Premium
Synthetic and Organocatalytic Studies of Quinidine Analogues with Ring‐Size Modifications in the Quinuclidine Moiety
Author(s) -
Breman Arjen C.,
van der Heijden Gydo,
van Maarseveen Jan H.,
Ingemann Steen,
Hiemstra Henk
Publication year - 2016
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201601917
Subject(s) - quinuclidine , ring size , chemistry , enantiopure drug , moiety , conjugate , ring (chemistry) , organocatalysis , epoxide , stereochemistry , catalysis , michael reaction , cinchona , enantioselective synthesis , organic chemistry , mathematical analysis , mathematics
Six highly enantiopure analogues of [2.2.2] were synthesized with five‐ or seven‐membered rings in the (original) quinuclidine skeleton. Five of these compounds were prepared through epoxide opening by a secondary cyclic amine, providing the nor‐ and homoquinuclidine moieties through five‐ and six‐membered ring formation. This method failed in the case of seven‐membered ring formation, so for that particular ring size a different synthetic route starting from 3‐quinuclidone was applied. The six novel analogues were examined as organocatalysts in four asymmetric conjugate addition reactions and the results compared with those of known cinchona alkaloid catalysts. This study shows that modification of the quinuclidine ring can have a substantial influence on catalyst activity and enantioselectivity. To acquire more insight into the characteristics of the new catalysts, the p K aH values were determined by means of fluorescence spectroscopy. Furthermore, relative reaction rates of conjugate thiol additions reactions catalyzed by these quinidine analogues were measured through polarimetry.