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Improved Access to Huprine Derivatives Functionalized at Position 9
Author(s) -
Oukoloff Killian,
Chao Sovy,
CieslikiewiczBouet Monika,
Mougeot Romain,
Jean Ludovic,
Renard PierreYves
Publication year - 2016
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201501433
Subject(s) - chemistry , moiety , covalent bond , combinatorial chemistry , azide , scaffold , ketone , borane , bicyclic molecule , stereochemistry , organic chemistry , catalysis , medicine , biomedical engineering
Abstract 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 Friedländer 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.