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 value of 11-saxitoxinethanoic acid was measured against rat Na 1.4, and found to be 17.0 nm, similar to those of the sulfated toxins gonyautoxin II and III.
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