Stereoselective synthesis of highly substituted piperidines

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