A new and efficient synthetic route to enantiopure (+)-anatoxin-a from (-)-cocaine hydrochloride

The potent nAChR agonist (+)-anatoxin-a was efficiently synthesized in enantiomerically pure form starting from a readily available confiscated grade (-)-cocaine hydrochloride. The eight-step synthesis providing novel extensions to existing methodology proceeded with 26% overall yield and with stereochemical integrity of the relevant original stereogenic centers. Key steps were an effective ring expansion of the (+)-2-tropinone 2 to the 9-azabicyclo[4.2.1]nonanone 5 with TMSCHN2/Al(CH3)(3) and the introduction of the required methyl ketone side chain in masked form by reacting the corresponding enol triflate 6 with ethyl vinyl ether/Pd(OAc2) under Heck reaction conditions. (C) 2000 Elsevier Science Ltd. All rights reserved.