C−H Bond Activation for the Synthesis of Heterocyclic Atropisomers Yields Hedgehog Pathway Inhibitors

Axially chiral 4‐arylisoquinolones are endowed with pronounced bioactivity, and methods for their efficient synthesis have gained widespread attention. However, enantioselective synthesis of axially chiral 4‐arylisoquinolones by means of C−H activation has not been reported to date. Described here is a rhodium (III)‐catalyzed C−H bond activation and annulation for the atroposelective synthesis of axially chiral 4‐arylisoquinolones. The method employs chiral cyclopentadienyl ligands embodying a piperidine ring as backbone and yields the atropisomers with good to excellent yields and enantioselectivity. Biological relevance of the 4‐arylisoquinolones was demonstrated by their investigation in different cellular assays, leading to the discovery of novel non‐SMO (SMO= smoothened) binding Hedgehog pathway inhibitors. Hedgehogs: A high‐yielding rhodium(III)‐catalyzed atroposelective synthesis of axially chiral 4‐arylisoquinolones using a novel chiral cyclopentadienyl ligand was developed to yield novel non‐SMO (SMO=smoothened) binding Hedgehog pathway inhibitors.