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.

Graphical abstractA 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.Figure optionsDownload full-size imageDownload as PowerPoint slide