Preparation of Pyrrolidine-Based PDE4 Inhibitors via Enantioselective Conjugate Addition of α-Substituted Malonates to Aromatic Nitroalkenes

The enantioselective conjugate addition of α-substituted malonates to aromatic nitroalkenes generates a stereocenter at the carbon bearing
the aromatic group and an adjacent prochiral center from the α-substituted malonate. Nitro reduction followed by diastereoselective cyclization
provides pyrrolidinones with two contiguous stereocenters, one of which is quaternary. This sequence was used for the preparation of the
PDE4 inhibitor IC86518. Additional examples of the enantioselective Michael addition illustrate the scope of the reaction.