Scalable total synthesis of saxitoxin and related natural products

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 elusive^4-12. 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.