Asymmetric catalytic conjugate additions with bifunctional organic catalysts

We have developed a highly enantioselective/diastereoselective conjugate addition of alpha-substituted beta-ketoesters to alpha, beta-unsaturated ketones with 6'-OH cinchona alkaloid derivatives as bifunctional organocatalysts. A wide range of alpha-substituted beta-ketoesters can be employed as donors while unprecedented wide range of alpha, beta-unsaturated ketones are suitable acceptors. With broad scopes and utilizing readily available and easily recyclable chiral organic catalysts in as little as 1.0 mol% loading, this reaction can be routinely accomplished in virtually quantitative yield under air- and moisture-tolerant conditions. We also discovered a structurally novel 6'-OH cinchona alkaloid by taking advantage of the easily tunable characteristics of this kind of catalyst, which is uniquely effective for the conjugate additions of alpha-substituted alpha-cyanoacetates/alpha-nitroesters as donors.;We also realized a highly efficient and general asymmetric conjugate addition of alpha-substituted-beta-ketoesters to alpha, beta-unsaturated aldehydes with the same bifunctional organic catalysts. The synthetic value of this reaction is emphasized by the direct generation of chiral aldehydes with all-carbon quaternary stereo centers. The structural importance of the 1, 4-adducts was demonstrated in two concise and flexible enantioselective syntheses of biologically interesting natural products.;Kinetic studies show the conjugate addition reaction has first order dependence on both the donor and the acceptor, but half order dependence on the 6'-OH bifunctional organic catalyst. The bifunctional catalyst exists in an equilibrium of monomer and dimer in the reaction solution. 6'-OH bifunctional catalysts are more active and selective in the asymmetric conjugate addition reactions compared to the monofunctional catalysts and the hydroxyl group is playing an important role as an activating and directing group. A transition state model was proposed based on systematic spectroscopic and kinetic studies. A net work of hydrogen bonds between the bifunctional catalyst and the conjugate addition donor and acceptor appears to be responsible for the activity and selectivity of the catalyst.