强效神经毒剂Anatoxin-a的不对称合成研究进展

doi:10.6023/cjoc202601017

有机化学 ›› 2026, Vol. 46 ›› Issue (6): 2193-2206.DOI: 10.6023/cjoc202601017 上一篇下一篇

综述与进展

强效神经毒剂Anatoxin-a的不对称合成研究进展

董梅^a^,^b, 林国强^b^,^c, 洪然^b^,^c, 黄莎华^a^,^*(), 谢昌敏^b^,^d^,^*()

^a 上海应用技术大学化工与能源技术学部上海 201418
^b 上海中医药大学创新中药研究院手性药物研究中心上海 201203
^c 中国科学院上海有机化学研究所生命过程小分子调控全国重点实验室上海 200032
^d 上海交通大学上海市手性药物分子工程重点实验室上海 200240

收稿日期:2026-01-13 修回日期:2026-02-23 发布日期:2026-04-13
通讯作者: 黄莎华, 谢昌敏
基金资助:
国家自然科学基金(22271194); 上海中医药大学科研启动经费和上海市手性药物分子工程重点实验室开放课题资助项目

Advances in the Asymmetric Synthesis of the Potent Neurotoxin Anatoxin-a

Mei Dong^a^,^b, Guo-Qiang Lin^b^,^c, Ran Hong^b^,^c, Sha-Hua Huang^a^,^*(), Changmin Xie^b^,^d^,^*()

^a Faculty of Chemical Engineering and Energy Technology, Shanghai Institute of Technology, Shanghai 201418
^b The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203
^c State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032
^d Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Shanghai Jiao Tong University, Shanghai, 200240

Received:2026-01-13 Revised:2026-02-23 Published:2026-04-13
Contact: Sha-Hua Huang, Changmin Xie
Supported by:
National Natural Science Foundation of China(22271194); Research Projects of Shanghai Laboratory for Molecular Engineering of Chiral Drugs, and the Startup from Shanghai University of Traditional Chinese Medicine

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摘要/Abstract

Anatoxin-a (ATX-a)是一种强效蓝藻神经毒素, 可作为烟碱型乙酰胆碱受体(nAChR)的高亲和力激动剂, 在环境毒理与神经药理学研究中均具有重要意义. 概述了ATX-a的生态环境影响和药理机制, 系统性总结了其不对称全合成研究进展. 主要不对称合成方法包括手性池原料利用、外消旋体拆分、辅基控制、手性锂试剂对映选择性烯醇化、酶催化拆分及催化不对称合成等. 现有合成方法在反应效率、底物普适性以及对母核骨架的修饰(如C1、C5~C8位点)方面仍存在局限. 未来通过发展高效的催化不对称合成策略, 有望进一步推动ATX-a及其类似物的制备与结构多样性衍生, 从而推动高灵敏度环境监测技术与nAChR靶向药物的开发. 旨在为跨学科研究提供合成化学与药理学、环境科学交叉融合的新视角.

关键词: Anatoxin-a, 不对称合成, 烟碱型乙酰胆碱受体(nAChR), 构效关系, 生态环境毒性

Anatoxin-a (ATX-a) is a potent cyanobacterial neurotoxin and a high-affinity agonist of nicotinic acetylcholine receptors (nAChRs), making it significant in environmental toxicology and neuropharmacology. This article summarizes its ecological impact and pharmacological mechanism, with a focus on reviewing advances in its asymmetric total synthesis. Key strategies developed include the chiral pool approach, racemate resolution, auxiliary control, enantioselective enolization mediated by chiral lithium reagents, enzymatic resolution, and catalytic asymmetric synthesis. Despite these advancements, current methods are limited in efficiency, generality, and their ability to modify challenging core positions such as C1 and C5-C8. Future progress depends on developing more efficient and versatile catalytic asymmetric strategies. Such innovations will enable the efficient preparation and structural diversification of ATX-a analogues, thereby supporting the creation of highly sensitive environmental monitoring tools and the discovery of nAChR-targeted therapeutics. This review aims to provide an integrated perspective that bridges synthetic chemistry, pharmacology, and environmental science.

Key words: anatoxin-a, asymmetric synthesis, nicotinic acetylcholine receptor (nAChR), structure-activity relationship, ecological toxicity

引用此文

董梅, 林国强, 洪然, 黄莎华, 谢昌敏. 强效神经毒剂Anatoxin-a的不对称合成研究进展[J]. 有机化学, 2026, 46(6): 2193-2206.

Mei Dong, Guo-Qiang Lin, Ran Hong, Sha-Hua Huang, Changmin Xie. Advances in the Asymmetric Synthesis of the Potent Neurotoxin Anatoxin-a[J]. Chinese Journal of Organic Chemistry, 2026, 46(6): 2193-2206.

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图/表 20

图1. Anatoxin、homoanatoxin及其降解产物

Figure 1. Anatoxin, homoanatoxin, and their degradation products

图2. 乙酰胆碱及其他相关天然nAChR配体

Figure 2. Acetylcholine and Other Related Natural nAChR Ligands

图3. ATX-a的构象、可修饰位点及其合成可及性

Figure 3. Conformations, modifiable sites, and synthetic accessibility of ATX-a

图4. ATX-a的代表性类似物

Figure 4. Representative analogues of ATX-a

图5. Cocaine和ATX-a的结构相关性

Figure 5. Structural correlation between Cocaine and ATX-a

图6. Edwards等的合成路线

Figure 6. Synthetic route by Edwards et al.

图7. Seitz等的合成路线

Figure 7. Synthetic route by Seitz et al.

图8. 焦谷氨酸衍生物与ATX-a的结构相关性

Figure 8. Structural correlation between pyroglutamic acid derivatives and ATX-a

图9. Rapoport等的合成路线

Figure 9. Synthetic route by Rapoport et al.

图10. Speckamp, Somfai和Skrinjar等的合成路线

Figure 10. Synthetic route by Speckamp, Somfai and Skrinjar et al.

图11. Mori等的合成路线

Figure 11. Synthetic route by Mori et al.

图12. Martin等的合成路线

Figure 12. Synthetic route by Martin et al.

图13. Stachulski等的合成路线

Figure 13. Synthetic route by Stachulski et al.

图14. Kanazawa等的合成路线

Figure 14. Synthetic route by Kanazawa et al.

图15. Abad-Somovilla等的合成路线

Figure 15. Synthetic route by Abad-Somovilla et al.

图16. Simpkins等的合成路线

Figure 16. Synthetic route by Simpkins et al.

图17. Aggarwal等的合成路线

Figure 17. Synthetic route by Aggarwal et al.

图18. Gallagher等的合成路线

Figure 18. Synthetic route by Gallagher et al.

图19. Trost等的合成路线

Figure 19. Synthetic route by Trost et al.

图20. Zakarian等的合成路线

Figure 20. Synthetic route by Zakarian et al.

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强效神经毒剂Anatoxin-a的不对称合成研究进展

Advances in the Asymmetric Synthesis of the Potent Neurotoxin Anatoxin-a

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