Asymmetric Synthesis of Chiral δ-Caprolactams: Access to a Key Intermediate of Ubrogepant

Abstract

Chiral δ-caprolactam constitutes the key pharmacophore of Calcitonin gene-related peptide receptor antagonists such as ubrogepant and atogepant, and its synthesis is quite challenging. Herein, we report a novel, robust, and potentially scalable asymmetric synthesis strategy for chiral δ-caprolactam. The δ-caprolactam scaffold is first constructed via a one-pot process, followed by sequential installation of three stereocenters through crystallization-induced dynamic kinetic resolution and catalytic hydrogenation. This protocol offers distinct advantages, including the absence of enzymatic catalysis and column chromatography.