Strategy for the Enantioselective Synthesis of trans-2,4-Disubstituted Piperidines:  Application to the CCR3 Antagonist IS811

A strategy for the enantioselective synthesis of trans-2,4-disubstituted piperidines is proposed and applied to the preparation of IS811, a potent CCR3 antagonist. The C2 stereocenter is derived from commercial (R)-epichlorohydrin, while the C4 stereocenter is installed via diastereoselective hydrogenation of an α,β-unsaturated lactone intermediate. Inversion of the original stereocenter via an efficient intramolecular S_N2 amination affords the piperidine core of IS811. An improved protocol for the lithiation of ethyl propiolate is reported.