3,5-Disubstituted
piperidines are versatile building blocks that
find broad application in medicinal chemistry programs. Here we describe
how all four diastereoisomers of a 5-aryl-substituted nipecotic acid
derivative were prepared on preparative scale in high enantiomeric
purity. The piperidine core structure was formed by catalytic hydrogenation
of the corresponding pyridine derivatives. After Boc-protection, the
resulting cis/trans mixture was
separated by preparative normal phase chromatography into the pure cis and pure trans racemates. Subsequent
preparative separation of those racemates by Simulated Moving Bed
chromatography (SMB) allowed us to obtain all four enantiopure isomers
in amounts between 80 and 140 g. The absolute configuration of all
compounds was determined by crystallization and X-ray spectroscopy
of suitable derivatives.