Diastereoselective synthesis of 2,3,6-trisubstituted piperidines.
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.
Humphrey
John M
JM
Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, USA. john.m.humphrey@pfizer.com
Arnold
Eric P
EP
Chappie
Thomas A
TA
Feltenberger
John B
JB
Nagel
Arthur
A
Simon
Wendy
W
Suarez-Contreras
Melani
M
Tom
Norma J
NJ
O'Neill
Brian T
BT
D001555:Benzene Derivatives / Q000138:chemical synthesis; D007659:Ketones / Q000737:chemistry*; D007700:Kinetics; D009574:Nitro Compounds / Q000737:chemistry*; D010880:Piperidines / Q000138:chemical synthesis*; D013237:Stereoisomerism
D001555:Benzene Derivatives; D007659:Ketones; D009574:Nitro Compounds; D010880:Piperidines