Synthesis of an Azabicyclo[3.1.0]hexanone Drug Candidate via Catalytic C–H Activation

Synthesis of an Azabicyclo[3.1.0]hexanone-Containing Inhibitor of NF-κB Inducing Kinase via Catalytic C–H Activation: J. J. Crawford, D. Liao, A. Kolesnikov, W. Lee, M. L. Landry

Synthesis 2020, 52, DOI: 10.1055/s-0040-1707279


A recently described lead compound displaying promising activity as a candidate therapeutic for treating autoimmune and inflammatory disorders, such as lupus erythematosus, incorporates a densely functionalized azabicyclo[3.1.0]hexanone core structure. An efficient entry to this synthetically challenging chiral molecular fragment has been recently described by the group of Dr. James Crawford at Genentech, Inc. (South San Francisco, USA). The process is based on just seven linear synthetic steps and relies on a key enantiocontrolled cyclization/C–H activation reaction promoted by a Pd(0) catalyst in the presence of a TADDOL-phosphonite ligand.

Dr. Crawford said: “The application of modern methodologies, such as this catalytic, enantioselective C–H activation, to drug discovery can streamline access to and enable the scalable synthesis of advanced molecular scaffolds, as in the case of this complex azabicyclo[3.1.0]hexanone NIK inhibitor.”

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