Divergent Synthesis of Natural Derivatives of (+)‐Saxitoxin Including 11‐Saxitoxinethanoic Acid

The bis‐guanidinium toxins are a collection of natural products that display nanomolar potency against select isoforms of eukaryotic voltage‐gated Na + ion channels. We describe a synthetic strategy that enables access to four of these poisons, namely 11‐saxitoxinethanoic acid, C13‐acetoxy saxitoxin, decarbamoyl saxitoxin, and saxitoxin. Highlights of this work include an unusual Mislow–Evans rearrangement and a late‐stage Stille ketene acetal coupling. The IC 50 value of 11‐saxitoxinethanoic acid was measured against rat Na V 1.4, and found to be 17.0 n m , similar to those of the sulfated toxins gonyautoxin II and III.