Dendrobates Arrow poisons, Histrionicotoxins

A retro-l,3-dipolar cycloaddition followed by an 1,3-dipolar cycloaddition was used for a highly efficient total synthesis of (-)-histrionicotoxin (4-354) (HTX) by Holmes and coworkers [123]. HTX is a spiropiperidine-containing alkaloid which was isolated by Doly, Witkop and coworkers [124] from the brightly colored poison-arrow frog Dendrobates histrionicus. It is of great pharmacological interest as a noncompetitive inhibitor of acetylcholine receptors. 

Further examples of the endocychc nitrone route to spirocychc adducts are the total syntheses of (—)-histrionicotoxin (230) by Holmes and of cyhndricines by Weinreb. Histrionicotoxin is one of many spiropiperidine alkaloids isolated from the poison-arrow frog Dendrobates histrionicus and has been the subject of many attempted total syntheses by a nitrone cycloaddition strategy that failed to provide the desired regioisomer, possibly through unfavorable steric interactions (265-268). Unlike these reports, Holmes and co-workers (101) found that the intermolecular reaction of nitrone (231), prepared by the 1,3-APT of the corresponding alkynyl-hydroxylamine carrying Oppolzer s chiral sultam auxiliary, afforded the styrene... 

Histrionicotoxin is a diyne isolated in small quantities from the skin of Dendrobates histrioni-cus, a colorful South American frog (Figure 11.3). This toxin, secreted by the frog as a natural defense mechanism, was used as a poison on arrow tips by the Choco tribe of South America. 

Alkynes are less common in nature than alkenes, although more than 1000 different alkynes have been isolated from natural sources. One such example is histrionicotoxin, which is one of the many toxins secreted by the South American frog, Dendrobates histrionicus, as a defense against predators. For many centuries. South American tribes have extracted the mixture of toxins from the frog s skin and placed it on the tips of arrows to produce poison arrows. 

Turning to the subject of many an adventure story, ichthyothereol is the active ingredient of a poisonous substance used in arrowheads by the Indians of the Lower Amazon River Basin. It causes convulsions in mammals. And histrionicotoxin is isolated from the skin of poison arrow frog, a highly colorful species of the genus Dendrobates. The frog secretes this compound and similar ones as defensive venoms and mucosal-tissue irritants against both mammals and reptiles. 

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