Tandem methods for the catalytic asymmetric preparation of enantioenriched â-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 â-amino alkenyl boranes. In situ boron-to-zinc transmetalation generates â-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 â-hydroxy enamines in good isolated yields (68-86%) with 54-98% enantioselectivity. The intermediate zinc â-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 â-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.
Aldehydes Amino Alcohols