Derivatives of Aristoquinoline Accessed through a Ritter-like Reaction

The alkaloid aristoquinoline (1a) and its non-natural isomer isoaristoquinoline (1b) are inhibitors of the α3β4 nicotinic acetylcholine receptor (nAChR). A Ritter-like reaction was used to form the [3.3.1]- and [3.2.1]-azabicyclic scaffolds found in 1a and 1b, respectively. Although the electronic properties of the aryl nitrile did not influence product ratios or enhance the enantioselectivity of the reaction, changes to the aliphatic core led to the exclusive formation of [3.2.1]-azabicyclic products. Reduction of the imine products yielded a series of 1a and 1b derivatives that inhibit α3β4 nAChRs, including several derivatives with improved potency relative to those of 1a and 1b.