Recent advances in the stereoselective synthesis of trans-3,4-disubstituted-piperidines: applications to (−)-paroxetine

Piperidine ring systems are the key structural elements in a vast array of natural products as well as in a large class of biologically active natural products, being also often embedded within scaffolds recognized as privileged structures by medicinal chemists. Accordingly, new stereoselective routes to substituted piperidines are of widespread interest. An overview of the asymmetric synthetic routes to trans-3,4-disubstituted piperidines, featuring the substitution pattern of (−)-paroxetine [(3S,4R)-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)piperidine], a well-known selective serotonin reuptake inhibitor (SSRI) used worldwide as an antidepressant in humans, is presented. This review is mainly focused on the enantioselective routes to (−)-paroxetine, which has become a very popular synthetic target to test the efficiency of new methodologies. Some recent stereoselective approaches to the racemic compound are also included.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide