A synthesis of (+)-saxitoxin

Abstract

An asymmetric synthesis of the bis-guanidinium poison, (+)-saxitoxin (STX), is described. Commencing from an N,O-acetal starting material made readily available through sulfamate ester C-H amination, the completed route to STX showcases the utility of oxathiazinane dioxide heterocycles for the assembly of polyfunctionalized amine derivatives. In the final preparative stages, an unusual nine-membered ring guanidine intermediate is oxidized selectively and made to undergo dehydrative cyclization to afford the tricyclic core of the natural product. Access to STX and related structures will provide unique pharmacological tools for the study of voltage-regulated Na+ ion channel proteins.