Diastereo- and enantioselective synthesis of 4,5,6-trisubstituted and 6-monosubstituted piperidin-2-ones

A convenient, versatile and highly diastereo- and enantioselective synthesis of 4,5,6-trisubstituted piperidin-2-ones 1 in satisfactory overall yields is described. The procedure involves the efficient and highly anti-diastereo- and enantioselective Michael addition of aldehydes to enoates via their lithiated SAMP hydrazones, followed by nucleophilic 1,2-addition of organometallic reagents to the C=N double bond of the corresponding aldehyde SAMP hydrazone-lithium ester enolate and subsequent lactamisation. In addition, 6-monosubstituted piperidin-2-ones 8 are prepared with enantiomeric excesses of ee = 79-92% via a similar three-step sequence starting from ethyl 5-oxovalerate (9).