Scalable total synthesis of saxitoxin and related natural products.

Saxitoxin (STX, 1), a potent neurotoxin from shellfish, first isolated in 1957, offers immense pharmaceutical potential due to its interaction with voltage-gated sodium channels, that are ubiquitously present in all excitable cells of the central and periphperal nervous system. Hundreds of synthetic studies towards this end have been disclosed thus far, yet, a fully modular and scalable approach to the family remains elusive. Thus, here we show how a tactical combination of radical retrosynthesis, biocatalysis, and C-H functionalization logic can be combined to solve this problem resulting in a scalable approach to the STX family in less than 10 steps including the first total synthesis of neosaxitoxin (neoSTX, 4), a hydroxylated naturally occurring STX analog previously under clinical investigation. The modular nature of the synthesis enables access to diverse analogs, that were previously inaccessible, and now have been evaluated through electrophysiological assays for biological activity.