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

doi:10.6023/cjoc202601017

Chinese Journal of Organic Chemistry ›› 2026, Vol. 46 ›› Issue (6): 2193-2206.DOI: 10.6023/cjoc202601017 Previous Articles Next Articles

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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
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: * E-mail: shahua@sit.edu.cn;changminxie@shutcm.edu.cn
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

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

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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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Fig. & Tab. 20

Figure 1. Anatoxin, homoanatoxin, and their degradation products

Figure 2. Acetylcholine and Other Related Natural nAChR Ligands

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

Figure 4. Representative analogues of ATX-a

Figure 5. Structural correlation between Cocaine and ATX-a

Figure 6. Synthetic route by Edwards et al.

Figure 7. Synthetic route by Seitz et al.

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

Figure 9. Synthetic route by Rapoport et al.

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

Figure 11. Synthetic route by Mori et al.

Figure 12. Synthetic route by Martin et al.

Figure 13. Synthetic route by Stachulski et al.

Figure 14. Synthetic route by Kanazawa et al.

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

Figure 16. Synthetic route by Simpkins et al.

Figure 17. Synthetic route by Aggarwal et al.

Figure 18. Synthetic route by Gallagher et al.

Figure 19. Synthetic route by Trost et al.

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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