Asymmetric carbon-carbon bond formations in conjugate additions of lithiated N-Boc allylic and benzylic amines to nitroalkenes: enantioselective synthesis of substituted piperidines, pyrrolidines, and pyrimidinones.
(-)-Sparteine mediated lithiations of N-Boc-allylic and benzylic amines provide configurationally stable intermediates which on conjugate additions to nitroalkenes provide highly enantioenriched enecarbamate products in good yields, and with high diastereoselectivities. Straightforward transformations of these adducts offer general routes to substituted 3,4-substituted piperidines, 3,4-substituted pyrrolidines, and 4,5-substituted pyrimidinones. Diastereoselective substitutions of intermediate lactams followed by reduction provide 3,4,5-substituted piperidines and 3,4-trisubstituted pyrrolidines. Lithiation adjacent to nitrogen of 3,4-substituted piperidines and pyrrolidines followed by diastereoselective substitution opens a route to 2,4,5- and 2,4,5,6-substituted piperidines as well as 2,3,4- and 2,3,4,5-substituted pyrrolidines. The enantiomers of the enecarbamate and 3,4-substituted piperidine products may be accessed by stannylation/transmetalation sequences as well as by further manipulation of 4-substituted piperidones. The methodology is used to synthesize both enantiomers of an aspartic peptidase inhibitor intermediate, 3-hydroxy-4-phenylpiperidine, as well as the antidepressant (+)-femoxetine.
Johnson
Timothy A
TA
Department of Chemistry, Roger Adams Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Jang
Doo Ok
DO
Slafer
Brian W
BW
Curtis
Michael D
MD
Beak
Peter
P
D000475:Alkenes / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D001596:Benzylamines / Q000737:chemistry*; D005563:Formic Acid Esters / Q000737:chemistry; D008094:Lithium / Q000737:chemistry*; D009574:Nitro Compounds / Q000737:chemistry*; D009942:Organometallic Compounds / Q000737:chemistry; D010880:Piperidines / Q000138:chemical synthesis*; D011744:Pyrimidinones / Q000138:chemical synthesis*; D011759:Pyrrolidines / Q000138:chemical synthesis*; D013237:Stereoisomerism
D000475:Alkenes; D000588:Amines; D001596:Benzylamines; D005563:Formic Acid Esters; D009574:Nitro Compounds; D009942:Organometallic Compounds; D010880:Piperidines; D011744:Pyrimidinones; D011759:Pyrrolidines; C000345:t-butyloxycarbonyl group; D008094:Lithium