Organocatalytic Conjugate Addition of Malonates to α,β-Unsaturated Aldehydes: Asymmetric Formal Synthesis of (−)-Paroxetine, Chiral Lactams, and Lactones

✍ Scribed by Sven Brandau; Aitor Landa; Johan Franzén; Mauro Marigo; Karl Anker Jørgensen

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 168 KB
• Volume: 45
• Category: Article
• ISSN: 0044-8249
• DOI: 10.1002/anie.200601025

✦ Synopsis

Chiral lactones and lactams are endowed with a large spectrum of biological properties [1] including very important pharmaceutical activities. [2] The chiral piperidines (À)paroxetine hydrochloride 1, marketed as paxil/seroxat, and (+)-femoxetine 2 are selective serotonin reuptake inhibitors and are used in the treatment of depression, obsessivecompulsive disorder, and panic (Figure 1). [3] The nonpeptide peptidomimetic type III inhibitor of renin, the piperidine Roche-1 3, was found to stabilize an enzyme conformation not previously observed for this enzyme. [4] All these compounds consist of a phenyl piperidine core structure with two trans-related substituents at C3 and C4. However, (À)paroxetine 1 possesses the opposite enantiomeric configuration relative to (+)-femoxetine 2 and Roche-1 3.

The synthesis of the antidepressants (À)-paroxetine 1 and (+)-femoxetine 2 is focused on enzymatic asymmetric desymmetrization, [3a, 5] chiral auxiliary-assisted, [6] or asymmetric Figure 1. Antidepressants (À)-paroxetine 1, (+)-femoxetine 2, and peptidomimetic inhibitor Roche-1 3.