Several neuronal nicotinic acetylcholine receptors (nAChRs) subtypes have emerged as potential targets for psychostimulant addiction therapy. Specifically, antagonizing the α3β4 nAChR reduces the self-administration as well as drug-seeking of cocaine and methampetamine in rodent models of addiction. Aristoquinoline, a quinoline alkaloid from <i>Aristotelia chilensis</i> was recently reported to inhibit human α3β4 nAChR selectively over the other human α7 and α4β2 subtypes. Thus, aristoquinoline serves as an excellent starting point that can be optimized into a potent and selective α3β4 nAChR antagonist. In pursuit of this goal, we successfully synthesized aristoquinoline in a short route employing an interrupted Ritter reaction. Although step-economical, the harsh reaction conditions produced a competing Wagner-Meerwein alkyl shift resulting in an undesirable by-product and poor overall yield. To improve upon our initial efforts, an intramolecular Aza-Prins-type cyclization was developed. This first-ever asymmetric synthesis of aristoquinoline delivers the alkaloid in a moderate yield accompanied with a high level of enantiopurity. With chiral pool terpenes and easily accessible aldehydes as starting materials, this route is amenable to the generation of diverse derivatives that will aid in establishing structure-activity relationships for this promising class of nAChR antagonists.

Asymmetric synthesis of aristoquinoline and its derivatives

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.