Histrionicotoxin (HTX,1) was isolated from skin extracts of the Colombian poison dart frogs, Dendrobates histrionicus. The alkaloid and the fully hydrogenated congener, perhydr ohistrioniocotoxin (PHTX,4) have become attractive synthetic targets owing to their unusual spiropiperidine structures (Fig. 1), the scarcity of natural sources, and their interesting pharmacological properties. Although four asymmetric syntheses of PHTX have been reported, the stereocontrol at the three contiguous asymmetric carbon centres was poor (low selectivity or step-wise elaboration). Our pivotal synthetic strategy is the stereocontrolled construction of three contiguous asymmetric carbon centers via a carbonyl ene reaction or a palladium-catalyzed carbonyl allylation based on the chirality at the quaternary carbon center constructed by the Pummerer-type reaction of the chiral vinylic sulfoxide(6). We describe here two types of stereocontrol in the formation of spiro skeletons via a carbonyl ene reaction and a palladium-catalyzed carbonyl allylation. An asymmetric formal synthesis of (+)-PHTX is also reported via a product obtained from the latter reaction.
