in Drug Design and Development. 2004, 128.
27. P. May, Bristol Med. Chir. J. 1911, 29, 354-356.
28. P. May. Longman, Green & Co.: London, 1918, 34.
29. E. H. Easson, E. Stedman, Biochem. J. 1933, 27, 1257-1266.
30. J. A. Le Bel Bull. Soc. Chim. Fr. 1874, 22, 337-347.
31. J. H. van 't Hoff Arch. Neerl. Sci. Exact. Nat. 1874, 9, 445-454.
32. E. Fischer Berichte der deutschen chemischen Gesellschaft 1894, 27, 3189-3232.
33. E. Fischer, J. Hirschberger Berichte der deutschen chemischen Gesellschaft 1889, 22, 365-376.
34. W. Marckwald Berichte der deutschen chemischen Gesellschaft 1904, 37, 349-354.
35. B. Lindström, L. J. Pettersson CATTECH 2003, 7, 130-138.
36. G. M. Kirchhoff Schweigger´s J. 1812, 4, 108.
37. J. J. Berzelius Royal Swedish Academy of Sciences 1835.
38. W. Ostwald. Nobel Lecture: On Catalysis. Retrieved from NobelPrize.org.
39. M. Roberts Catal. Lett. 2000, 67, 1-4.
40. R. Shridhar Gadre Reson. 2003, 8, 77-83.
41. Catalyst Market Size Worth $34.1 Billion By 2025. Retrieved from https://www.grandviewresearch.com/press-release/catalyst-market-analysis/
42. Catalyst Market Size, Share, Trends, Industry Growth Report 2019-2025. Retrieved from https://www.grandviewresearch.com/industry-analysis/catalyst-market
43. J. Smidt, W. Hafner, R. Jira, J. Sedlmeier, R. Sieber, R. Rüttinger, H. Kojer Angew. Chem. 1959, 71, 176-182.
44. W. Hafner, R. Jira, J. Sedlmeier, J. Smidt Chem. Ber. 1962, 95, 1575-1581.
45. J. Smidt, W. Hafner, R. Jira, R. Sieber, J. Sedlmeier, A. Sabel Angew. Chem. Int. Ed. 1962, 1, 80-88.
46. Patent : J. Smidt, W. Hafner, J. Sedlmeier, R. Jira, R. Rüttinger (Cons. f.elektrochem.Ind.), DE 1 049 845, 1959, Anm. 04.01.1957.
47. J. W. Walker, V. K. Krieble. J. Chem. Soc., Trans. 1909, 95, 1369-1377.
48. L. Rosenthaler Biochem. Z. 1908, 14, 238-253.
49. G. Bredig, P. S. Fiske Biochem. Z. 1912, 46, 7-23.
50. W. S. Knowles, M. J. Sabacky Chem. Commun. (London), 1968, 0, 1445-1446.
51. L. Horner, H. Siegel, H. Büthe Angew. Chem. Int. Ed. 1968, 7, 942.
52. T. P. Dang, H. B. Kagan J. Chem. Soc. D 1971, 0, 481.
53. W. S. Knowles, M. J. Sabacky, B. D. Vineyard, and D. J. Weinkauff J. Am. Chem. Soc. 1975, 97, 2567-2568.
54. A. Miyashita, A. Yasuda, H. Takaya, K. Toriumi, T. Ito, T. Souchi, and R. Noyori J. Am. Chem. Soc. 1980, 102, 7932-7934.
55. S. Akutagawa Appl. Catal., A 1995, 128, 171-207.
56. R. Noyori, T. Ikeda, T. Ohkuma, M. Widhalm, M. Kitamura, H. Takaya, S. Akutagawa, N. Sayo, T. Saito, T. Taketomi, and H. Kumobayashi J. Am. Chem. Soc. 1989, 111, 9134-9135.
57. T. Katsuki, K. B. Sharpless J. Am. Chem. Soc. 1980, 102, 5974-5976.
58. B. E. Rossiter, T. Katsuki, K. B. Sharpless J. Am. Chem. Soc. 1981, 103, 464-465.
59. B. List, R. A. Lerner, C. F. Barbas III J. Am. Chem. Soc. 2000, 122, 2395-2396.
60. K. A. Ahrendt, C. J. Borths, D. W. C. MacMillan J. Am. Chem. Soc. 2000, 122, 4243-4244.
61. D. W. C. MacMillan Nature 2008, 455, 304-308.
62. B. M. Trost Angew. Chem. Int. Ed. 1995, 34, 259-281.
63. P. T. Anastas, J. C. Warner. 1998. Green Chemistry: Theory and Practice. Oxford University Press: New York, p.30.
64. E. Grazi, P. T. Rowley, T. Cheng, O. Tchola, B. L. Horecker Biochem. Biophys. Res. Commun. 1962, 9, 38-43.
65. E. Grazi, T. Cheng, B. L. Horecker Biochem. Biophys. Res.
Commun. 1962, 7, 250-253.
66. T. Gefflaut, C. Blonski, J. Perie, M. Willson Prog. Biophys. molec. Biol. 1995, 63, 301-340.
67. Y. Hayashi, H. Gotoh, T. Hayashi, M. Shoji Angew. Chem. Int. Ed. 2005, 44, 4212-4215.
68. J. Franzén, M. Marigo, D. Fielenbach, T. C. Wabnitz, A. Kjærsgaard, K. A. Jørgensen J. Am. Chem. Soc. 2005, 127, 18296-8304.
69. E. J. Corey, R. K. Bakshi, S. Shibata J. Am. Chem. Soc. 1987, 109, 5551-5553.
70. A. Wassermann J. Chem. Soc. 1942, 618-621.
71. P. Yates, P. Eaton J. Am. Chem. Soc. 1960, 82, 4436-4437.
72. M. S. Sigman, E. N. Jacobsen J. Am. Chem. Soc. 1998, 120, 4901-4902.
73. L. Hedstrom Chem. Rev. 2002, 102, 4501-4524.
74. T. R. Kelly, B. Meghani, V. S. Ekkundi Tetrahedron Lett. 1990, 31, 3381-3384.
75. M. C. Etter, S. M. Reutzel J. Am. Chem. Soc. 1991, 113, 2586-2598.
76. D. P. Curran, L. H. Kuo J. Org. Chem. 1994, 59, 3259-3261.
77. D. L. Severance, W. L. Jorgensen J. Am. Chem. Soc. 1992, 114, 10966-10968.
78. J. P. Malerich, K. Hagihara, V. H. Rawal J. Am. Chem. Soc. 2008, 130, 14416-14417.
79. A. J. Arduengo III, R. L. Harlow, M. Kline J. Am. Chem. Soc. 1991, 113, 361-363.
80. R. Breslow J. Am. Chem. Soc. 1958, 80, 3719-3726.
81. K. Öfele J. Organomet. Chem. 1968, 12, P42-43.
82. W. A. Herrmann Angew. Chem. Int. Ed. 2002, 41, 1290-1309.
83. D. Enders, K. Breuer, G. Raabe, J. Runsink, J. H. Teles, J.‐P. Melder, K. Ebel, S. Brode Angew. Chem. Int. Ed. 1995, 34, 1021-1023.
84. K. Öfele, W. A. Herrmann, D. Mihalios, M. Elison, E. Herdtweck, W. Scherer, J. Mink J. Organomet. Chem. 1993, 459, 177-184
85. P. Schwab, R. H. Grubbs, J. W. Ziller J. Am. Chem. Soc. 1996, 118, 100-110.
86. T. M. Trnka, R. H. Grubbs Acc. Chem. Res. 2001, 34, 18-29.
87. M. Scholl, S. Ding, C.W. Lee, R. H. Grubbs Org. Lett. 1999, 1, 953-956.
88. A. Lapworth J. Chem. Soc., Trans. 1903, 83, 995-1005.
89. X. Bugaut, F. Glorius Chem. Soc. Rev. 2012, 41, 3511-3522.
90. K. Ishihara, M. Miyata, K. Hattori, T. Tada, H. Yamamoto J. Am. Chem. Soc. 1994, 116, 10520-10524.
91. N. T. McDougal, S. E. Schaus J. Am. Chem. Soc. 2003, 125, 12094-12095.
92. T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe Angew. Chem. Int. Ed. 2004, 43, 1566 -1568.
93. D. Uraguchi, M. Terada J. Am. Chem. Soc. 2004, 126, 5356-5357.
94. D. Uraguchi, K. Sorimachi, M. Terada J. Am. Chem. Soc. 2004, 126, 11804-11805.
95. R. Maji, S. C. Mallojjala, S. E. Wheeler Chem. Soc. Rev. 2018, 47, 1142-1158.
96. T. L. B. Boivin Tetrahedron 1987, 43, 3309-3362.
97. P. A. Clarke, S. Santos Eur. J. Org. Chem. 2006, 2006, 2045-2053.
98. C. S. Barry, N. Bushby, J. P. H. Charmant, J. D. Elsworth, J. R. Hardingb, C. L. Willis Chem. Commun. 2005, 5097-5099.
99. K. L. Erickson, K. R. Gustafson, L. K. Pannell, J. A. Beutler, M. R. Boyd J. Nat. Prod. 2002, 65, 1303-1306.
100. H. Uehara, R. Imashiro, G. Hernández-Torres, C. F. Barbas III Proc. Natl. Acad. Sci. USA 2010, 107, 20672-20677.
101. H. Ishikawa, S. Sawano, Y. Yasui, Y. Shibata, Y. Hayashi Angew. Chem. Int. Ed. 2011, 50, 3774-3779.
102. L. C. R. Pasteur Hebd. Séance Acad. Sci. Paris. 1848, 26, 535-538.
103. G. P. Moss Pure & Appl. Chem. 1996, 68, 2193-2222.
104. I. Deb, M. Dadwal, S. M. Mobin, I. N. N. Namboothiri Org. Lett. 2006, 8, 1201-1204.
105. H.-H. Kuan, R. J. Reddy, K. Chen Tetrahedron 2010, 66, 9875-9879.
106. J. J. Li, E. J. Corey. Drug Discovery: Practices, Processes, and Perspectives. John Wiley & Sons. 2013, p189.
107. M. Jia, T. Wei, K. Yang, W. F. Xu Mini Rev Org Chem 2011, 8, 197-210.
108. (2S,3R)-3-Amino-2-hydroxy-4-phenylbutyric acid hydrochloride. Retrieved from http://www.sigmaaldrich.com
109. N. Gogoi, J. Boruwa, N. C. Barua Tetrahedron Lett. 2005, 46, 7581-7582.
110. D. Seebach, A. Fadel, Helv. Chim. Acta 1985, 68, 1243-1250.
111. P. Vachal, E. N. Jacobsen Org. Lett. 2000, 26, 867-870.
112. E. Angelini, C. Balsamini, F. Bartoccini, S. Lucarini, G. Piersanti J. Org. Chem. 2008, 73, 5654-5657.
113. X. Han, H. Wu, W. Wang, C. Dong, P. Tien, S. Wu, H.-B. Zhou Org. Biomol. Chem. 2014, 12, 8308-8317.
114. M. Righi, F. Bartoccini, S. Lucarini, G. Piersanti Tetrahedron 2011, 67, 7923-7928.
115. K. Brak, E. N. Jacobsen Angew. Chem. Int. Ed. 2013, 52, 534-561.
116. M. Yamanaka, J. Itoh, K. Fuchibe, T. Akiyama J. Am. Chem. Soc. 2007, 129, 6756-6764.
117. W. Schrader, P. P. Handayani, J. Zhou, B. List Angew. Chem. Int. Ed. 2009, 48, 1463-1466.
118. M. Fleischmann, D. Drettwan, E. Sugiono, M. Rueping, R. M. Gschwind Angew. Chem. Int. Ed. 2011, 50, 6364-6369.
119. P. Christ, A. G. Lindsay, S. S. Vormittag, J.-M. Neudçrfl, A. Berkessel, A. C. OʼDonoghue Chem. Eur. J. 2011, 17, 8524-8528.
120. S. Mayer, B. List Angew. Chem. Int. Ed. 2006, 45, 4193-4195.
121. N. J. A. Martin, B. List J. Am. Chem. Soc. 2006, 128, 13368-13369.
122. M. Rueping, A. P. Antonchick, T. Theissmann Angew. Chem. Int. Ed. 2006, 45, 3683-3686.
123. M. Terada, H. Tanaka K. Sorimachi J. Am. Chem. Soc. 2009, 131, 3430-3431.
124. M. Terada, T. Yamanaka, Y. Toda Chem. Eur. J. 2013, 19, 13658-13662.
125. M. Rueping, U. Uria, M.-Y. Lin, I. Atodiresei J. Am. Chem. Soc. 2011, 133, 3732-3735.
126. B. Guo, G. Schwarzwalder, J. T. Njardarson Angew. Chem. Int. Ed. 2012, 51, 5675-5678.
127. G. L. Hamilton, T. Kanai, F. D. Toste J. Am. Chem. Soc. 2008, 130, 14984-14986.
128. I Čorić, B. List Nature 2012, 483, 315-319.
129. N. Tsuji, J. L. Kennemur, T. Buyck, S. Lee, S. Prévost, P. S. J. Kaib, D. Bykov, C. Farès, B. List Science 2018, 359, 1501-1505.
130. I. T. Raheem, P. S. Thiara, E. A. Peterson, E. N. Jacobsen J. Am. Chem. Soc. 2007, 129, 13404-13405.
131. Y.-X. Jia, J. Zhong, S.-F. Zhu, C.-M. Zhang, Q.-L. Zhou Angew. Chem. Int. Ed. 2007, 46, 5565-5567.
132. M. Fleischmann, D. Drettwan, E. Sugiono, M. Rueping, R. M. Gschwind Angew. Chem. Int. Ed. 2011, 50, 6364-6369.