"Saxitoxin (STX, 1), a potent neurotoxin from shellfish, first isolated in 19571, offers immense pharmaceutical potential due to its interaction with voltage-gated sodium channels2, that are ubiquitously present in all excitable cells of the central and periphperal nervous system3. Hundreds of synthetic studies towards this end have been disclosed thus far, yet, a fully modular and scalable approach to the family remains elusive4-12."
"Thus, here we show how a tactical combination of radical retrosynthesis, biocatalysis, and CH 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 investigation13."
A tactical combination of radical retrosynthesis, biocatalysis, and C–H functionalization enables a scalable, modular synthesis of the saxitoxin family in fewer than ten steps. The route achieves the first total synthesis of neosaxitoxin, a hydroxylated natural STX analog previously under clinical investigation. The modular strategy permits access to diverse analogs that were previously inaccessible. Select analogs were evaluated using electrophysiological assays to measure biological activity against voltage-gated sodium channels. The approach addresses the longstanding lack of a fully modular, scalable route to STX and enables expanded synthetic and pharmacological exploration of STX derivatives.
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