Download PDF
Synfacts 2022; 18(08): 0925
DOI: 10.1055/s-0041-1737709
Chemistry in Medicine and Biology

The Hidden Symmetry of (±)-Histrionicotoxin

Contributor(s):
Dirk Trauner
,
Matthew DiCairano
Karatholuvhu MS, Sinclair A, Newton AF, Alcaraz M.-L, Stockman RA, *, Fuchs PL. * University of East Anglia, Norwich and AstraZeneca, Loughborough, UK; Purdue University, West Lafayette, USA
A Concise Total Synthesis of dl-Histrionicotoxin.

J. Am. Chem. Soc. 2006;
128: 12656-12657
DOI: 10.1021/ja065015x.
CrossrefPubMedGoogle Scholar
› Further Information
 
 PDF Download Permissions and Reprints

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

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany


   Permissions and Reprints