Intramolecular Hydroamidation of Alkenes Enabling Asymmetric Synthesis of β-Lactams via Unprecedented Mechanism of NiH Catalysis

Abstract

Synthetic methods for constructing enantioenriched β-lactams are highly valuable given the ubiquity of this privileged heterocyclic unit in bioactive compounds, most notably in antibiotics such as penicillins and carbapenems. Intramolecular hydroamidation of β,γ-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 an unprecedented 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, which represents the first example of such a type of processes that enables the access to enantioenriched β-lactams.