Recent Progress in the Total Synthesis of Morphine Alkaloids★

doi:10.6023/cjoc202505029

Chinese Journal of Organic Chemistry ›› 2025, Vol. 45 ›› Issue (9): 3098-3112.DOI: 10.6023/cjoc202505029 Previous Articles Next Articles

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吗啡类生物碱的全合成研究新进展^★

刘小宇, 许庭瑞, 秦勇^*()

四川大学华西药学院成都 610041

收稿日期:2025-05-26 修回日期:2025-06-19 发布日期:2025-08-11
基金资助:
国家自然科学基金(21991114); 四川省科技计划(2024ZYD0100)

Recent Progress in the Total Synthesis of Morphine Alkaloids^★

Xiaoyu Liu, Tingrui Xu, Yong Qin^*()

West China School of Pharmacy, Sichuan University, Chengdu 610041

Received:2025-05-26 Revised:2025-06-19 Published:2025-08-11
Contact: *E-mail: yongqin@scu.edu.cn
About author:
^★ Academic Papers of the 27^th Annual Meeting of the China Association for Science and Technology.
Supported by:
National Natural Science Foundation of China(21991114); Sichuan Science and Technology Program(2024ZYD0100)

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

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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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Fig. & Tab. 15

Figure 1. Chemical structures of representative morphine alkaloids

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

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

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

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

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

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

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

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

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

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

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

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

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

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

References 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.

吗啡类生物碱的全合成研究新进展^★

Recent Progress in the Total Synthesis of Morphine Alkaloids^★

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吗啡类生物碱的全合成研究新进展★

Recent Progress in the Total Synthesis of Morphine Alkaloids★

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Fig. & Tab. 15

References 36

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吗啡类生物碱的全合成研究新进展^★

Recent Progress in the Total Synthesis of Morphine Alkaloids^★