Diastereoselective FeCl3·6H2O / NaBH4 Reduction of Oxime Ether for the Synthesis of β-Lactamase Inhibitor Relebactam.

Relebactam, a potent beta-lactamase inhibitor, in combination with Primaxin is an FDA-approved (Recarbrio) treatment for serious and antibiotic-resistant bacterial infections. An efficient synthesis of key chiral piperidine intermediate 1 suitable for large-scale preparation of relebactam is described. The key steps include a unique highly diastereoselective FeCl3 center dot 6H(2)O/NaBH4 reduction of a chiral oxime ether and chemoselective amidation of the resulting unprotected pipecolic acid. Nuclear magnetic resonance studies and density functional theory calculations were carried out on the substrate-Fe(III) complexes, which shed light on diastereoselective reduction.