| We developed a novel class of acid-base bifunctional catalyst system based on C6'-OH cinchona alkaloid derivatives, which are efficient catalysts for the highly enantioselective conjugate addition of malonates and beta-ketoesters to a variety of beta-substituted nitroalkenes. Furthermore, they were found to be able to promote conjugate additions of a wide range of trisubstituted nucleophiles to a variety of beta-substituted nitroalkenes to create adjacent quaternary and tertiary stereocenters in one step in excellent enantioselectivities and great diastereoselectivities. After identifying a gauche-open active conformer for C6'-OH cinchona alkaloids in the transition state, a transition state assembly featuring acid-base bifunctional catalysis via a network of hydrogen bonding between the substrates and the catalyst was established.; We utilized these cinchona alkaloid catalysts to further develop the first highly enantioselective conjugate addition with vinyl sulfones generating chiral building blocks containing solo all-carbon quaternary stereocenters with the versatile sulfone functionality.; These novel bifunctional organic catalysts can also promote highly enantioselective Henry reaction with alpha-ketoesters, a reaction that is mechanistically distinct from conjugate addition reactions. These results indicate that the C6'-OH cinchona alkaloids are potentially broadly effective acid-base bifunctional catalysts.; In order to understand how cinchona alkaloid catalysts differentiate the two enantiotopic carbonyls in the highly enantioselective alcoholysis of cyclic anhydrides, we designed and synthesized a novel rigid catalyst to mimic the cinchona alkaloid catalyst that was locked in an app-close conformer. The remarkably similar enantioselectivity afforded by the conformationally rigid catalyst and DHQD-PHN, one of the best catalysts for the asymmetric alcoholysis strongly indicates that the latter adopts an app-close conformer in the transition state. These results provided crucial insights that allowed us to formulate a transition model. This model reveals an interesting strategy for the chiral recognition of the enantiotopic carbonyl functional groups by the cinchona alkaloid catalysts. |
