Malagasy生物碱的合成研究进展

doi:10.6023/cjoc202407032

摘要/Abstract

Malagasy生物碱具有特征的反式稠合C/D环系以及多个连续手性中心, 为其合成研究带来了巨大挑战. 此类生物碱还具有潜在的抗疟增效活性, 尤其是malagashanine作为天然增敏剂, 可以提升耐药疟原虫对于氯喹的敏感性. 独特而极具挑战性的结构以及明确的药理活性, 使得此类天然产物的合成研究颇具吸引力, 同时对于新型抗疟药物的研发也具有重要价值. 本综述总结了目前Malagasy生物碱的合成研究进展, 包括半合成研究、核心骨架构建以及全合成研究.

关键词: Malagasy生物碱, 全合成, 骨架构建, 半合成, 抗疟活性

The Malagasy alkaloids have characteristic trans-fused C/D ring systems and multiple chiral centers, which pose great challenge for their synthesis research. These alkaloids also have potential synergistic anti-malarial activity, especially malagashanine as a natural sensitizer, which can enhance the sensitivity of drug-resistant plasmodium to chloroquine. The unique and challenging structure combined with preonunced pharmacological activity makes the synthesis of these natural products attractive, and their synthesis research also has important value for the development of new antimalarial drugs. The current research progress in the synthesis of the Malagasy alkaloidshis is summarized, including semi-synthesis, core skeleton construction, and total synthesis.

Key words: Malagasy alkaloids, total synthesis, skeleton construction, semi-synthesis, antimalarial activity

引用此文

何卫刚, 刘亚东, 邓迎开, 孙先宇. Malagasy生物碱的合成研究进展[J]. 有机化学, 2025, 45(4): 1153-1165.

Weigang He, Yadong Liu, Yingkai Deng, Xianyu Sun. Recent Progress in the Synthesis of the Malagasy Alkaloids[J]. Chinese Journal of Organic Chemistry, 2025, 45(4): 1153-1165.

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

分享此文

图/表 16

图1. Malagasy生物碱及相关生物碱

Figure 1. Malagasy alkaloids and the related alkaloids

图2. 具有疟疾治疗作用的化学增敏剂

Figure 2. Chemosensitizers for antimalarial therapy

图式1. Malagasy生物碱推测的生源合成途径

Scheme 1. Proposed biosynthetic pathways of the Malagasy alkaloids

图式2. Trigalo课题组尝试malagashanine的半合成路线

Scheme 2. Trigalo group’s attempt at semi-synthesis of malagashanine

图式3. Canesi课题组合成malagashanol核心骨架的路线

Scheme 3. Route for preparing the core skeleton of malagashanol by Canesi?s group

图式4. 串联环化策略构建Malagasy生物碱四环骨架

Scheme 4. Construction of tetracyclic skeleton of the Malagasy alkaloids using tandem cyclization strategy

图式5. 串联环化策略构建mattogrossine核心骨架

Scheme 5. Construction of core skeleton of mattogrossine using tandem cyclization strategy

图式6. 利用[2＋2＋2]环加成策略构建吲哚生物碱核心四环骨架

Scheme 6. Construction of core tetracyclic skeleton of indole alkaloid using the [2＋2＋2] cycloaddition strategy

图式7. 通过双键还原反应构建反式稠合骨架

Scheme 7. Construction of trans-fused skeleton through reduction reaction

图式8. 通过串联Michael加成构建A/B/C三环体系

Scheme 8. Construction of A/B/C tricyclic system through tandem Michael addition

图式9. Blakey课题组对malagashanine的全合成(I)

Scheme 9. Total synthesis of magagashanine by Blakey’s group (I)

图式10. Blakey课题组对malagashanine的全合成(II)

Scheme 10. Total synthesis of magagashanine by Blakey’s group (II)

图式11. Blakey课题组合成11-demethoxymyrtoidine的尝试

Scheme 11. Blakey’s attempt to synthesize 11-demethoxymyrtoydine

图式12. 唐勇与王丽佳课题组myrtoidine类似物的合成路线

Scheme 12. Tang and Wang’s total synthesis of myrtoidine analogue

图式13. Waser课题组对于11-demethoxy-16-epi-myrtoidine的形式全合成

Scheme 13. Waser’s formal synthesis of 11-demethoxy-16-epi-myrtoidine

图式14. 唐勇与王丽佳课题组对Malagasy生物碱的全合成

Scheme 14. Total synthesis of the Malagasy alkaloids by Tang and Wang’s group

参考文献 33

[1]	Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, K. J. Am. Chem. Soc. 1954, 76, 4749.
[2]	Caira, M. R.; Rasoanaivo, P. J. Chem. Crystallogr. 1995, 25, 725.
[3]	Martin, M.-T.; Rasoanaivo, P.; Palazzino, G.; Galeffi, C.; Nicoletti, M.; Trigalo, F.; Frappier, F. Phytochemistry 1999, 51, 479.
[4]	Angeno, L.; Belem-Pinheiro, M. L.; Imbiriba Da Rocha, A. F.; Poukens-Renwart, P.; Quetin-Leclercq, J.; Warin, R. Phytochemistry 1990, 29, 2746.
[5]	(a) Schäfer, T. M.; de Carvalho, L. P.; Inoue, J.; Kreidenweiss, A.; Held, J. Expert Opin. Drug Dis. 2024, 19, 209. doi: 10.1080/17460441.2023.2284820 pmid: 38108082
	(b) Lu, F. Chin. J. Schistosomiasis Control 2024, 36, 233 (in Chinese). pmid: 38108082
	(陆凤, 中国血吸虫病防治杂志, 2024, 36, 233.) pmid: 38108082
[6]	Boudhar, A.; Ng, X. W.; Loh, C. Y.; Chia, W. N.; Tan, Z. M.; Nosten, F.; Dymock, B. W.; Tan, K. S. W. Eur. J. Med. Chem. 2016, 119, 231. doi: 10.1016/j.ejmech.2016.04.058 pmid: 27173385
[7]	(a) Henry, M.; Alibert, S.; Orlandi-Pradines, E.; Bogreau, H.; Fusai, T.; Rogier, C.; Barbe, J.; Pradines, B. Curr. Drug Targets 2006, 7, 935. pmid: 22242848
	(b) Peyton, D.H. Curr. Top. Med. Chem. 2012, 12, 400. doi: 10.2174/156802612799362968 pmid: 22242848
[8]	Martiney, J. A.; Cerami, A. Slater, A. F. G. J. Biol. Chem. 1995, 270, 22393. doi: 10.1074/jbc.270.38.22393 pmid: 7673225
[9]	Menezes, C. M. S.; Kirchgatter, K.; Di Santi, S. M.; Savalli, C.; Monteiro, F. G.; Paula, G. A.; Ferreira, E. I. Rev. Soc. Bras. Med. Trop. 2003, 36, 5.
[10]	Bhattacharjee, A. K.; Kyle, D. E.; Vennerstrom, J. L. Antimicrob. Agents Chemother. 2001, 45, 2655. doi: 10.1128/AAC.45.9.2655-2657.2001 pmid: 11502547
[11]	Deane, K.J.; Summers, R. L.; Lehane, A. M.; Martin, R. E.; Barrow, R. A. ACS Med. Chem. Lett. 2014, 5, 576.
[12]	Menezes, C. M. S.; Kirchgatter, K.; Di Santi, S.M.; Savalli, C.; Monteiro, F. G.; Paula, G. A.; Ferreira, E. I. Mem. Inst. Oswaldo Cruz 2002, 97, 1033.
[13]	Frédérich, M.; Hayette, M.-P.; Tits, M.; Mol, P. D.; Angenot, L. Planta Med. 2001, 67, 523. pmid: 11509972
[14]	Ye, Z.; Dyke, K. V.; Rossan, R. N. Malar. J. 2013, 12, 117.
[15]	Rasoanaivo, P.; Ratsimamanga-Urverg, S.; Milijaona, R.; Rafatro, H.; Rakoto-Ratsimamanga, A.; Galeffi, C.; Nicoletti, M. Planta Med. 1994, 60, 13. pmid: 8134408
[16]	Rafatro, H.; Ramanitrahasimbola, D.; Rasoanaivo, P.; Ratsima- manga-Urverg, S.; Rakoto-Ratsimamanga, A.; Frappier, F. Biochem. Pharmacol. 2000, 59, 1053. pmid: 10704934
[17]	Ramanitrahasimbola, D.; Rasoanaivo, P.; Ratsimamanga, S.; Vial, H. Mol. Biochem. Parasitol. 2006, 146, 58.
[18]	Trigalo, F.; Joyeau, R.; Pham, V. C.; Youté, J. J.; Rasoanaivoa, P.; Frappier, F. Tetrahedron 2004, 60, 5471.
[19]	Maertens, G.; Deruer, E.; Denis, M.; Canesi, S. J. Org. Chem. 2020, 85, 6098. doi: 10.1021/acs.joc.0c00572 pmid: 32227835
[20]	G., Maertens and S., Canesi, Chem.-Eur. J. 2016, 22, 7090. doi: 10.1002/chem.201601319 pmid: 27002898
[21]	He, W.; Hu, J.; Wang, P.; Chen, L.; Ji, K.; Yang, S.; Li, Y.; Xie, Z.; Xie, W. Angew. Chem., Int. Ed. 2018, 57, 3806.
[22]	Wang, Y.; Xie, F.; Lin, B.; Cheng, M.; Liu, Y. Chem.-Eur. J. 2018, 24, 14302.
[23]	Delgado, R.; Blakey, S. B. Eur. J. Org. Chem. 2009, 1506.
[24]	Kong, A.; Andreansky, E. S.; Blakey, S. B. J. Org. Chem. 2017, 82, 4477.
[25]	Zhao, L.-P.; Zhang, S.-Y.; Liu, H.-K.; Cheng, Y.-J.; Liu, Z.-P.; Wang, L.; Tang, Y. J. Am. Chem. Soc. 2023, 145, 15553. doi: 10.1021/jacs.3c04989 pmid: 37401830
[26]	Morikawa, T.; Harada, S.; Nishida, A. J. Org. Chem. 2015, 80, 8859.
[27]	Beemelmanns, C.; Reissig, H.-U. Angew. Chem., Int. Ed. 2010, 49, 8021.
[28]	Kang, T.; Zhao, P.; Yang, J.; Lin, L.; Feng, X.; Liu, X. Chem.-Eur. J. 2018, 24, 3703.
[29]	Kong, A.; Mancheno, D. E.; Boudet, N.; Delgado, R.; Andreansky, E. S.; Blakey, S. B. Chem. Sci. 2017, 8, 697. doi: 10.1039/c6sc03578g pmid: 28451219
[30]	Kazerouni, A. M.; Mancheno, D. E.; Blakey, S. B. Heterocycles 2019, 99, 389. doi: 10.3987/COM-18-S(F)32
[31]	Zhu, J.; Cheng, Y.-J.; Kuang, X.-K.; Wang, L.; Zheng, Z.-B.; Tang, Y. Angew. Chem., Int. Ed. 2016, 55, 9224.
[32]	Robert, E. G. L.; Pirenne, V.; Wodrich, M. D.; Waser, J. Angew. Chem., Int. Ed. 2023, 62, e202302420.
[33]	Cheng, Y.-J.; Zhao, L.-P.; Wang, L.; Tang, Y. CCS Chem. 2023, 5, 124.