Stereoselective Synthesis of Highly Substituted Piperidines

Enantiopure piperidines 4 may be accessed in very good overall yields and high stereoselectivity from the bifunctional products 2 of the silyloxy Cope rearrangement of chiral aldol products 1 by sequential nucleophilic addition of primary amines and subsequent hydrogenation. The reaction is proposed to proceed by initial imine formation followed by an intramolecular aza-conjugate addition to the α,β-unsaturated imide. The stereoselectivity is controlled by A(1.2) strain between the imine N-alkyl group and the conjugate double bond. In an alternate approach, polyalkyl-substituted piperidines were prepared by the addition of organozinc reagents to cyanopiperidines readily obtained from the Cope products in the presence of a silver salt.