Total Synthesis of (−)‐Histrionicotoxin through a Stereoselective Radical Translocation–Cyclization Reaction

Stereoselective total syntheses of (−)‐histrionicotoxin and (−)‐histrionicotoxin 235A are described. The 1‐azaspiro[5.5]undecane skeleton was constructed diastereoselectively by a radical translocation–cyclization reaction involving a chiral cyclic acetal; the use of tris(trimethylsilyl)silane was crucial for the high diastereoselectivity. The cyclization product was converted into (−)‐histrionicotoxin 235A through a one‐pot partial‐reduction–allylation reaction of a derivative containing an unprotected lactam. Finally, two terminal alkenes were transformed into enynes with the 1,3‐amino alcohol protected as an oxathiazolidine oxide to complete the total synthesis of (−)‐histrionicotoxin. A powerful protection strategy enabled the efficient synthesis of (−)‐histrionicotoxin. The diastereoselective construction of the 1‐azaspiro[5.5]undecane skeleton by a radical translocation–cyclization reaction was made possible by a chiral cyclic acetal (see scheme), whereas the unprotected lactam underwent reduction and allylation, and the alkene groups were converted into enynes following novel protection of the 1,3‐amino alcohol as an oxathiazolidine oxide.