基于[3+2]环加成反应的氮杂螺[3,4]环辛烷的合成

doi:10.6023/cjoc201407002

有机化学 ›› 2015, Vol. 35 ›› Issue (1): 137-143.DOI: 10.6023/cjoc201407002 上一篇下一篇

研究论文

基于[3+2]环加成反应的氮杂螺[3,4]环辛烷的合成

王雯, 陆秀宏, 董肖椿, 赵伟利

复旦大学药学院上海 201203

收稿日期:2014-07-01 修回日期:2014-09-19 发布日期:2014-09-25
通讯作者: 董肖椿, 赵伟利 E-mail:xcdong@fudan.edu.cn;zhaoweili@fudan.edu.cn
基金资助:
教育部博士点基金(No. 20130071110071)、上海市自然科学基金(No. 12ZR1403300)和上海市科技支撑(No. 13431900102)资助项目.

Synthesis of Azaspiro[3.4]octanes via [3+2] Cycloaddition

Wang Wen, Lu Xiuhong, Dong Xiaochun, Zhao Weili

School of Pharmacy, Fudan University, Shanghai 201203

Received:2014-07-01 Revised:2014-09-19 Published:2014-09-25
Supported by:
Project supported by the Specialized Research Fund for the Doctoral Program of Higher Education of China (No. 20130071110071), the Shanghai Municipal Natural Science Foundation (No. 12ZR1403300), the Shanghai Municipal Science & Technology Pillar Program for Bio-pharmaceuticals (No. 13431900102).

文章分享

1. 基于[3+2]环加成反应的氮杂螺[3,4]环辛烷的合成.PDF(5129KB)

摘要/Abstract

哌嗪、吗啉是小分子药物中常见的结构片段, 2,6-二氮杂螺[3,4]环辛烷和2-氧-6-氮杂螺[3,4]环辛烷等四元螺环化合物作为其类似物, 在药物化学领域具有良好的应用前景. 本研究以廉价易得的丙二酸二乙酯或丙烯酸乙酯为起始原料, 经[3+2]环加成反应, 可便捷高效地完成6-苄基-2,6-二氮杂螺[3,4]环辛烷和2-氧-6-氮杂螺[3,4]环辛烷克级水平的合成.

关键词: 2,6-二氮杂螺[3,4]环辛烷, 2-氧-6-氮杂螺[3,4]环辛烷, [3+2]环加成

Piperazine and morpholine are common modules in drugs. Design and synthesis of their surrogates may help to explore the chemical and patent space in medicinal chemistry. In this article, through [3+2] cycloaddition, the improved synthesis of 6-benzyl-2,6-diazaspiro[3.4]octane oxalate and 2-oxa-6-azaspiro[3.4]octane as substitutes of piperazine and morpholine was provided, respectively. Multi-gram quantities of the compounds could be easily obtained in relatively high yields.

Key words: 2,6-diazaspiro[3,4]octane, 2-oxa-6-azaspiro[3,4]octane, [3+2] cycloaddition

引用此文

王雯, 陆秀宏, 董肖椿, 赵伟利. 基于[3+2]环加成反应的氮杂螺[3,4]环辛烷的合成[J]. 有机化学, 2015, 35(1): 137-143.

Wang Wen, Lu Xiuhong, Dong Xiaochun, Zhao Weili. Synthesis of Azaspiro[3.4]octanes via [3+2] Cycloaddition[J]. Chin. J. Org. Chem., 2015, 35(1): 137-143.

导出引用 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

分享此文

参考文献

[1] Lameijer, E. W.; Kok, J. N.; Back, T.; Jzerman, A. P. J. Chem. Inf. Model. 2006, 46, 553.
[2] Law, V.; Knox, C.; Djoumbou, Y.; Jewison, T.; Guo, A. C.; Liu, Y.; Maciejewski, A.; Arndt, D.; Wilson, M.; Neveu, V.; Tang, A.; Gabriel, G.; Ly, C.; Adamjee, S.; Dame, Z. T.; Han, B.; Zhou, Y.; Wishart, D. S. Nucleic Acids Res. 2014, 42(D1), D1091.
[3] (a) Wuitschik, G.; Rogers-Evans, M.; Müller, K.; Fischer, H.; Wagner, B.; Schuler, F.; Polonchuk, L.; Carreira, E. M. Angew. Chem., Int. Ed. 2006, 45, 7736. (b) Burkhard, J.; Carreira, E. M. Org. Lett. 2008, 10, 3525. (c) Wuitschik, G.; Carreira, E. M.; Wagner, B.; Fischer, H.; Parrilla, I.; Schuler, F.; Rogers-Evans, M.; Müller, K. J. Med. Chem. 2010, 53, 3227. (d) Li, D. B.; Rogers-Evans, M.; Carreira, E. M. Org. Lett. 2013, 15, 4766. (e) Burkhard, J. A.; Guérot, C., Knust, H.; Carreira, E. M. Org. Lett. 2012, 14, 66. (f) Burkhard, J. A.; Guérot, C.; Knust, H.; Rogers-Evans, M.; Carreira, E. M. Org. Lett. 2010, 12, 1944. (g) Li, D. B.; Rogers-Evans, M.; Carreira, E. M. Org. Lett. 2011, 13, 6134. (h) Guérot, C.; Tchitchanov, B. H.; Knust, H.; Carreira, E. M. Org. Lett. 2011, 13, 780. (i) Burkhard, J. A.; Wuitschik, G.; Rogers-Evans, M.; Müller, K.; Carreira, E. M. Angew. Chem., Int. Ed. 2010, 49, 9052. (j) Wuitschik, G.; Rogers-Evans, M.; Buckl, A.; Bernasconi, M.; Märki, M.; Godel, T.; Fischer, H.; Wagner, B.; Parrilla, I.; Schuler, F.; Schneider, J.; Alker, A.; Schweizer, W. B.; Müller, K.; Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47, 4512. (k) Burkhard, J. A.; Wagner, B.; Fischer, H.; Schuler, F.; Müller, K.; Carreira, E. M. Angew. Chem., Int. Ed. 2010, 49, 3524.
[4] (a) Zhao, Y. C.; Wang, W.; Li, F.; Wang, F.; Zheng, X. F.; Yun, H. Y.; Zhao, W. L.; Dong, X. C. Tetrahedron Lett. 2013, 54, 5849. (b) Zhao, F.; Lin, Z. H.; Wang, F.; Zhao, W. L.; Dong, X. C. Bioorg. Med. Chem. Lett. 2013, 23, 5385. (c) Zhao, W. L.; Dong, X. C.; Zhang, W. X.; Wang, F.; Li, J.; Zhao, Y. C.; Zhao, F.; Wang, W. CN 102796110, 2012 [Chem. Abstr. 2012, 158, 56273]. (d) Zhao, W. L.; Dong, X. C.; Zhang, W. X.; Wang, F.; Li, J.; Zhao, Y. C.; Zhao, F.; Wang, W. CN 102796109, 2012 [Chem. Abstr. 2012, 158, 56272].
[5] (a) Antonios-Mccrea, W. R.; Barsanti, P. A.; Hu, C.; Jin, X.; Martin, E. J.; Pan, Y.; Lin, X.; Pfister, K. B.; Renhowe, P. A.; Sendzik, M.; Sutton, J.; Wan, L. WO 2012101062, 2012 [Chem. Abstr. 2012, 157, 294927]. (b) Yu, H.; Li, J.; Richardson, T. E.; Bharathi, P.; Heasley, B. H.; Goutopoulos, A. WO 2013012848, 2013 [Chem. Abstr. 2013, 158, 215679]. (c) Geneste, H.; Ochse, M.; Drescher, K.; Behl, B.; Laplanche, L.; Dinges, J.; Jakob, C. WO 2013000994, 2013 [Chem. Abstr. 2013, 158, 158576]. (d) Bodil Van Niel, M.; Fauber, B.; Gaines, S.; Gobbi, A.; Rene, O.; Vesey, D.; Ward, S. WO 2014009447, 2014 [Chem. Abstr. 2014, 160, 219224]. (e) Abeywardane, A.; Brunette, S. R.; Burke, M. J.; Kirrane, T. M., Jr.; Man, C. C.; Marshall, D. R.; Padyana, A. K.; Razavi, H.; Sibley, R.; Smith, K.; Lana, L.; Snow, R. J.; Sorcek, R. J.; Takahashi, H.; Taylor, S. J.; Turner, M. R.; Young, E. R. R.; Zhang, Q.; Zhang, Y.; Zindell, R. M. WO 2014014874, 2014 [Chem. Abstr. 2014, 160, 234272].
[6] Yoon, S. J.; Chung, Y. H.; Lee, C. W.; Oh, Y. S.; Kim, N. D.; Lim, J. K.; Jin, Y. H. WO 199900393, 1999 [Chem. Abstr. 1999, 130, 110281].
[7] Engel, W.; Eberlein, W.; Trummlitz, G.; Mihm, G.; Doods, H.; Mayer, N.; De Jonge, A. EP 417631, 1991 [Chem. Abstr. 1999, 115, 159188].
[8] Wuitschik, G.; Rogers-Evans, M.; Buckl, A.; Bernasconi, M.; Märki, M.; Godel, T.; Fischer, H.; Wagner, B.; Parrilla, I.; Schuler, F.; Schneider, J.; Alker, A.; Schweizer, W. B.; Müller, K.; Carreira, E. M. Angew. Chem., Int. Ed. 2008, 120, 4588.
[9] Xu, R.; Czarniecki, M.; De Man, J.; Pan, J. P.; Qiang, L.; Root, Y.; Ying, S. H.; Su, J.; Sun, X. J.; Zhang, Y. P.; Yu, T.; Zhang, Y.; Hu, T.; Chen, S. H. Tetrahedron Lett. 2011, 52, 3266.
[10] (a) Grafton, M.; Mansfield, A. C.; Fray, M. J. Tetrahedron Lett. 2010, 51, 1026. (b) Morimoto, Y.; Achiwa, K. Chem. Pharm. Bull. 1987, 35, 3845. (c) Ellsworth, E. L.; Sciotti, R. J.; Starr, J. T. WO 2005026165, 2005 [Chem. Abstr. 2005, 142, 336263]. (d) Wang, X. X.; Zhou, G. C. Chin. J. Synth. Chem. 2009, 17, 260 (in Chinese). (王贤洵, 周国川, 合成化学, 2009, 17, 260.)
[11] (a) Gribble, G. W. In Comprehensive Organic Synthesis, Vol. 8, Eds.: Trost, B. M., Fleming, I., Pergamon, Oxford, 1991, p. 603. (b) Kaiser, H. P.; Muchowski, J. M. J. Org. Chem. 1984, 49, 4203.
[12] (a) Wheland, G. W. In Advanced Organic Chemistry, 2nd ed., Wiley, J.; Sons, Inc., New York, 1949, p. 373. (b) Brown, F. R.; Van Gulick, M. N. J. Org. Chem. 1956, 21, 1046.
[13] (a) Padwa, A.; Dent, W. J. Org. Chem. 1987, 52, 235. (b) Pandey, G.; Banerjee, P.; Gadre, R. S. Chem. Rev. 2006, 106, 4484.
[14] Bachman, G. B.; Tanner, H. A. J. Org. Chem. 1939, 4, 493. (b) Ballesteros, P.; Roberts, B. W.; Wong, J. J. Org. Chem. 1983, 48, 3603. (c) Ponticello, I. S. US 4056543, 1978 [Chem. Abstr. 1978, 88, 51497]. (d) De Keyser, J. L.; De Cock, C. J. C.; Poupaert, J. H.; Dumont, P. J. Org. Chem. 1988, 58, 4859.
[15] Page, P. C. B.; Gambera, G.; Hayman, C. M.; Edgar, M. Synlett 2006, 3411.
[16] Rajesh, K. M.; Cristina, M. C.; Kevin, D. R.; Edward, T. Org. Lett. 2007, 9, 575.
[17] (a) Yu, C. Z.; Liu, B.; Hu, L. Q. J. Org. Chem. 2011, 66, 5413.
(b) Zarudii, F. S.; Lazareva, D. N.; Kurmaeva, E. S.; Chalova, O. B.; Kiladze, T. K.; Kantor, E. A.; Rakhmankulov, D. L. Pharm. Chem. J. 1985, 19, 108. (c) Tsai, F. H.; Overberger, C. G.; Zand, R. Biopolymers 1990, 30, 1039. (d) Zhao, D. L.; Chen, C. Y.; Xu, F.; Tan, L. S.; Tillyer, R.; Pierce, E. M.; Moore, R. J. Org. Synth. 2000, 77, 12.
[18] Huang, H. M.; Liu, X. C.; Deng, J.; Qiu, M.; Zheng, Z. Org. Lett. 2006, 8, 3359.
[19] Chen, Y.; Kervio, E.; Retey, J. Helv. Chim. Acta 2002, 85, 552
[20] Morimoto, Y.; Achiwa, K. Chem. Pharm. Bull. 1987, 35, 3845.
[21] Engel, W.; Eberlein, W.; Trummlitz, G.; Mihm, G.; Doods, H.; Mayer, N.; De Jonge, A. EP 417631, 1991 [Chem. Abstr. 1991, 115, 159188].
[22] Aranha, R. M.; Bowser, A. M.; Madalengoitia, J. S. Org. Lett. 2009, 11, 575.

基于[3+2]环加成反应的氮杂螺[3,4]环辛烷的合成

Synthesis of Azaspiro[3.4]octanes via [3+2] Cycloaddition

PDF

补充材料

可视化

摘要/Abstract

引用此文

分享此文

参考文献

相关文章 1

编辑推荐

相关统计

本文评价