Stereoselective synthesis of β-hydroxy enamines, aminocyclopropanes, and 1,3-amino alcohols via asymmetric catalysis.
Tandem methods for the catalytic asymmetric preparation of enantioenriched β-hydroxy (E)-enamines and aminocyclopropanes are presented. The diastereoselective hydrogenation of enantioenriched (E)-trisubstituted hydroxy enamines to generate 1,2-disubstituted-1,3-amino alcohols is also outlined. These methods are initiated by highly regioselective hydroboration of N-tosyl-substituted ynamides with diethylborane to generate β-amino alkenyl boranes. In situ boron-to-zinc transmetalation generates β-amino alkenylzinc reagents. These functionalized vinylzinc intermediates are subsequently added to aldehydes in the presence of a catalyst derived from an enantioenriched amino alcohol (morpholino isoborneol, MIB). The catalyst promotes highly enantioselective C-C bond formation to provide β-hydroxy enamines in good isolated yields (68-86%) with 54-98% enantioselectivity. The intermediate zinc β-alkoxy enamines can be subjected to a tandem cyclopropanation to afford aminocyclopropyl carbinols with three continuous stereocenters in a one-pot procedure with good yields (72-82%), enantioselectivities of 76-94%, and >20:1 diastereomeric ratios. Diastereoselective hydrogenation of isolated enantioenriched β-hydroxy enamines over Pd/C furnished syn-1,2-disubstituted-1,3-amino alcohols in high yields (82-90%) with moderate to excellent diastereoselectivities. These methods were used in an efficient preparation of the enantioenriched precursor to PRC200-SS derivatives, which are potent serotonin-norepinephrine-dopamine reuptake inhibitors.
Valenta
Petr
P
P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, USA.
Carroll
Patrick J
PJ
Walsh
Patrick J
PJ
D000447:Aldehydes / Q000737:chemistry; D000605:Amino Alcohols / Q000138:chemical synthesis*; D002384:Catalysis; D003521:Cyclopropanes / Q000138:chemical synthesis*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D013237:Stereoisomerism
D000447:Aldehydes; D000605:Amino Alcohols; D003521:Cyclopropanes