Enantioselectivity Model for Pd-Catalyzed C–H Functionalization Mediated by the Mono-N-protected Amino Acid (MPAA) Family of Ligands

The mono-N-protected amino acid (MPAA) family of ligands is arguably the most prolific scaffold for enabling enantioselective C–H activation via metal insertion. However, its mechanism for asymmetric induction is not fully understood. Here, we developed a practical model for asymmetric induction from the viewpoint of rationalizing chiral, bidentate ligands for C–H activation via metal insertion. The model is validated against Pd­(II)-catalyzed C–H activation in 2-benzhydrylpyridine mediated by the [(cyclohexyloxy)­carbonyl]-l-leucine (MPAA) ligand. We found that full control elements of enantioselectivity are (a) inherent strain in the bidentate coordination of substrate and the ability of the ligand to enhance it, (b) the gearing effect that restricts the C–H bond activation to one face of the Pd catalyst, (c) potential interactions between the ligand and substrate, and (d) chelate inversion which is controlled by the ligand-anchored base that restricts the C–H bond activation to one side of the Pd catalyst. We also identified two pathways for loss of enantioselectivity: (1) equilibration of the ligand half-chair conformations and (2) loss of bidentate coordination through partial dissociation of the ligand. We applied this general enantioselectivity model to explain the observed increase in enantioselectivity of the Pd­(II)-catalyzed asymmetric C–H activation of 1,1-disubstituted cyclobutanes upon replacing Boc-protected l-leucine (MPAA) ligand by the chiral mono-N-protected α-amino-O-methylhydroxamic acid (MPAHA) ligand. We found that the observed trend in enantioselectivity upon replacing MPAA and MPAHA is due to increased interactions between the ligand and substrate. We proposed a strategy for the use of such a model to design highly selective chiral ligands for C–H functionalization.