Stereocontrolled synthesis of 3-hydroxy-2-piperidinone carboxamides by catalytic ring-opening aminolysis of bridged <i>δ</i> -lactam-γ-lactones

The α-hydroxy-δ-valerolactam, 3-hydroxypiperidine, and piperidine-3-carboxamide topologies are resident in several natural products and pharmaceuticals, including anticonvulsant and antithrombotic agents. A modular and stereocontrolled strategy that merges these privileged scaffolds into one motif could facilitate the discovery of more small molecules with medicinal value. Here, we demonstrate that bridged valerolactam-butyrolactones can be skeletally remodelled to highly decorated 3-hydroxy-2-piperidinone carboxamides by catalytic and site-selective deconstructive aminolysis with primary and secondary amines. The products are obtained in a sterocontrolled manner following oxidative addition and concomitant trapping with the amine. The scaffold hopping proceeds with exclusive acyl C-O bond cleavage under palladium catalysis and represents the first catalytic method for activating the acyl C-O bonds of γ-lactones.