Asymmetric, Nearly Barrierless C(sp3)–H Activation Promoted by Easily-Accessible N-Protected Aminosulfoxides as New Chiral Ligands

Although chiral sulfoxides are important motifs in medicinal chemistry and asymmetric synthesis, design and applications of sulfoxide ligands are still limited, in particular in the context of asymmetric C–H activation. We disclose herein the conception and synthesis of enantiopure N/S ligands: N-protected aminosulfoxides. The potential of these auxiliaries in asymmetric C(sp3)–H activation is demonstrated as high enantioselectivity is reached during a Pd-catalyzed direct arylation of cyclopropane carboxylic acid derivatives. Besides, the capacity of these ligands goes far beyond as yet unknown direct alkynylation could also be performed with an enantiomeric ratio up to 92:8. The preliminary mechanistic studies shed light on their original mode of action including: 1) key noncovalent interactions between the chiral complex and the substrate allowing stabilization of agostic M–H–C interaction and 2) π-stacking ligand-substrate bonding. DFT investigations suggest that, thanks to this unusual ligand/substrate activation, commonly recognized as difficult, the cleavage of the C–H bond is virtually barrier-less