Chiral Synthesis of Phosphodiesterase Inhibitor, (R)-(-)-Rolipram, by Means of Enantioselective Deprotonation Strategy

Abstract

Enantioselective synthesis of the antidepressant (R)-(-)-rolipram(1) has been achieved by using an enantioselective deprotonation of the cyclobutanone derivative as a key step.Recently we developedl a novel procedure for the chiral synthesis of y-butyrolactones in high enantiomeric excess by using an enantioselective deprotonation2 of the correspondii cyclobutanone derivatives as a key step.This methodology has been successfully employed in the chiral synthesis of physiologically active natural products.3Here we report a further application of this synthetic strategy to the synthesis of the rolipram antidepressant rolipram, 4-(3-(cyclopentyloxy)-4-methoxyphenyl)p~oEdin-2-one, which is known to be the selective, prototypical inhibitor of the calcium-independent, low Km cyclic adenosine monophosphate (cAIvlF')-specific phosphodiesterase (PDE)~-6 designated PDE IV.738 Since the pharmacological activity ofnz