Intramolecular hydroamidation of alkenes enabling asymmetric synthesis of beta-lactams via transposed NiH catalysis

Abstract

Synthetic methods for constructing enantioenriched beta-lactams are highly valuable given their ubiquity in bioactive compounds, most notably in antibiotics such as penicillins and carbapenems. Intramolecular hydroamidation of beta,gamma-unsaturated amides would provide a convenient means to reach this alluring chemical space, yet it remains limited due to the regioselectivity issue arising from the difficulty associated with the formation of strained four-membered rings. Here we describe a NiH-catalysed strategy that addresses this challenge through the use of readily accessible alkenyl dioxazolone derivatives. The reaction transcends the conventional NiH operation mode via a transposed mechanism initiated by N-activation, thus allowing for proximal C-N bond formation with excellent regioselectivity, regardless of the electronic properties of substituents. This mechanistic platform is also highly effective for the enantioselective intramolecular hydroamidation of alkenes to enable a convenient access to enantioenriched beta-lactams.