Preparation of 2,3,4-trisubstituted piperidines by a formal hetero-ene reaction of amino acid derivatives

N-Benzyl- or N-tosyl-N-(4-methyl-3-pentenyl)amino aldehyde benzylimines, which are obtained from alanine, leucine, or phenylalanine methyl esters in five steps, can be cyclized diastereoselectively in the presence of Lewis acids to give 3-amino-2,4-dialkyl-substituted piperidines. The product distribution and diastereoselectivity depends on the type of Lewis acid and nitrogen-protecting group. Benzyl-protected imines give 2-alkyl-3-(benzylamino)-4-isopropenyl piperidines with FeCl3 and 2-alkyl-3-(benzylideneamino)-4-isopropylpiperidines with TiCl4. Tosyl-protected imines show a decreased level of selectivity. The relative configurations of the piperidines were established by NMR and X-ray crystal structure analyses. Iminium ion cyclization followed by two competitive ionic pathways, i.e. either proton elimination or hydride transfer are discussed for these reactions.