A Stereoselective Organopalladium Route toward Perhydrohistrionicotoxin

Article abstract of DOI:10.1021/jo00275a023

An efficient stereocontrolled route to the spirocyclic alkaloid perhydrohistrionicotoxin (2) is described.The readily available 2-substituted 1,3-cyclohexadiene 4 was converted regio- and stereoselectively to the chloro acetate 5 by using organopalladium methodology.Chemoselective S_N2' displacement of the chloride via a copper-catalyzed Grignard reaction furnished 6, thus establishing the correct relative configuration at two adjacent centers.Further elaboration to the δ-amino alkene 10 was followed by a completely stereoselective iodocyclization reaction which yielded azaspirocycle 11.This compound was transformed to depentylperhydrohistrionicotoxin (3) in essentially one operation, thus completing a formal total synthesis of the title alkaloid.The overall yield of 3 from 4 was 23percent for nine operations.An alternative route to advanced intermediate 8 was also developed, the key step being the coupling of enol triflate 15 with the appropriate lithium organocuprate reagent.