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 β-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.