Stereoselective Synthesis of β-Hydroxy Enamines, Aminocyclopropanes, and 1,3-Amino Alcohols via Asymmetric Catalysis
journal contributionposted on 13.10.2010, 00:00 authored by Petr Valenta, Patrick J. Carroll, Patrick J. Walsh
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.
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enamineMIBdiastereoselective hydrogenationtandem cyclopropanationPRCfunctionalized vinylzinc intermediatesAsymmetric CatalysisTandem methodsDiastereoselective hydrogenationregioselective hydroborationyieldaminocyclopropyl carbinolsmorpholino isoborneolStereoselective Synthesishydroxyalkenylzinc reagentscatalystenantioenriched precursorpreparationalkenyl boranes