Concise Total Synthesis of (–)-Galanthamine: An Efficient Base-Promoted Lactamization Strategy

doi:10.6023/cjoc202512039

Chinese Journal of Organic Chemistry ›› 2026, Vol. 46 ›› Issue (6): 2423-2430.DOI: 10.6023/cjoc202512039 Previous Articles Next Articles

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(–)-加兰他敏的简洁全合成: 一种高效的碱促进内酰胺化策略

刘则琳^a, 何泗泉^a, 阿迪拉•阿布都热西提^a, 金钟^b^,^*()

^a 喀什大学化学与环境科学学院新疆喀什 844006
^b 新疆大学化学学院乌鲁木齐 830046

收稿日期:2026-12-26 修回日期:2026-03-04 发布日期:2026-04-03
基金资助:
国家自然科学基金(22171145); 国家自然科学基金(32560660); 新疆人才发展基金(XJRC-2025-KJ-YJ-CXPT-146); 新疆维吾尔自治区自然科学基金(2024D01A13); 喀什大学创新研究团队计划资助项目

Concise Total Synthesis of (–)-Galanthamine: An Efficient Base-Promoted Lactamization Strategy

Zelin Liu^a, Siquan He^a, Abudurexiti Adila^a, Zhong Jin^b^,^*()

^a College of Chemistry and Enviromental Sciences, Kashi University, Kashi, Xinjiang 844006
^b College of Chemistry, Xinjiang University, Urumqi 830046

Received:2026-12-26 Revised:2026-03-04 Published:2026-04-03
Contact: * E-mail: zjin@nankai.edu.cn
Supported by:
National Natural Science Foundation of China(22171145); National Natural Science Foundation of China(32560660); Talent Development Project of Xinjiang Uygur Autonomous Region(XJRC-2025-KJ-YJ-CXPT-146); Natural Science Foundation of Xinjiang Uygur Autonomous Region(2024D01A13); Program for Innovative Research Team in Kashi University

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Abstract

An efficient lactamization strategy using ethyl 3-(6-oxocyclohex-1-en-1-yl)propanoate (3) as the starting material for concise total synthesis of (–)-galanthamine (1) is presented. Naturally occurring phytomedicine (–)-galanthamine was obtained with a total yield of 19.2% in concise steps. This approach features a mild and convenient intramolecular oxidative amidation reaction between aromatic aldehyde and N-carbamate promoted by sodium hydride for synthesis of the key benzo[c]azepine ring.

Key words: (–)-galanthamine, intramolecular oxidative amidation, total synthesis, Alzheimer’s disease

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Zelin Liu, Siquan He, Abudurexiti Adila, Zhong Jin. Concise Total Synthesis of (–)-Galanthamine: An Efficient Base-Promoted Lactamization Strategy[J]. Chinese Journal of Organic Chemistry, 2026, 46(6): 2423-2430.

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Fig. & Tab. 8

Figure 1. Structures of (–)-galanthamine and (–)-benzgalan- thamine

Scheme 1. Strategies for synthesis of benzo[c]azepine rings in galanthamine

Scheme 2. Retrosynthetic analysis of (–)-galanthamine

Scheme 3. Preparation of the intermediate 6

Scheme 4. Preparation of the key intermediate 8

Entry	Base (x)	Solvent	Temperature/℃	Yield/%
1	LDA (2.0)	THF	65	0
2	NaH (2.0)	THF	65	55
3	KH (2.0)	THF	65	51
4	KOH (2.0)	THF	65	0
5	t-BuOK (2.0)	THF	65	0
6	NaH (2.0)	THF	25	93 (91)^a
7	NaH (1.3)	THF	0	62 (89)^b
8	NaH (1.3)	DMF	25	88
9	NaH (1.3)	DME	25	76
10	NaH (1.3)	1,4-Dioxane	25	83

Table 1. Optimization for base-promoted intramolecular oxidative amidation of aldehydes

Scheme 5. Plausible mechanism for intramolecular oxidative amidation of aldehydes

Scheme 6. Final synthesis of (–)-galanthamine

References 25

[1]	(a) Jin, Z.; Yang, H.-D.; Xu, X.-H.; Yao, G.-M. In Natural Products, Eds.: Ramawat, K. G.; Mérillon, J.-M., Springer-Verlag GmbH Germany, 2025, Chapter 18.
	(b) Jin, Z.; Yao, G.-M. Nat. Prod. Rep. 2019, 36, 1462. doi: 10.1039/C8NP00055G
[2]	(a) Scott, L. J.; Goa, K. L. Drugs 2000, 60, 1095. doi: 10.2165/00003495-200060050-00008 pmid: 11129124
	(b) Prvulovic, D.; Hampel, H.; Pantel, J. Expert Opin. Drug Metab. Toxicol. 2010, 6, 345. doi: 10.1517/17425251003592137 pmid: 11129124
[3]	Cheng, B.; Wang, Q.; Chen, F. Nat. Prod. Rep. 2024, 41, 1060. doi: 10.1039/D4NP00001C
[4]	Marco-Contelles, J.; do Carmo Carreiras, M.; Rodriguez, C.; Villarroya, M.; Garcia, A. G. Chem. Rev. 2006, 106, 116. pmid: 16402773
[5]	(a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2000, 122, 11262. doi: 10.1021/ja002231b
	(b) Trost, B. M.; Tang, W. Angew. Chem., Int. Ed. 2002, 41, 2795. doi: 10.1002/1521-3773(20020802)41:15<2795::AID-ANIE2795>3.0.CO;2-2
	(c) Guillou, C.; Beunard, J.-L.; Gras, E.; Thal, C. Angew. Chem., Int. Ed. 2001, 40, 4745. doi: 10.1002/1521-3773(20011217)40:24<>1.0.CO;2-C
[6]	(a) Miller, I. R.; Mclean, N. J.; Moustafa, G. A. I.; Ajavakom, V.; Kemp, S. C.; Bellingham, R. K.; Camp, N. P.; Brown, R. C. D. J. Org. Chem. 2022, 87, 1325. doi: 10.1021/acs.joc.1c02638 pmid: 35007075
	(b) Satcharoen, V.; McLean, N. J.; Kemp, S. C.; Camp, N. P.; Brown, R. C. D. Org. Lett. 2007, 9, 1867. doi: 10.1021/ol070255i pmid: 35007075
[7]	Nugent, J.; Matousova, E.; Banwell, M. G. Eur. J. Org. Chem. 2015, 3771.
[8]	Hu, X.-D.; Tu, Y.-Q.; Zhang, E.; Gao, S.; Wang, S.; Wang, A.; Fan, C-A.; Wang, M. Org. Lett. 2006, 8, 1823. doi: 10.1021/ol060339b
[9]	Zhang, Q.; Zhang, F.-M.; Zhang, C.-S.; Liu, S.-Z.; Tian, J.-M.; Wang, S.-H.; Zhang, X.-M.; Tu, Y.-Q. J. Org. Chem. 2019, 84, 12664. doi: 10.1021/acs.joc.9b01971 pmid: 31498620
[10]	Chen, P.; Bao, X.; Zhang, L.-F.; Ding, M.; Han, X.-J.; Li, J.; Zhang, G.-B.; Tu, Y.-Q.; Fan, C.-A. Angew. Chem., Int. Ed. 2011, 50, 8161. doi: 10.1002/anie.v50.35
[11]	Chen, J.-Q.; Xie, J.-H.; Bao, D.-H.; Liu, S.; Zhou, Q.-L. Org. Lett. 2012, 14, 2714. doi: 10.1021/ol300913g
[12]	Li, L.; Yang, Q.; Wang, Y.; Jia, Y. Angew. Chem., Int. Ed. 2015, 54, 6255. doi: 10.1002/anie.v54.21
[13]	(a) Liu, C.-H.; Yu, Z.-X. Org. Biomol. Chem. 2016, 14, 5945. doi: 10.1039/C6OB00660D pmid: 25558884
	(b) Feng, Y.; Yu, Z.-X. J. Org. Chem. 2015, 80, 1952. doi: 10.1021/jo502604p pmid: 25558884
[14]	Zhang, Y.; Shen, S.; Fang, H.; Xu, T. Org. Lett. 2020, 22, 1244. doi: 10.1021/acs.orglett.9b04337 pmid: 31904968
[15]	Chang, Y.-P.; Ma, X.; Shao, H.; Zhao, Y.-M. Org. Lett. 2021, 23, 9659. doi: 10.1021/acs.orglett.1c03943
[16]	For selected examples, (a) Xiong, Z.; Weidlich, F.; Sanchez, C.; Wirth, T. Org. Biomol. Chem. 2022, 20, 4123. doi: 10.1039/D2OB00669C
	(b) Pollok, D.; Groβmann, L. M.; Behrendt, T.; Opatz, T.; Waldvogel, S. R. Chem.-Eur. J. 2022, 28, e202201523.
	(c) Kodama, S.; Hamashima, Y.; Nishide, K.; Node, M. Angew. Chem., Int. Ed. 2004, 43, 2659. doi: 10.1002/anie.v43:20
	(d) Node, M.; Kodama, S.; Hamashima, Y.; Baba, T.; Hamamichi, N.; Nishide, K. Angew. Chem., Int. Ed. 2001, 40, 3060. doi: 10.1002/1521-3773(20010817)40:16<>1.0.CO;2-A
	(e) Kita, Y.; Arisawa, M.; Gyoten, M.; Nakajima, M.; Gamada, R.; Tohma, H.; Takada, T. J. Org. Chem. 1998, 63, 6625. doi: 10.1021/jo9807868
[17]	(a) Pal, S.; Majumder, S.; Niyogi, S.; Shyamal, P.; Mondal, D.; Das, B.; Bisai, A. Chem. Sci. 2024, 15, 19851. doi: 10.1039/D4SC04361H pmid: 20377273
	(b) Hu, N.; He, Y.-T.; Lan, P.; Banwell, M. G.; White, L. V. Aust. J. Chem. 2022, 75, 974. doi: 10.1071/CH22183 pmid: 20377273
	(c) Chang, J. H.; Kang, H.-U.; Jung, I.-H.; Cho, C.-G. Org. Lett. 2010, 12, 2016. doi: 10.1021/ol100617u pmid: 20377273
	(d) Magnus, P.; Sane, N.; Fauber, B. P.; Lynch, V. J. Am. Chem. Soc. 2009, 131, 16045. doi: 10.1021/ja9085534 pmid: 20377273
[18]	(a) Qiu, J.-Y.; Zeng, W.-L.; Xie, H.; Wang, W-Y.; Li, W. Angew. Chem., Int. Ed. 2023, 62, e202218961. pmid: 30720819
	(b) Majumder, S.; Yadav, A.; Pal, S.; Khatua, A.; Bisai, A. J. Org. Chem. 2022, 87, 7786. doi: 10.1021/acs.joc.2c00420 pmid: 30720819
	(c) Venkatesh, T.; Mainkar, P. S.; Chandrasekhar, S. Org. Biomol. Chem. 2019, 17, 2192. doi: 10.1039/c8ob03123a pmid: 30720819
	(d) Ishikawa, T.; Kudo, K.; Kuroyabu, K.; Uchida, S.; Kudoh, T.; Saito, S. J. Org. Chem. 2008, 73, 7498. doi: 10.1021/jo801316s pmid: 30720819
[19]	(a) Küenburg, B.; Czollner, L.; Fröhlich, J.; Jordis, U. Org. Process Res. Dev. 1999, 3, 425. doi: 10.1021/op990019q
	(b) Czollner, L.; Frantsits, W.; Küenburg, B.; Hedenig, U.; Fröhlich, J.; Jordis, U. Tetrahedron Lett. 1998, 39, 2087. doi: 10.1016/S0040-4039(98)00294-9
[20]	Hwu, J. R.; Hakimelahi, G. H.; Chou, C. T. Tetrahedron Lett. 1992, 33, 6469. doi: 10.1016/S0040-4039(00)79017-4
[21]	Ishihara, K.; Yano, T. Org. Lett. 2004, 6, 1983. pmid: 15176799
[22]	Wang, X.; Wang, D. Z. Tetrahedron 2011, 67, 3406. doi: 10.1016/j.tet.2011.03.052
[23]	Zhang, H.; Xu, N.; Su, B.; Zhang, J.; Zhang, C.; Zhang, Z.; Guo, B.; Xu, S.; Wang, S.; Rang, R. J. Org. Chem. 2024, 89, 7579. doi: 10.1021/acs.joc.4c00246
[24]	Kulkarni, S. S.; Hu, X.; Manetsch, R. Chem. Commun. 2013, 49, 1193. doi: 10.1039/c2cc37289d
[25]	Fischer, J.; Savage, G. P.; Coster, M. J. A. Org. Lett. 2011, 13, 3376. doi: 10.1021/ol201130h pmid: 21648396

(–)-加兰他敏的简洁全合成: 一种高效的碱促进内酰胺化策略

Concise Total Synthesis of (–)-Galanthamine: An Efficient Base-Promoted Lactamization Strategy

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Fig. & Tab. 8

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