Scalable total synthesis of saxitoxin and related natural products

Yinliang Guo, Yiheng Li, Sihan Chen, Yige Wu, Oscar Poll, Zhouyang Ren, Zhonglin Liu, Roman Vlkolinsky, Michal Bajo, Christopher K. Prier, Kai-Jiong Xiao, Benjamin F. Cravatt, Marisa Roberto () and Phil S. Baran ()
Additional contact information
Yinliang Guo: Scripps Research
Yiheng Li: Scripps Research
Sihan Chen: Scripps Research
Yige Wu: Scripps Research
Oscar Poll: Scripps Research
Zhouyang Ren: Scripps Research
Zhonglin Liu: Scripps Research
Roman Vlkolinsky: Scripps Research
Michal Bajo: Scripps Research
Christopher K. Prier: Merck & Co., Inc.
Kai-Jiong Xiao: Merck & Co., Inc.
Benjamin F. Cravatt: Scripps Research
Marisa Roberto: Scripps Research
Phil S. Baran: Scripps Research

Nature, 2025, vol. 646, issue 8084, 351-357

Abstract: Abstract Saxitoxin (STX, 1), a potent neurotoxin from shellfish, first isolated in 1957 (ref. 1), offers immense pharmaceutical potential owing to its interaction with voltage-gated sodium channels2, which are ubiquitously present in all excitable cells of the central and peripheral nervous system3. Hundreds of studies towards its synthesis have been disclosed so far, yet a fully modular and scalable approach to the family remains elusive4–12. Here we show how a tactical combination of radical retrosynthesis, biocatalysis and C–H functionalization logic can be used to solve this problem, resulting in a scalable approach to the STX family in fewer than ten steps, including the first total synthesis of neosaxitoxin (neoSTX, 4), a hydroxylated naturally occurring STX analogue previously under clinical investigation13. The modular nature of the synthesis enables access to diverse analogues that were previously inaccessible and have now been evaluated through electrophysiological assays for biological activity.

Date: 2025
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DOI: 10.1038/s41586-025-09551-5

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