MK-8712

An efficient method to synthesize the β-lactams with high regioselectivity via Pd-catalyzed C(sp(3))-H bond activation and intramolecular amination of simple and readily available aminoquinoline carboxamides was demonstrated. C6F5I plays a significant role in the formation of the C-N bond of the four-membered ring β-lactams. High yield along with wide substrate scope and functional group tolerance makes this reaction applicable to build natural-product-derived β-lactams. This method has been applied to the efficient synthesis of the β-lactamase inhibitor MK-8712.

The bridged monobactam β-lactamase inhibitor MK-8712 (1) effectively inhibits class C β-lactamases. Side chain N-alkylated and ring-opened analogs of 1 were prepared and evaluated for combination with imipenem to overcome class C β-lactamase mediated resistance. Although some analogs were more potent inhibitors of AmpC, none exhibited better synergy with imipenem than 1.