3,5-Disubstituted Piperidine Derivatives—A Scalable Route to All Four Stereoisomers

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.