Enabling Asymmetric Synthesis of ABBV-3748, a Corrector Compound for the Treatment of Cystic Fibrosis

ABBV-3748 is a C2 corrector for the treatment of cystic fibrosis profiled among AbbVie’s CFTR portfolio. A decagram-scale enabling asymmetric synthesis is described which addresses numerous shortcomings of the original route. Highlights include an InBr 3 -catalyzed intramolecular hydroarylation reaction that rapidly assembles the chromane core, an exceptionally efficient asymmetric hydrogenation of a primary enamide, and identification of t BuMgCl as a uniquely effective base in a challenging acyl sulfonamide formation.