American Chemical Society
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Diastereoselective Synthesis of 2,3,6-Trisubstituted Piperidines

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posted on 2009-06-19, 00:00 authored by John M. Humphrey, Eric P. Arnold, Thomas A. Chappie, John B. Feltenberger, Arthur Nagel, Wendy Simon, Melani Suarez-Contreras, Norma J. Tom, Brian T. O’Neill
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 a nitroketone and phenylmethanimine, followed by a ring-closure condensation. Relative stereocontrol was achieved between C-2 and C-3 by kinetic protonation of a nitronate or by equilibration of the nitro group under thermodynamic control. Stereocontrol at C-6 was accomplished by utilizing a variety of imine reduction methods. The C-2/C-6-cis stereochemistry was established via triacetoxyborohydride iminium ion reduction, whereas the trans relationship was set either by triethylsilane/TFA acyliminium ion reduction or by Lewis acid catalyzed imine reduction with lithium aluminum hydride.