Oxidative nucleophilic addition of amide enolates to π-deficient aromatic and heteroaromatic ring systems

Abstract

In summary, a novel spirocyclisation approach based on the oxidative nucleophilic addition of amide enolates to π-deficient aromatic rings was developed. This protocol allowed the preparation of complex and diverse heterocyclic bis-lactam scaffolds, which proved to be valuable cores for medicinal chemistry applications. Several spirocyclic inhibitors of PRMT5 were thus prepared, with the spirocyclisation tolerating diverse substituents, allowing tuning of biological activity as well as modulation of physicochemical properties.