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

Abstract

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.