Synthesis of 2,6‐Disubstituted Piperidine‐Bearing α‐Amino Acid Side‐Chains

A straightforward synthesis of 2,6‐disubstituted piperidines bearing α‐amino acid side‐chains was developed. Synthesis was based on a Horner−Wadsworth−Emmons condensation of a β‐ketophosphonate derived from an α‐amino acid residue with a β‐homologated aldehyde of an N ‐protected amino acid residue. The generated α‐β unsaturated ketones were then reduced, deprotected, and cyclized in a hydrogenation/hydrogenolysis one‐pot procedure to yield piperidine 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. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)