Derivatives\nof Aristoquinoline Accessed through a\nRitter-like Reaction

The alkaloid aristoquinoline (<b>1a</b>) and its\nnon-natural\nisomer isoaristoquinoline (<b>1b</b>) are inhibitors of the\nα3β4 nicotinic acetylcholine receptor (nAChR). A Ritter-like\nreaction was used to form the [3.3.1]- and [3.2.1]-azabicyclic scaffolds\nfound in <b>1a</b> and <b>1b</b>, respectively. Although\nthe electronic properties of the aryl nitrile did not influence product\nratios or enhance the enantioselectivity of the reaction, changes\nto the aliphatic core led to the exclusive formation of [3.2.1]-azabicyclic\nproducts. Reduction of the imine products yielded a series of <b>1a</b> and <b>1b</b> derivatives that inhibit α3β4\nnAChRs, including several derivatives with improved potency relative\nto those of <b>1a</b> and <b>1b</b>.