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

[2,3]=4 toxins: A synthetic strategy that enables access to four naturally occurring guanidinium toxins, namely saxitoxin, decarbamoyl saxitoxin, C13‐acetoxy saxitoxin, and C11‐saxitoxinethanoic acid, is detailed. Highlights of this work include an unusual Mislow–Evans rearrangement and a late‐stage Stille ketene acetal cross‐coupling reaction.

Abstract

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 IC₅₀ value of 11‐saxitoxinethanoic acid was measured against rat Na_V1.4, and found to be 17.0 nm, similar to those of the sulfated toxins gonyautoxin II and III.

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