DFT Mechanistic Investigation of an Enantioselective Tsuji–Trost Allylation Reaction

Abstract

A comprehensive mechanistic examination of an asymmetric palladium-catalyzed Tsuji−Trost allylation reaction that identifies the enantioselective step was completed utilizing DFT computational tools and the nudged elastic band method. Key components of the study include (a) plausible reaction pathways for the full interconversion of a square-planar palladium allyl enolate intermediate with low barriers relative to the subsequent enantioselectivity-determining reductive C−C coupling step, thereby disputing the previously identified mechanism, (b) a detailed analysis of the factors influencing the stereochemical control involved in forming the preferred configuration via the reductive C−C coupling step, (c) a comprehensive examination of the competing outer-sphere mechanism that includes a metal counterion as an escort to the nucleophile in order to modulate the effects of modeling the reaction step of oppositely charged species, and (d) examination of the possible role water plays in stabilizing a keto-coordinated adduct of Pd II -η 1 -allyl, formed early in the catalytic cycle, relative to a carboxylate-coordinated adduct, the known resting state of the reaction. Barrier energies for the enantioselective C−C coupling are investigated with several levels of theory, and together they support a reaction mechanism consistent with the preferred formation of the correct enantiomer on the basis of the enantiomer of the ligand selected.

The Evolution of Decarboxylative Allylation: Overcoming pKa Limitations

“…This enolate can couple through an inner‐sphere process as suggested by Stoltz and Goddard or through ionization and outer‐sphere attack on the allyl ligand . The inner‐sphere vs. outer sphere couplings with PHOX‐ligated Pd have been further analysed in greater detail by Morehead Jr. and Sargent . Their studies support the decarboxylation mechanism depicted in Scheme and conclude that, with PHOX ligand, the inner‐sphere C−C bond formation is the step that provides enantioselection.…”

“…Their studies support the decarboxylation mechanism depicted in Scheme and conclude that, with PHOX ligand, the inner‐sphere C−C bond formation is the step that provides enantioselection. Further conformational analysis of the highly asynchronous inner‐sphere process provides insight into the nature of the enantioselection …”

Proofreading Experimentally Assigned Stereochemistry Through Q2MM Predictions in Pd-Catalyzed Allylic Aminations

“…4,6,9,10,11 The selectivity in this reaction depends on a complex interplay between steric interactions favoring a certain allyl geometry, dynamic interconversion through exo-endo isomerization of the allyl moiety, and electronic effects whereby the ligand can influence the regioselectivity of nucleophilic attack. 6,12 The catalytic cycle of this reaction proceeds 6,[13][14][15] through an oxidative addition to form the reactive  3 -allyl palladium intermediate, which has been studied by X-ray crystallography.…”

Proofreading Experimentally Assigned Stereochemistry Through Q2MM Predictions in Pd-Catalyzed Allylic Aminations

“…4,6,9,10,11 The selectivity in this reaction depends on a complex interplay between steric interactions favoring a certain allyl geometry, dynamic interconversion through exo-endo isomerization of the allyl moiety, and electronic effects whereby the ligand can in uence the regioselectivity of nucleophilic attack. 6,12 The catalytic cycle of this reaction proceeds 6,[13][14][15] through an oxidative addition to form the reactive h 3allyl palladium intermediate, which has been studied by X-ray crystallography. (Figure 1B).…”

“…16 There have been a few methods developed to predict stereoselectivity in asymmetric catalysis. 22,23 Calculation of the transition state structures and the energy difference between the structures leading to the R and S enantiomers by DFT 13,15,24 is slow and typically does not sample a su ciently large number of conformations. Another method is to predict stereoselectivity by tting to various steric and electronic parameters.…”