Unprecedented Hydrophobic Amplification in Noncovalent Organocatalysis on Water: Hydrophobic Chiral Squaramide Catalyzed Michael Addition of Malonates to Nitroalkenes

In this study, water was demonstrated to be an exceptionally efficient reaction medium for the noncovalent, hydrogen-bonding-promoted enantioselective Michael addition of malonates to diverse nitroolefins using cinchona-based squaramide catalysts. A significant increase in the reaction rate was observed when the reaction was performed on water rather than in the conventional organic solvents, because of the hydrophobic hydration effect. This hydrophobic amplification was significantly dependent upon the hydrophobicity of the C3-substituent (vinyl or ethyl) of cinchona-based catalysts. Thus, the use of more hydrophobic catalyst with an ethyl group at the C3-position, even a highly challenging Michael donor such as dimethyl methylmalonate was also smoothly converted to the desired adduct. Furthermore, because of the remarkable rate acceleration under on water conditions, the catalyst loading also significantly decreased. Thus, in the case of beta-ketoesters, even 0.01 mol % of catalyst loading was enough to complete the reaction at room temperature, affording the corresponding Michael adducts with perfect diastereo- and enantioselectivity (up to >99:1 d.r., up to 99% ee). The developed on water protocol was successfully applied for the scalable syntheses of an antidepressant (S)-rolipram and an anticonvulsant (S)-pregabalin.