Histrionicotoxin cycloaddition

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... 

The intramolecular 1,3-dipolar cycloaddition reaction of azides has become an increasingly useful process for the construction of natural products and molecules of theoretical interest.192 193 For example, 2-substituted azido enone (238) was prepared from the corresponding bromide by treatment with sodium azide. Thermolysis of this material afforded aziridinyl ketone (240) presumably via a transient dipolar cycloadduct (239).193 Ketone (240) was subsequently converted to an intermediate previously used to prepare histrionicotoxin (241 Scheme 56). 

The nitrone protection strategy has also been used in the total synthesis of (-)-histrionicotoxin (84) and some related alkaloids. The bicyclic isoxazolidine 82 underwent the cycloreversion-cycloaddition reaction at 190 °C to give the key intermediate 83 in high yield (82%) <02JCS(P1)1494>. 

The final synthesis we will examine was reported by Holmes (Cambridge, UK) and a closely related synthesis has been reported by Fuchs (Purdue). We will examine the Holmes synthesis. This synthesis keys off the 1,3-N, 0 relationship in histrionicotoxin (2). Recall that this should trigger nitrone cycloaddition as a possible route to consider to this target. This suggests 82 as a reasonable target that could be moved forward to histrionicotoxin. The issue here was one of regiochemistry in the key cycloaddition. Would nitrone 83 undergo cycloaddition to provide 82 or 84. ... 

Epi-( )-Perhydrohistrionicotoxin Aza-spi-rocycle (—)-histrionicotoxin was isolated from the skin extracts of the neotropical tree frog Dendrobates histrioni-cus [146]. In addition to its unique aza-spirocenter, (—)-histrionicotoxin and its samrated derivatives have shown potency as noncompetitive blockers of nicotinic receptorgated channels [147], thereby making them attractive and popular targets for synthetics chemists [148,149]. As illustrated in Scheme 12.71, our synthetics efforts featured a highly stereoselective aza-[3- -3] cycloaddition of... 

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