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.
