title: Mechanism and enantioselectivity in palladium-catalyzed conjugate addition of arylboronic acids to β-substituted cyclic enones: insights from computation and experiment.
abstract: 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.
authors.affiliation: The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology , Pasadena, California 91125, United States.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Holder
authors.forename: Lufeng
authors.initials: L
authors.lastname: Zou
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Marziale
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Lan
authors.forename: Michele
authors.initials: M
authors.lastname: Gatti
authors.forename: Kotaro
authors.initials: K
authors.lastname: Kikushima
authors.forename: K N
authors.initials: KN
authors.lastname: Houk
authors.forename: Brian M
authors.initials: BM
authors.lastname: Stoltz
mesh_terms: D001897:Boronic Acids / Q000737:chemistry*; D002384:Catalysis; D007659:Ketones / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D010165:Palladium / Q000737:chemistry*; D012492:Salts / Q000737:chemistry; D013237:Stereoisomerism; D013379:Substrate Specificity; D014867:Water / Q000737:chemistry
chemical_list: D001897:Boronic Acids; D007659:Ketones; D012492:Salts; D014867:Water; D010165:Palladium
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