Journal of Organic Chemistry 2006-11-10

Strategy for the enantioselective synthesis of trans-2,4-disubstituted piperidines: application to the CCR3 antagonist IS811.

Goss S Kauffman, Paul S Watson, William A Nugent

Index: J. Org. Chem. 71 , 8975, (2006)

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Abstract

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 alpha,beta-unsaturated lactone intermediate. Inversion of the original stereocenter via an efficient intramolecular S(N)2 amination affords the piperidine core of IS811. An improved protocol for the lithiation of ethyl propiolate is reported.