Deconstructing cytisine: The syntheses of (±)-cyfusine and (±)-cyclopropylcyfusine, fused ring analogs of cytisine

A novel fused tricyclic analog (11) of cytisine has been prepared (coined ‘cyfusine’) and determined to have high affinity at neuronal nicotinic acetylcholine receptors. A [3 + 2] cycloaddition protocol permitted entry into a 3,4-differentially difunctionalized dihydropyrrole (7). The penultimate cyclization was accomplished using the modified Van Tamelen conditions developed in our earlier synthesis of (±)-cytisine. Sequential ring-forming reactions ([3 + 2] cycloaddition/cyclopropanation/pyridone cyclization) gives a unique cyclopropyl analog (16) possessing a skeleton isoatomic with that of cytisine.