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.