title: Mechanism, reactivity, and selectivity in palladium-catalyzed redox-relay Heck arylations of alkenyl alcohols.
abstract: The enantioselective Pd-catalyzed redox-relay Heck arylation of acyclic alkenyl alcohols allows access to various useful chiral building blocks from simple olefinic substrates. Mechanistically, after the initial migratory insertion, a succession of β-hydride elimination and migratory insertion steps yields a saturated carbonyl product instead of the more general Heck product, an unsaturated alcohol. Here, we investigate the reaction mechanism, including the relay function, yielding the final carbonyl group transformation. M06 calculations predict a ΔΔG(‡) of 1 kcal/mol for the site selectivity and 2.5 kcal/mol for the enantioselectivity, in quantitative agreement with experimental results. The site selectivity is controlled by a remote electronic effect, where the developing polarization of the alkene in the migratory insertion transition state is stabilized by the C-O dipole of the alcohol moiety. The enantioselectivity is controlled by steric repulsion between the oxazoline substituent and the alcohol-bearing alkene substituent. The relay efficiency is due to an unusually smooth potential energy surface without high barriers, where the hydroxyalkyl-palladium species acts as a thermodynamic sink, driving the reaction toward the carbonyl product. Computational predictions of the relative reactivity and selectivity of the double bond isomers are validated experimentally.
authors.affiliation: Lab of Computational Chemistry and Drug Design, Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School , Shenzhen 518055, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Xu
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Hilton
authors.forename: Xinhao
authors.initials: X
authors.lastname: Zhang
authors.forename: Per-Ola
authors.initials: PO
authors.lastname: Norrby
authors.forename: Yun-Dong
authors.initials: YD
authors.lastname: Wu
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Sigman
authors.forename: Olaf
authors.initials: O
authors.lastname: Wiest
mesh_terms: D000438:Alcohols / Q000138:chemical synthesis* / Q000737:chemistry; D000475:Alkenes / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D060326:Chemistry Techniques, Synthetic; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010165:Palladium / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D000438:Alcohols; D000475:Alkenes; D010165:Palladium