Studies of asymmetric reactions catalyzed by cinchona alkaloids

We have developed a highly enantioselective Henry reaction with 6'-OH cinchona alkaloid derivatives as bifunctional catalysts. A range of aromatic aldehydes were employed as acceptors. Utilizing readily available and easily recyclable catalysts with 10 mol % loading, this reaction can be routinely accomplished in high yields and enansioselectivities under air- and moisture-tolerant conditions. We discovered this 6'-OH cinchona alkaloid by taking advantage of the easily tunable C-9 position of the catalyst which is uniquely effective for the highly enantioselective addition of nitromethane to aromatic aldehydes.;Kinetic studies show that the reaction has first order dependence on aldehyde, nitromethane and catalyst. Kinetic isotope studies suggest that the addition of nitromethane to aldehyde is the rate-determining step of the reaction.;We also realized the first enantioselective aza-Henry reaction with ketoimines with the same bifunctional organic catalyst. The synthetic value of this reaction is emphasized by the importance of the 1,2 diamine structural motif in biologically active natural products. A range of aromatic ketoimines were synthesized and converted to the addition product in moderate to excellent enantioselectivities.;Highly enantio- and diastereoselective conjugate addition of alpha-substituted-beta-ketoesters to Michael acceptor fumarates was realized using the 6'-OH bifunctional organic catalyst beta-isocuperidine (beta-ICD). A number of alpha-substituted-beta-ketoesters were added to various fumarates to give the 1, 4 addition products in high yields and selectivities exemplifying the versatility of the reaction.