Synthesis of Enantiopure trans-3,4-Disubstituted Piperidines. An Enantiodivergent Synthesis of (+)- and (−)-Paroxetine

摘要: Reaction of (R)-phenylglycinol with methyl 5-oxopentanoate gave either bicyclic lactam cis-1 (the kinetic product) or its isomer trans-1 (under equilibrating conditions) as the major products, which were converted to corresponding (cis trans) unsaturated lactams 4 and 5. On treatment lithium alkyl (or aryl) cyanocuprates, these chiral building blocks undergo conjugate addition give enantiopure trans-3,4-substituted 2-piperidone derivatives in high yield stereoselectivity. The synthetic potential this transformation is illustrated by synthesis (+)-femoxetine two enantiomers known antidepressant paroxetine.