吗啡类生物碱的全合成研究新进展★

doi:10.6023/cjoc202505029

摘要/Abstract

吗啡类生物碱因具有复杂多环骨架与重要药理活性, 长期被视为合成化学领域的核心挑战之一. 综述了2017~2024年报道的吗啡类生物碱全合成研究进展, 着重剖析了以精准构建核心多环骨架及关键手性中心为目标的创新合成策略. 相关研究不仅彰显了合成化学的科学性和艺术性, 而且为推动吗啡类药物的工业化生产与新药开发奠定了重要基础.

关键词: 吗啡, 生物碱, 天然产物, 全合成, 合成方法与策略

Morphine alkaloids have long been regarded as one of the core challenges in synthetic chemistry due to their complex polycyclic skeletons and significant pharmacological activities. The research progress in the total synthesis of morphine alkaloids reported from 2017~2024 is summarized, with a focus on analyzing innovative synthetic strategies aimed at precisely constructing core polycyclic skeletons and key chiral centers. These studies not only demonstrate the science and art of synthetic chemistry, but also lay an important foundation for promoting the industrial production of morphine alkaloid drugs and the development of new pharmaceuticals.

Key words: morphine, alkaloid, natural product, total synthesis, synthetic method and strategy

引用此文

刘小宇, 许庭瑞, 秦勇. 吗啡类生物碱的全合成研究新进展^★[J]. 有机化学, 2025, 45(9): 3098-3112.

Xiaoyu Liu, Tingrui Xu, Yong Qin. Recent Progress in the Total Synthesis of Morphine Alkaloids^★[J]. Chinese Journal of Organic Chemistry, 2025, 45(9): 3098-3112.

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图/表 15

图1. 代表性吗啡类生物碱的化学结构

Figure 1. Chemical structures of representative morphine alkaloids

图式1. Chen研究组关于(±)-羟考酮的全合成及(＋)-羟考酮的形式全合成

Scheme 1. Total synthesis of (±)-oxycodone and formal total synthesis of (＋)-oxycodone by Chenʼs group

图式2. Opatz研究组关于(-)-蒂巴因和(-)-羟考酮的全合成

Scheme 2. Total synthesis of (-)-thebaine and (-)-oxycodone by Opatzʼs group

图式3. Hudlicky研究组关于(＋)-羟考酮的第一和第二代全合成

Scheme 3. The first and second generation total syntheses of (＋)-oxycodone by Hudlickyʼs group

图式4. Hudlicky研究组关于(＋)-羟考酮的第三和第四代全合成

Scheme 4. The third and fourth generation total syntheses of (＋)-oxycodone by Hudlickyʼs group

图式5. 涂永强/张辅民研究组关于(-)-可待因和(-)-吗啡的全合成

Scheme 5. Total synthesis of (-)-codeine and (-)-morphine by Tu and Zhangʼs group

图式6. Ellman研究组关于(-)-纳曲酮的全合成

Scheme 6. Total synthesis of (-)-naltrexone by Ellmanʼs group

图式7. Metz研究组关于(±)-蒂巴因酮A的全合成

Scheme 7. Total synthesis of (±)-thebainone A by Metzʼs group

图式8. Dong研究组关于(-)-蒂巴因酮A的全合成

Scheme 8. Total synthesis of (-)-thebainone A by Dongʼs group

图式9. 秦勇/钟武研究组关于吗啡类生物碱的第一代不对称全合成

Scheme 9. The first generation asymmetric total synthesis of morphine alkaloids by Qin and Zhongʼs group

图式10. 秦勇/钟武研究组关于吗啡类生物碱的第二代不对称全合成

Scheme 10. The second generation asymmetric total synthesis of morphine alkaloids by Qin and Zhongʼs group

图式11. Banwell/蓝平研究组关于(-)-可待因的全合成

Scheme 11. Total synthesis of (-)-codeine by Banwell and Lanʼs group

图式12. Smith研究组关于(±)-蒂巴因的全合成及(-)-蒂巴因的形式全合成

Scheme 12. Total synthesis of (±)-thebaine and formal total synthesis of (-)-thebaine by Smithʼs group

图式13. Bisai研究组关于(-)-可待因的全合成

Scheme 13. Total synthesis of (-)-codeine by Bisaiʼs group

图式14. Nakamura研究组关于(±)-吗啡的形式全合成

Scheme 14. Formal total synthesis of (±)-morphine by Nakamuraʼs group

参考文献 36

[1]	Wicks, C.; Hudlicky, T.; Rinner, U. In the Alkaloids: Chemistry and Biology, Vol. 86, Ed.: Knölker, H.-J., Academic Press, 2021, p. 145.
[2]	Gates, M.; Tschudi, G. J. Am. Chem. Soc. 1952, 74, 1109.
[3]	Novak, B. H.; Hudlicky, T.; Reed, J. W.; Mulzer, J.; Trauner, D. Curr. Org. Chem. 2000, 4, 343.
[4]	Zezula, J.; Hudlicky, T. Synlett 2005, 388.
[5]	Rinner, U.; Hudlicky, T. Top. Curr. Chem. 2012, 309, 33. doi: 10.1007/128_2011_133 pmid: 21547687
[6]	Reed, J. W.; Hudlicky, T. Acc. Chem. Res. 2015, 48, 674.
[7]	Li, Q.; Zhang, H. Chin. J. Org. Chem. 2017, 37, 1629 (in Chinese).
	(李其林, 张洪彬, 有机化学, 2017, 37, 1629.) doi: 10.6023/cjoc201702048
[8]	Chen, D. Y.-K.; Park, A. Chem. Commun. 2018, 54, 13018.
[9]	Kimishima, A.; Umihara, H.; Mizoguchi, A.; Yokoshima, S.; Fukuyama, T. Org. Lett. 2014, 16, 6244. doi: 10.1021/ol503175n pmid: 25423610
[10]	Rubush, D. M.; Morges, M. A.; Rose, B. J.; Thamm, D. H.; Rovis, T. J. Am. Chem. Soc. 2012, 134, 13554. doi: 10.1021/ja3052427 pmid: 22871165
[11]	Lipp, A.; Ferenc, D.; Gütz, C.; Geffe, M.; Vierengel, N.; Schollmeyer, D.; Schäfer, H. J.; Waldvogel, S. R.; Opatz, T. Angew. Chem.,Int. Ed. 2018, 57, 11055.
[12]	Lipp, A.; Selt, M.; Ferenc, D.; Schollmeyer, D.; Waldvogel, S. R.; Opatz, T. Org. Lett. 2019, 21, 1828.
[13]	Endoma-Arias, M. A. A.; Makarova, M.; Dela Paz, H. E.; Hudlicky, T. Synthesis 2019, 51, 225.
[14]	Makarova, M.; Endoma-Arias, M. A. A.; Dela Paz, H. E.; Simionescu, R.; Hudlicky, T. J. Am. Chem. Soc. 2019, 141, 10883. doi: 10.1021/jacs.9b05033 pmid: 31184866
[15]	Endoma, M. A.; Bui, V. P.; Hansen, J.; Hudlicky, T. Org. Process Res. Dev. 2002, 6, 525.
[16]	Zhang, Q.; Zhang, F.-M.; Zhang, C.-S.; Liu, S.-Z.; Tian, J.-M.; Wang, S.-H.; Zhang, X.-M.; Tu, Y.-Q. Nat. Commun. 2019, 10,
[17]	Tian, J.-M.; Yuan, Y.-H.; Tu, Y. Q.; Zhang, F.-M.; Zhang, X.-B.; Zhang, S.-H.; Wang, S.-H.; Zhang, X.-M. Chem. Commun. 2015, 51, 9979.
[18]	Sun, D.; Pedersen, B.; Ellman, J. A. Chem. Sci. 2019, 10, 535.
[19]	Duttwyler, S.; Lu, C.; Rheingold, A. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2012, 134, 4064. doi: 10.1021/ja2119833 pmid: 22356093
[20]	Phillips, E. M.; Mesganaw, T.; Patel, A.; Duttwyler, S.; Mercado, B. Q.; Houk, K. N.; Ellman, J. A. Angew. Chem.,Int. Ed. 2015, 54, 12044.
[21]	Wang, Y.; Hennig, A.; Küttler, T.; Hahn, C.; Jäger, A.; Metz, P. Org. Lett. 2020, 22, 3145.
[22]	Hou, S.-H.; Prichina, A. Y.; Dong, G. Angew. Chem.,Int. Ed. 2021, 60, 13057.
[23]	Xue, Y.; Dong, G. Acc. Chem. Res. 2022, 55, 2341.
[24]	Zhou, X.; Li, W.; Zhou, R.; Wu, X.; Huang, Y.; Hou, W.; Li, C.; Zhang, Y.; Nie, W.; Wang, Y.; Song, H.; Liu, X.-Y.; Zheng, Z.; Xie, F.; Li, S.; Zhong, W.; Qin, Y. CCS Chem. 2021, 3, 1376.
[25]	He, H.; Xue, F.; Hu, Z.; Li, P.; Xiao, Q.; Zhang, M.; Xue, F.; Zhang, D.; Song, H.; Liu, X.-Y.; Zheng, Z.; Li, S.; Zhong, W.; Qin, Y. Org. Chem. Front. 2022, 9, 2322.
[26]	Tang, Y.; Zhang, Y.; Zhao, J.; Xue, F.; He, H.; Xue, F.; Liu, X.-Y.; Qin, Y. Tetrahedron Lett. 2022, 104, 154027.
[27]	Tang, P.; Wang, H.; Zhang, W.; Chen, F.-E. Green Synth. Catal. 2020, 1, 26.
[28]	White, L. V.; Hu, N.; He, Y.-T.; Banwell, M. G.; Lan, P. Angew. Chem.,Int. Ed. 2022, 61, 27.
[29]	Trost, B. M.; Tang, W. J. Am. Chem. Soc. 2002, 124, 14542.
[30]	Nguyen, T. M.; Nicewicz, D. A. J. Am. Chem. Soc. 2013, 135, 9588. doi: 10.1021/ja4031616 pmid: 23768239
[31]	Tolchin, Z. A.; Dukes, D. M.; Gharbaoui, L. M.; Smith, J. M. Org. Lett. 2023, 25, 8424.
[32]	Taylor, M. S.; Tokunaga, N.; Jacobsen, E. N. Angew. Chem.,Int. Ed. 2005, 44, 6700.
[33]	García Mancheño, O.; Asmus, S.; Zurro, M.; Fischer, T. Angew. Chem.,Int. Ed. 2015, 54, 8823.
[34]	Mondal, A.; Pal, S.; Khatua, A.; Mondal, A.; Bisai, A. J. Org. Chem. 2024, 89, 12485.
[35]	Kage, M.; Yamakoshi, H.; Tabata, M.; Ohashi, E.; Noguchi, K.; Watanabe, T.; Uchida, M.; Takada, M.; Ikeuchi, K.; Nakamura, S. Chem. Sci. 2024, 15, 19070.
[36]	Iijima, I.; Rice, K. C.; Silverton, J. V. Heterocycles 1977, 6, 1157.