Asymmetric Synthesis of Spirocyclic β-Lactams through Copper-Catalyzed Kinugasa/Michael Domino Reactions

Abstract

The first copper-catalyzed highly chemo-, regio-, diastereo-, and enantioselective Kinugasa/Michael domino reaction for the desymmetrization of prochiral cyclohexadienones is described. In the presence of a chiral copper catalyst, alkyne-tethered cyclohexadienones couple with nitrones to generate the chiral spirocyclic lactams with excellent stereoselectivity (up to 97 % ee, >20:1 dr). The new method provides direct access to versatile highly functionalized spirocyclic β-lactams possessing four contiguous stereocenters, including one quaternary and one tetra-substituted stereocenter.

Keywords: asymmetric synthesis; copper; cyclohexadienone; desymmetrization; β-lactams.