The total synthesis of the analgesic alkaloid epibatidine

Abstract

Several synthetic routes to the analgesic alkaloid epibatidine have been explored. Approaches starting from tropinone, involving either ring-cleavage followed by intramolecular aldol reaction, or Favorskii ring-contraction, were not successful. A successful route was established, involving cycloaddition of an N-protected pyrrole with ethynyl p-tolyl sulfone to prepare the required azabicyclo[2.2.1] skeleton. Completion of the synthesis required subsequent partial hydrogenation, addition of a metallated pyridine to an alkenyl sulfone, desulfonylation and brief functional group interchange and nitrogen deprotection. The synthesis proceeds in only six steps from the starting N-Boc pyrrole and furnishes the natural product in about 24% yield overall.