Synthesis of 2,6-disubstituted piperidine-bearing α-amino acid side-chains

A straightforward synthesis of 2,6-disubstituted piperidines bearing alpha-amino acid side-chains was developed. Synthesis was based on a Homer-Wadsworth-Emmons condensation of a beta-ketophosphonate derived from an alpha-amino acid residue with a beta-homologated aldehyde of an N-protected amino acid residue. The generated alpha-beta unsaturated ketones were then reduced, deprotected, and cyclized in a hydrogenation/hydrogenolysis one-pot procedure to yield piperid-me moieties. Introduction of a new conformational restriction in the obtained molecules allowed total assignment of the stereocenters by NMR experiments. This assignment allowed us to propose a mechanistic pathway during the cyclization process, explaining the loss of exocyclic carbon-center configuration. (C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.