Development of an Enantioselective [3 + 2] Cycloaddition To Synthesize the Pyrrolidine Core of ABBV-3221 on Multikilogram Scale

Abstract

The tetrasubstituted pyrrolidine core of ABBV-3221 was synthesized by catalytic, enantioselective cycloaddition. A Cu(I) catalyst system was identified as ideal for further development, which gave a 78% yield of 99% purity product after optimization. The processes of catalyst selection, optimization, and crystallization of the cycloaddition product are described herein.