Improved Access to Huprine Derivatives Functionalized at Position 9

Herein, we present an improved synthetic pathway to huprine derivatives (the most potent family of non-covalent acetylcholinesterase inhibitors described to date) with different functional groups at the C9-position of the scaffold. Our approach enables selection of the desired terminal function prior to construction of the huprine scaffold and consists of three main steps: enol formation from a bicyclic ketone, Suzuki–Miyaura cross coupling with different borane derivatives and a Friedlander condensation to access to the quinoline moiety. This synthetic route was found particularly useful for construction of huprine scaffolds equipped with methylene chains bearing different terminal groups such as hydroxy, azide, nitro, amino and carboxylic groups. These functionalized huprines are used as key intermediates in the preparation of multi-target directed ligands for the treatment of Alzheimer's disease or in the preparation of resins for purification of cholinesterases by affinity chromatography.