Preparation of enantiopure 4-oxygenated pipecolic acid derivatives

Two approaches to enantiopure 4-oxo- and 4-(R)-hydroxypipecolic acid derivatives from protected L-aspartic acid were developed. The first route exploits an intramolecular Michael addition on the stable enaminone 8. Hydrogenation and concomitant decarboxylation gave the I-ore derivative 11 which was reduced selectively to the 4-(R)-hydroxy derivative 12. The second route starts with a Michael addition followed by an intramolecular Dieckmann condensation to build the piperidine ring. The 4-oxo derivatives 11 and 19 are thus obtained in an expeditious manner on large scale without any chromatographic purification. Both sequences proved to be highly stereoselective. (C) 1997 Elsevier Science Ltd.