Diastereoselective Synthesis of 2,3,6-Trisubstituted Piperidines

• DOI: 10.1021/jo9003184
• Publication Date: 2009-05-14T12:51:34Z
• Authors: John M. Humphrey; Eric P. Arnold; Thomas A. Chappie; John B. Feltenberger; Arthur Nagel; Wendy Simon; Melani Suarez-Con...; Norma J. Tom; Brian T. O’Neill
• Keywords: Iminium; Triethylsilane; Imine; Nitronate

We report the diastereoselective and chromatography-free syntheses of four 2-phenyl-6-alkyl-3-aminopiperidines. Ring construction was accomplished through a nitro-Mannich reaction linking nitroketone phenylmethanimine, followed by ring-closure condensation. Relative stereocontrol achieved between C-2 C-3 kinetic protonation nitronate or equilibration nitro group under thermodynamic control. Stereocontrol at C-6 utilizing variety imine reduction methods. The C-2/C-6-cis stereochemistry established via triacetoxyborohydride iminium ion reduction, whereas trans relationship set either triethylsilane/TFA acyliminium Lewis acid catalyzed with lithium aluminum hydride.