Mechanism and Enantioselectivity in Palladium-Catalyzed Conjugate Addition of Arylboronic Acids to β‑Substituted Cyclic Enones: Insights from Computation and Experiment

Enantioselective
conjugate additions of arylboronic acids to β-substituted
cyclic enones have been previously reported from our laboratories.
Air- and moisture-tolerant conditions were achieved with a catalyst
derived in situ from palladium­(II) trifluoroacetate
and the chiral ligand (S)-t-BuPyOx.
We now report a combined experimental and computational investigation
on the mechanism, the nature of the active catalyst, the origins of
the enantioselectivity, and the stereoelectronic effects of the ligand
and the substrates of this transformation. Enantioselectivity is controlled
primarily by steric repulsions between the t-Bu group
of the chiral ligand and the α-methylene hydrogens of the enone
substrate in the enantiodetermining carbopalladation step. Computations
indicate that the reaction occurs via formation of a cationic arylpalladium­(II)
species, and subsequent carbopalladation of the enone olefin forms
the key carbon–carbon bond. Studies of nonlinear effects and
stoichiometric and catalytic reactions of isolated (PyOx)­Pd­(Ph)I complexes
show that a monomeric arylpalladium–ligand complex is the active
species in the selectivity-determining step. The addition of water
and ammonium hexafluorophosphate synergistically increases the rate
of the reaction, corroborating the hypothesis that a cationic palladium
species is involved in the reaction pathway. These additives also
allow the reaction to be performed at 40 °C and facilitate an
expanded substrate scope.