posted on 2021-07-19, 16:33authored byTyler
G. Saint-Denis, Nelson Y. S. Lam, Nikita Chekshin, Paul F. Richardson, Jason S. Chen, Jeff Elleraas, Kevin D. Hesp, Daniel C. Schmitt, Yajing Lian, Chan Woo Huh, Jin-Quan Yu
Enantioselective C(sp3)–H activation has gained
considerable attention from the synthetic chemistry community. Despite
the intense interest in these reactions, the mechanisms responsible
for enantioselection are still vague. In the course of the development
of aryl thioether-directed-C(sp3)–H arylation, we
noticed extreme variation in sensitivity of two substrate classes
to substituent effects of ligands and directing groups: whereas 3-pentylsulfides
(prochiral α-center) responded positively to substitution on
ligands and directing groups, isobutyl sulfides (prochiral β-center)
were entirely insensitive. Quantitative structure-selectivity relationship
(QSSR) analyses of directing group and ligand substitution and the
development of a class of mono-N-acetyl protected
amino anilamide (MPAAn) ligands led to high enantiomeric ratios (up
to 99:1) for thioether-directed-C(sp3)–H arylation.
Key to the realization of this method was the exploitation of transient
chirality at sulfur, which relays stereochemical information from
the ligand backbone to enantiotopic carbons of the substrate in a
rate- and enantiodetermining cyclometallation deprotonation. The absolute
stereochemistry of the products for these two substrates were revealed
to be opposite. Density functional theory (DFT) evaluation of all
possible diastereomeric transition states confirmed initial premises
that guided rational ligand and directing group design. The implications
of this study will assist in the further development of enantioselective
C(sp3)–H activation, namely by highlighting the
noninnocence of directing groups, distal steric influences, and the
delicate interplay between steric Pauli repulsion and London dispersion
in enantioinduction.