Stereoselective Synthesis of Delgocitinib and Its Diastereomer Using Organocatalyzed Michael Addition

Herein, we describe the stereoselective synthesis of delgocitinib and its diastereomer. Delgocitinib, a Janus kinase (JAK) inhibitor, is characterized by a diaza-spirocyclic structure consisting of pyrrolidine and azetidine rings. The organocatalyzed Michael addition of propanal with fumarate or maleimide facilitated the formation of contiguous tertiary stereogenic centers, leading to the stereoselective production of each diastereomer. Intramolecular C-H amination reactions introduced a nitrogen atom on one of the tertiary carbons, and subsequent azetidine formation constructed the spirocyclic system.