手性氨基酚的合成和拆分以及它们在不对称合成中的应用
摘要
手性氨基-羟基化合物是一类用于催化不对称合成和手性辅助合成的重要配体。已经被成功开发的氨基醇配体绝大多数起始于手性源化合物。但是，非手性源的氨基-羟基手性配体的设计和合成已经成为目前不对称合成研究中的一个重要内容和发展趋势。因此，在天然手性源中几乎不存在的、或者不易从天然手性源转化得到的手性氨基酚将是一类重要的研究目标．
本文选择了Betti碱及其手性衍生物为研究目标，完成了Betti碱的拆分、手性配体结构的合成，以及它们在催化不对称合成中的初步应用。
第一章主要解决了Betti碱1的拆分问题．我们发现了外消旋Betti碱1在拆分中发生分解的原因，并开发出一条以丙酮为拆分溶剂的拆分方法，经过对各种条件的优化，在以50克的拆分规模上，Betti碱1的拆分化学收率达到84％，光学收率达到99％ee。
第二章，我们使用手性Betti碱S-1与水杨醛和Cu(Ⅱ)反应，得到相应的双核铜配合物，并用X-射线单晶结构分析确认了手性配合物和外消旋配合物在结构上的差异。并对其催化诱导环丙烷化反应进行了初步的探讨。
最后使用手性Betti碱S-1和它的N-取代衍生物为配体对硼烷还原潜手性酮的反应进行了探讨。虽然未能得到满意的手性诱导结果，但观察到温度对产物立体选择性的显著影响。
Chiral amino-hydroxy compounds have been proved to be a very efficient class of ligands in a variety of catalytic asymmetric syntheses and chiral auxiliary synthesis catalyzed by metallic ions. Most of them were derived from a few readily available natural products. To increase understanding of asymmetric synthesis, design and synthesis of chiral ligands from non-natural resource is essential. Therefore, chiral amino-phenol compounds are gaining progressive importance.
The thesis here described the chiral resolution of Betti Base and the synthesis of their derivatives, as well as their applications as chiral ligands in asymmetric synthesis.
In the Chapter One, we found the reason that led the decomposition of Betti Base 1 in the process of chiral resolution and an efficient resolution procedure was developed using acetone as the solvent. In the scale of 50 grams, it gave the resolution results in up to 84% yield and 99%ee.
In the Chapter Two, bis-nuclear coordination compounds were prepared by the reaction of compound 5-1, 2-hydroxybenzaldehyde and Cu(OAc)2. Their structures were confirmed by X-ray diffraction analysis and the catalytic properties were tested in the asymmtric cyclopropanation.
The TV-substituted 5-1 were also synthesized and the catalytic properties were tested in the asymmtric reduction of 2'-bromoacetophenone.
本文选择了Betti碱及其手性衍生物为研究目标，完成了Betti碱的拆分、手性配体结构的合成，以及它们在催化不对称合成中的初步应用。
第一章主要解决了Betti碱1的拆分问题．我们发现了外消旋Betti碱1在拆分中发生分解的原因，并开发出一条以丙酮为拆分溶剂的拆分方法，经过对各种条件的优化，在以50克的拆分规模上，Betti碱1的拆分化学收率达到84％，光学收率达到99％ee。
第二章，我们使用手性Betti碱S-1与水杨醛和Cu(Ⅱ)反应，得到相应的双核铜配合物，并用X-射线单晶结构分析确认了手性配合物和外消旋配合物在结构上的差异。并对其催化诱导环丙烷化反应进行了初步的探讨。
最后使用手性Betti碱S-1和它的N-取代衍生物为配体对硼烷还原潜手性酮的反应进行了探讨。虽然未能得到满意的手性诱导结果，但观察到温度对产物立体选择性的显著影响。
Chiral amino-hydroxy compounds have been proved to be a very efficient class of ligands in a variety of catalytic asymmetric syntheses and chiral auxiliary synthesis catalyzed by metallic ions. Most of them were derived from a few readily available natural products. To increase understanding of asymmetric synthesis, design and synthesis of chiral ligands from non-natural resource is essential. Therefore, chiral amino-phenol compounds are gaining progressive importance.
The thesis here described the chiral resolution of Betti Base and the synthesis of their derivatives, as well as their applications as chiral ligands in asymmetric synthesis.
In the Chapter One, we found the reason that led the decomposition of Betti Base 1 in the process of chiral resolution and an efficient resolution procedure was developed using acetone as the solvent. In the scale of 50 grams, it gave the resolution results in up to 84% yield and 99%ee.
In the Chapter Two, bis-nuclear coordination compounds were prepared by the reaction of compound 5-1, 2-hydroxybenzaldehyde and Cu(OAc)2. Their structures were confirmed by X-ray diffraction analysis and the catalytic properties were tested in the asymmtric cyclopropanation.
The TV-substituted 5-1 were also synthesized and the catalytic properties were tested in the asymmtric reduction of 2'-bromoacetophenone.
引文
[1](a)钱延龙，陈新滋主编，金属有机化学与催化，化学工业出版社，1997。
(b)林国强，陈耀全，陈新滋，李月明著，手性合成—不对称反应及其应用，科学出版社，2000。
[2]Corey, E. J.; Hetal, C.J.Angew. Chem., Int. Ed. Engl., 1998, 37, 1986.
[3]Corey, E. J.; Bakshi, R.K.; Shibata, S.J. Am. Chem. Soc., 1987, 109, 5551.
[4]Jones, T. K.; Mohan, J. J.; Wavier, L. C.; Blacklock, T. J.; Mathre, D. J.; Sohar,P.; Turner Jones, E. T.; Reamer, R. A.; Roberts, F. E.; Grabowski, E. J. J. J. Org.Chem., 1991, 56, 763.
[5]Corey, E. J.; Imai, N.; Zhang, H.-Y. J. Am. Chem. Soc., 1991, 113, 6005.
[6]Lowenthal, R. E.; Abiko, A.; Masamune, S. Tetrahedron Lett., 1991, 32, 7373.
[7]Evans, D. A.; Woerpel, K. A.; Hinman, M.; Faul, M. M. J Am. Chem. Soc.,1991, 113, 726.
[8]Muller, D.; Umbricht, G.; Weber, B.; Pfaltz, A. Helv. Chim. Acta 1991, 74, 232.
[9](a)Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.; Barnes, D. M.J. Am. Chem. Soc., 1993, 115, 5328. (b) Hansen, K. B.; Finney, N. S.; Jacobsen,E.N. Angew. Chem. Int. Ed. Engl., 1995, 34, 676.
[10]Evans, D. A.; Miller, S. J. Lecka, T. J. Am. Chem. Soc., 1993, 115, 6460.
[11]Von-Matt, P.; Pfaltz, A. Tetrahedron: Asymmetry 1991, 2, 691.
[12]Helmchen, G.; Krotz, A.; Ganz, K.-T.; Hansen, D. Synlett 1991, 257.
[13]Nakamura, M.; Arui, M.; Nakumura, E. J. Am. Chem. Soc., 1995, 117, 1179.
[14](a)Evans, D. A,; Takacs, J. M.; McGee, L. R. Ennis, M. D.; Mathre, D. J.;Bartroli, J. Pure & Appl. Chem., 1981, 53, 1109. (b)Enders, D.; Thiebes, C.Pure & Appl. Chem., 2001, 73, 573. (c) Meyers, A.I.; Andres, C.J. Resek, J.E.;Woodall, C.C.; Mclaughlin,L. P. H.; Price, D. A. Tetrahedron 1999, 55, 8931.
[15]Soai, K.; Niwa, S. Chem. Rev.,1992,92,833.
[16]Soai, K.; Yamamoto, M.; Hayasaka, T.J. Org. Chem., 1991, 56, 4264.
[17]Noyori, R.;Kitamura,M.; Suga, S.; Kawai, K. J. Am. Chem. Soc.,1986, 108,6071.
[18]Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am. Chem. Soc.,1987,109,7111.
[19]Li, Z.; Zheng, Z.; Wan, B.; Chen, H.J. Molecular Catalysis A:Chemical 2001,165,67.
[20] 钟增培，曹承君，朱良，有机化学1999，19，448．
[21] (a) Smrcina, M.; Lorenc, M.; Hanus, V.; Kocovsky, P. Synlett 1991, 231． (b) Smrcina, M.; Lorenc, M.; Hanus, V.; Sedmera,P.; Kocovsky, P. J. Org. Chem., 1992, 57, 1917． (c) Smrcina, M.; Polakova, J.; Vyskocil, S.; Kocovsky, P. J. Org. Chem., 1993, 55, 4534． (d) Smrcina, M.; Vyskocil, S. Maca, B.; Polasek, M.; Claxton, T. A.; Abbott, A. P.; Kocovsky, P. J. Org. Chem., 1994,59,2156．
[22] (a) Camera, E. M.; Lee, W.; Singer, R. A. J, Am. Chem. Soc., 1995, 117, 12360． (b) Kim, Y.; Singer, R. A. Carreira, E. M. Angew. Chem. Int. Ed. Engl, 1998, 37, 1261．
[23] Carreira, E. M.; Lee, W.; Singer, R. A. J. Am. Chem. Soc., 1995, 117, 3649．
[24] Vyskocil, S.; Jaraz, S.; Smrcina, M.; Sticha, M.; Hanus, V.; Polasek, M.; Kocovsky, P. J. Org. Chem., 1998, 63, 7727．
[25] Cardelliccnio, C.; Ciccarella, G.; Naso, R; Schingaro, E.; Scordari, F. Tetrahedron: Asymmetry 1998, 9, 3667．
[26] Cardelliccnio, C.; Ciccarella, G.; Naso, R; Schingaro, E.; Scordari, F. Tetrahedron: Asymmetry 1998, 9, 3667．
[27] (a) Cimarelli, C.; Mazzanti, A.; Palmieri, G.; Volpini, E. J. Org. Chem., 2001, 66, 4759． (b) Cimarelli, C.; Palmieri, G.; Volpini, E. Tetrahedron 2001, 57, 6089．
[28] 陆军博士学位毕业论文，南京大学，2001。
[29] Palmieri, G. Tetrahedron: Asymmetry, 2000, 77, 3361．
[30] Liu, D.-X.; Zhang, L.-C.; Wang, Q.; Da, C.-S.; Xin, Z.-Q.; Wang, R.; Choi, M. C. K.; Chan, A. S. C. Org. Lett., 2001, 3, 2733．
[31] Vyskocil, S.; Smrcina, M.; Sticha, M.; Hanus, V; Polasek, M.; Kocovsky, P. J. Org. Chem., 1998, 63, 7738．
[32] Yamazaki, N.; Ito, T.; Kibayashi, C. Tetrahedron Lett., 1999, 40, 739．
(b)林国强，陈耀全，陈新滋，李月明著，手性合成—不对称反应及其应用，科学出版社，2000。
[2]Corey, E. J.; Hetal, C.J.Angew. Chem., Int. Ed. Engl., 1998, 37, 1986.
[3]Corey, E. J.; Bakshi, R.K.; Shibata, S.J. Am. Chem. Soc., 1987, 109, 5551.
[4]Jones, T. K.; Mohan, J. J.; Wavier, L. C.; Blacklock, T. J.; Mathre, D. J.; Sohar,P.; Turner Jones, E. T.; Reamer, R. A.; Roberts, F. E.; Grabowski, E. J. J. J. Org.Chem., 1991, 56, 763.
[5]Corey, E. J.; Imai, N.; Zhang, H.-Y. J. Am. Chem. Soc., 1991, 113, 6005.
[6]Lowenthal, R. E.; Abiko, A.; Masamune, S. Tetrahedron Lett., 1991, 32, 7373.
[7]Evans, D. A.; Woerpel, K. A.; Hinman, M.; Faul, M. M. J Am. Chem. Soc.,1991, 113, 726.
[8]Muller, D.; Umbricht, G.; Weber, B.; Pfaltz, A. Helv. Chim. Acta 1991, 74, 232.
[9](a)Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.; Barnes, D. M.J. Am. Chem. Soc., 1993, 115, 5328. (b) Hansen, K. B.; Finney, N. S.; Jacobsen,E.N. Angew. Chem. Int. Ed. Engl., 1995, 34, 676.
[10]Evans, D. A.; Miller, S. J. Lecka, T. J. Am. Chem. Soc., 1993, 115, 6460.
[11]Von-Matt, P.; Pfaltz, A. Tetrahedron: Asymmetry 1991, 2, 691.
[12]Helmchen, G.; Krotz, A.; Ganz, K.-T.; Hansen, D. Synlett 1991, 257.
[13]Nakamura, M.; Arui, M.; Nakumura, E. J. Am. Chem. Soc., 1995, 117, 1179.
[14](a)Evans, D. A,; Takacs, J. M.; McGee, L. R. Ennis, M. D.; Mathre, D. J.;Bartroli, J. Pure & Appl. Chem., 1981, 53, 1109. (b)Enders, D.; Thiebes, C.Pure & Appl. Chem., 2001, 73, 573. (c) Meyers, A.I.; Andres, C.J. Resek, J.E.;Woodall, C.C.; Mclaughlin,L. P. H.; Price, D. A. Tetrahedron 1999, 55, 8931.
[15]Soai, K.; Niwa, S. Chem. Rev.,1992,92,833.
[16]Soai, K.; Yamamoto, M.; Hayasaka, T.J. Org. Chem., 1991, 56, 4264.
[17]Noyori, R.;Kitamura,M.; Suga, S.; Kawai, K. J. Am. Chem. Soc.,1986, 108,6071.
[18]Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am. Chem. Soc.,1987,109,7111.
[19]Li, Z.; Zheng, Z.; Wan, B.; Chen, H.J. Molecular Catalysis A:Chemical 2001,165,67.
[20] 钟增培，曹承君，朱良，有机化学1999，19，448．
[21] (a) Smrcina, M.; Lorenc, M.; Hanus, V.; Kocovsky, P. Synlett 1991, 231． (b) Smrcina, M.; Lorenc, M.; Hanus, V.; Sedmera,P.; Kocovsky, P. J. Org. Chem., 1992, 57, 1917． (c) Smrcina, M.; Polakova, J.; Vyskocil, S.; Kocovsky, P. J. Org. Chem., 1993, 55, 4534． (d) Smrcina, M.; Vyskocil, S. Maca, B.; Polasek, M.; Claxton, T. A.; Abbott, A. P.; Kocovsky, P. J. Org. Chem., 1994,59,2156．
[22] (a) Camera, E. M.; Lee, W.; Singer, R. A. J, Am. Chem. Soc., 1995, 117, 12360． (b) Kim, Y.; Singer, R. A. Carreira, E. M. Angew. Chem. Int. Ed. Engl, 1998, 37, 1261．
[23] Carreira, E. M.; Lee, W.; Singer, R. A. J. Am. Chem. Soc., 1995, 117, 3649．
[24] Vyskocil, S.; Jaraz, S.; Smrcina, M.; Sticha, M.; Hanus, V.; Polasek, M.; Kocovsky, P. J. Org. Chem., 1998, 63, 7727．
[25] Cardelliccnio, C.; Ciccarella, G.; Naso, R; Schingaro, E.; Scordari, F. Tetrahedron: Asymmetry 1998, 9, 3667．
[26] Cardelliccnio, C.; Ciccarella, G.; Naso, R; Schingaro, E.; Scordari, F. Tetrahedron: Asymmetry 1998, 9, 3667．
[27] (a) Cimarelli, C.; Mazzanti, A.; Palmieri, G.; Volpini, E. J. Org. Chem., 2001, 66, 4759． (b) Cimarelli, C.; Palmieri, G.; Volpini, E. Tetrahedron 2001, 57, 6089．
[28] 陆军博士学位毕业论文，南京大学，2001。
[29] Palmieri, G. Tetrahedron: Asymmetry, 2000, 77, 3361．
[30] Liu, D.-X.; Zhang, L.-C.; Wang, Q.; Da, C.-S.; Xin, Z.-Q.; Wang, R.; Choi, M. C. K.; Chan, A. S. C. Org. Lett., 2001, 3, 2733．
[31] Vyskocil, S.; Smrcina, M.; Sticha, M.; Hanus, V; Polasek, M.; Kocovsky, P. J. Org. Chem., 1998, 63, 7738．
[32] Yamazaki, N.; Ito, T.; Kibayashi, C. Tetrahedron Lett., 1999, 40, 739．