Synthesis of conformationally restricted acetylcholine analogues. Comparing lipase-mediated resolution with simulated moving bed chromatography of arylated beta-hydroxy-pyrrolidines

Abstract

The enantiodivergent synthesis of new, conformationally restricted acetylcholine analogues was accomplished using arylated endocyclic enecarbamates as key intermediates. Stereoselective hydroboration of the aryl enecarbamates provided the corresponding aryl-ss-hydroxy-pyrrolidines. Acetylation, deprotection, followed by N-bismethylation, led to the desired betaine products. The kinetic resolution of the intermediate alcohols was performed by lipase-mediated hydrolysis of its acetate derivatives, resulting in excellent enantioselectivities (E > 100). An enzymatic enantiopreference predicted by the Kazlauskas's model was confirmed following Riguera's protocol. Finally, chromatographic resolution of racemic alcohol 5a was evaluated by semi-preparative scale chiral simulated moving bed chromatography and its performance compared with biocatalysis. (c) 2007 Elsevier Ltd. All rights reserved.