The Hidden Symmetry of (±)-Histrionicotoxin

Key words

histrionicotoxin - Wittig olefination - 1,3-dipolar cycloaddition - bidirectional synthesis

Significance

Histrionicotoxin (HTX) is a natural product isolated from the skin of poison dart frogs (Dendrobatidae). It is a noncompetitive antagonist of the nicotinic acetylcholine receptor and, when bound, increases the affinity of the receptor for the native agonist acetylcholine while simultaneously stabilizing this desensitized state. Due to its low natural abundance (<180 μg per frog), histrionicotoxin is best produced through total synthesis. A collaborative effort between the Stockman and Fuchs groups delivered (±)-histrionicotoxin in 16.5% overall yield.

Comment

An efficiently synthesized ketodiene underwent double olefin metathesis to afford a ketodinitrile. Key to the synthesis is a tandem Michael addition/1,4-prototropic shift/1,3-dipolar cycloaddition to afford the kinetic product. Heating this product gives the thermodynamically more stable regioisomers via a retro-1,3-dipolar cycloaddition/1,3-dipolar cycloaddition. Reduction followed by double Wittig olefination set the stage for the completion of the synthesis via a chromium-mediated dehalogenation of the bischloroenyne.

Publication History

Article published online:
18 July 2022