流感病毒神经氨酸酶抑制剂Tamiflu和茼蒿素类似物的合成
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摘要
本论文分为两部分。第一部分致力于发展新的合成螺环缩酮烯醇醚环氧化物的方法。我们小组早期发展的合成方法,通过2,5-二取代呋喃可以快速构建天然拒食剂茼蒿素所需的螺环母核结构。我们试图通过直接选择性氧化茼蒿素环内双键构建环氧,但一直没有成功。改变策略,将环氧化的构建放在螺环母核结构形成之前实施。通过反复尝试,我们最终实现了茼蒿素类似物环内双键选择性氧化的问题。新的合成路线是通过m-CPBA参与的2,5-二取代呋喃的重排,Luche反应选择性地还原中间体烯酮,m-CPBA环氧化,CSA促进的分子内缩酮交换反应,构建了我们预期的母核结构,最后通过硒试剂的参与,成功发生脱水反应生成所需的双键,从而完成了螺环缩酮烯醇醚环氧化物的合成。应用新发展的方法,我们对底物进行了拓展,成功合成了几个类似物,并对天然产物(-)-AL-2进行了合成尝试,但是没有取得成功。
论文的第二部分内容是发展了一种具有市场应用前景的抗流感药物达菲的合成方法,我们以12步的线性步骤、12%的总收率完成了消旋体达菲的合成。该合成路线首先通过保护的吡咯和溴丙炔酸乙酯发生Diels-Alder反应得到一个氮桥环化合物,再以碱消除实现了目标分子所需的环己胺母核的构建,该方法可以从廉价的吡咯引入目标分子所需的第一个氮原子;第二个氮原子的引入是将邻位顺式二醇中间体以环亚硫酸酯保护,再开环亚硫酸酯实现的;化合物的立体构型是通过最初的Diels-Alder反应确定的。最后将关键中间体化合物通过辅基的拆分,实现了光学纯度达菲的合成。
This dissertation includes two independent parts. The first part deals with development of new methodologies for the synthesis of epoxy functionality-containing spirocycles. The need for such methodologies stems from our earlier investigations on natural antifeedant Tonghaosu, where an expeditious access to the spirobicyclic framework based on rearrangement of 2,5-disubstituted furan was established but selective introduction of an epoxy group in the spirocycle repeatedly failed. In the present work efforts were made again in construction of an epoxy ring at the carbonsα,βto the spiroketal center. However, instead of direct modification of the spirobicyclic dienes as in the earlier endeavors, incorporation of the epoxy functionality now was attempted before the target framework took the final shape. A successful route was eventually established, consisting of m-CPBA mediated spiroketalization of the 2,5-disubstituted furan, a region- and stereo-selective Luche reduction of the intermediate enone, an epoxidation with m-CPBA, a CSA-mediated intramolecular ketal exchange reaction (which led to rearrangement of the initial spirocycle into the desired final framework), and a selenium mediated dehydration to introduce the exocyclic carbon-carbon double bond. Attempts in applying the newly established method in synthesis of (?)-AL-2, a natural product with a similar bicyclic spiro-structure, are also detailed.
The second part of this thesis presents the studies on development of practical routes to the marketed anti-flu drug Tamiflu. Efforts along this line were first directed to the racemic product, which eventually led to a 12-step efficient route to Tamiflu with an overall yield of 12%. The cyclohexane framework was constructed using a Diels-Alder reaction between a protected pyrrole and a bromoacetylene, which allowed for introduction of one nitrogen atom with desired configuration from the inexpensive pyrrole after converting the initial bridged adduct into the cyclohexane by a base mediated elimination. Introduction of the second nitrogen atom of the target structure was achieved via a ring-opening substitution of a cyclic sulfate derived from the corresponding cis vicinal diol, with the relative configurations decided by the stereochemistry of the initial Diels-Alder adduct. Separation of the diastereomers of a key intermediate with the aid of an amino acid derived oxazolidinethione, the advanced intermediate was also obtained in enantiopure form, which allowed for synthesis of optically active Tamiflu.
论文的第二部分内容是发展了一种具有市场应用前景的抗流感药物达菲的合成方法,我们以12步的线性步骤、12%的总收率完成了消旋体达菲的合成。该合成路线首先通过保护的吡咯和溴丙炔酸乙酯发生Diels-Alder反应得到一个氮桥环化合物,再以碱消除实现了目标分子所需的环己胺母核的构建,该方法可以从廉价的吡咯引入目标分子所需的第一个氮原子;第二个氮原子的引入是将邻位顺式二醇中间体以环亚硫酸酯保护,再开环亚硫酸酯实现的;化合物的立体构型是通过最初的Diels-Alder反应确定的。最后将关键中间体化合物通过辅基的拆分,实现了光学纯度达菲的合成。
This dissertation includes two independent parts. The first part deals with development of new methodologies for the synthesis of epoxy functionality-containing spirocycles. The need for such methodologies stems from our earlier investigations on natural antifeedant Tonghaosu, where an expeditious access to the spirobicyclic framework based on rearrangement of 2,5-disubstituted furan was established but selective introduction of an epoxy group in the spirocycle repeatedly failed. In the present work efforts were made again in construction of an epoxy ring at the carbonsα,βto the spiroketal center. However, instead of direct modification of the spirobicyclic dienes as in the earlier endeavors, incorporation of the epoxy functionality now was attempted before the target framework took the final shape. A successful route was eventually established, consisting of m-CPBA mediated spiroketalization of the 2,5-disubstituted furan, a region- and stereo-selective Luche reduction of the intermediate enone, an epoxidation with m-CPBA, a CSA-mediated intramolecular ketal exchange reaction (which led to rearrangement of the initial spirocycle into the desired final framework), and a selenium mediated dehydration to introduce the exocyclic carbon-carbon double bond. Attempts in applying the newly established method in synthesis of (?)-AL-2, a natural product with a similar bicyclic spiro-structure, are also detailed.
The second part of this thesis presents the studies on development of practical routes to the marketed anti-flu drug Tamiflu. Efforts along this line were first directed to the racemic product, which eventually led to a 12-step efficient route to Tamiflu with an overall yield of 12%. The cyclohexane framework was constructed using a Diels-Alder reaction between a protected pyrrole and a bromoacetylene, which allowed for introduction of one nitrogen atom with desired configuration from the inexpensive pyrrole after converting the initial bridged adduct into the cyclohexane by a base mediated elimination. Introduction of the second nitrogen atom of the target structure was achieved via a ring-opening substitution of a cyclic sulfate derived from the corresponding cis vicinal diol, with the relative configurations decided by the stereochemistry of the initial Diels-Alder adduct. Separation of the diastereomers of a key intermediate with the aid of an amino acid derived oxazolidinethione, the advanced intermediate was also obtained in enantiopure form, which allowed for synthesis of optically active Tamiflu.
引文
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1.高阳.新型昆虫拒食剂—茼蒿素及其类似物的合成与反应研究[D].上海:中国科学院上海有机化学研究所, 1997.
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4. DeShong, P.; Waltermire, R. E.; Ammon, H. L. J. Am. Chem. Soc. 1998, 110, 1901-1910.
5. Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226.
6. Katritzky, A. R.; Ji, Y.; Fang, Y. F.; Prakash, I. J. Org. Chem. 2001, 66, 5613-5615.
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1. Salman, H.; Abraham, Y.; Tal, S.; Meltzman, S.; Kapon, M.; Tessler, N.; Speiser, S.; Eichen, Y. Eur. J. Org. Chem. 2005, 2207–2212.
2. Andersen, N. G.; Maddaford, S. P.; Keay, B. A. J. Org. Chem. 1996, 61, 2885-2887.
3. Zhang, C.–M.; Trudell, M. L. J. Org. Chem. 1996, 61, 7189-7191.
4. Singh, S.; Basmadjian, G. P. Tetrahedron Letters. 1997, 38, 6829-6830.
5. (a) Leung-Toung, R.; Liu, Y.-Z.; Muchowski, J. M.; Wu, Y.-L. Synthesis of (rac)-conduramines from pyrrole. Tetrahedron Lett. 1994, 35, 1639-1642. (b), Leung-Toung, R.; Liu, Y.-Z.; Muchowski, J. M.; Wu, Y.-L. J. Org. Chem. 1998, 63, 3235-3250.
6. Shie, J. J.; Fang, J. M.; Wang, S. Y.; Tsai, K. C.; Cheng, Y. S. E.; Yang, A. S.; Hsiao, S. C.; Su, C. Y.; Wong, C. H. J. Am. Chem. Soc. 2007, 129, 11892-11893.
7.刘鹤华.有机过氧化物与单电子氧化—还原中心的相互作用.上海:中国科学院上海有机化学研究所,2004.
8. Bromfield, K. M.; Graden, H.; Hagberg, D. P.; Olssonb, T.; Kann, N. Chem. Commun. 2007, 3183–3185.
9. Yeung, Y. Y.; Hong, S.; E. J. Corey. J. Am. Chem. Soc. 2006, 128, 6310-6311.
10.魏万国.肿瘤抑制因子p53失活复性物质Chlorofusin的全合成研究.上海:中国科学院上海有机化学研究所,2005.
11. Wu, Y. K.; Sun, Y. P.; Yang, Y. Q.; Hu, Q.; Zhang, Q. J. Org. Chem. 2004, 69, 6141-6144.
2. VanBeek, T. A.; DeGroor, A. Recl. Trav. Chim. Pays. Bas. 1986, 105, 513.
3. Munakadta, K. Appl. Chem. 1975, 42, 57.
4. Ley, S. V.; Toogod, P. L. Chemistry in Britain, 1990, 31.
5. J. Rebur, C. R. Acad. Sci. Paris, 1998, 307 (III), 75.
6. Okuz, S.; Wagner, H. J. Nat. Prod. 1982, 45, 374.
7. Sanz, J. F.; Falco, E.; Marco, A. Liebigs. Ann. Chem. 1990, 303.
8. Wu, Z. H.; Wang, J.; Li, J. C.; Chen, Y. Z.; Yu, A. J.; Feng, Z. R.; Shen, J.; Wu, Y.–L.; Gao, P. E.; Wang, Y. L. Natural Product R&D [China], 1994, 6, 1.
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12. Linde, H.; et al. Araneim-Forsch 1972, 22, 583.
13. Towers, G. H. N. et al. Lloydia, 1977, 40, 487-498. (CA: 87, 197343q)
14. Tada, M.; Chiba, K. Agric. Biol. Chem. 1984, 48, 1367.
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