Pyrrolizidine is among the saturated N-heterocyclic scaffolds most frequently found in natural products and pharmaceutically relevant substances. Herein, a strategy for the synthesis of polysubstituted pyrrolizidine-3-ones by catalytic reductive domino-type recyclization of properly functionalized isoxazoline N-oxides was developed. The process is diastereoselective, and one diastereomer (out of four possible ones) is predominant in many of the studied cases. Using the developed method, modifications of potent GSK's PDE4 inhibitor and MSD's potent hNK1 antagonist were prepared.