Histrionicotoxin cycloaddition synthesis

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. 

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. ... 

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