期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 132, 期 40, 页码 14179-14190出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja105435y
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资金
- NIH (National Institute of General Medical Sciences) [GM58101]
- NSF [CHE-0848467, CHE-0840438]
- NIH [IS10RR023444]
- Isabel and Alfred Bader Foundation
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [0840438, 0848467] Funding Source: National Science Foundation
Tandem methods for the catalytic asymmetric preparation of enantioenriched beta-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 beta-amino alkenyl boranes. In situ boron-to-zinc transmetalation generates beta-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 beta-hydroxy enamines in good isolated yields (68-86%) with 54-98% enantioselectivity. The intermediate zinc beta-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 beta-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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