Synthesis of enantiopure trans-3,4-disubstituted piperidines. An enantiodivergent synthesis of (+)- and (-)-paroxetine

Reaction of (R)-phenylglycinol with methyl 5-oxopentanoate gave either bicy clic lactam cis-1 (the kinetic product) or its isomer trans-1 (under equili brating conditions) as the major products, which were converted to the corr esponding (cis or trans) unsaturated lactams 4 and 5. On treatment with lit hium alkyl (or aryl) cyanocuprates, these chiral building blocks undergo co njugate addition to give enantiopure trans-3,4-substituted 2-piperidone der ivatives in high yield and stereoselectivity. The synthetic potential of th is transformation is illustrated by the synthesis of (+)-femoxetine and the two enantiomers of the known antidepressant paroxetine.