Synthesis of enantiopure trans-3,4-disubstituted piperidines. An enantiodivergent synthesis of (+)- and (-)-paroxetine.
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 the corresponding (cis or trans) unsaturated lactams 4 and 5. On treatment with lithium alkyl (or aryl) cyanocuprates, these chiral building blocks undergo conjugate addition to give enantiopure trans-3,4-substituted 2-piperidone derivatives in high yield and stereoselectivity. The synthetic potential of this transformation is illustrated by the synthesis of (+)-femoxetine and the two enantiomers of the known antidepressant paroxetine.
Amat
M
M
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028-Barcelona, Spain. amat@farmacia.far.ub.es
Bosch
J
J
Hidalgo
J
J
Cantó
M
M
Pérez
M
M
Llor
N
N
Molins
E
E
Miravitlles
C
C
Orozco
M
M
Luque
J
J
D018687:Antidepressive Agents, Second-Generation / Q000138:chemical synthesis* / Q000737:chemistry; D007202:Indicators and Reagents; D017374:Paroxetine / Q000138:chemical synthesis* / Q000737:chemistry; D010880:Piperidines / Q000138:chemical synthesis*; D013237:Stereoisomerism
D018687:Antidepressive Agents, Second-Generation; D007202:Indicators and Reagents; D010880:Piperidines; D017374:Paroxetine