The Reaction Mechanism of the Enantioselective Tsuji Allylation: Inner-Sphere and Outer-Sphere Pathways, Internal Rearrangements, and Asymmetric C–C Bond Formation

Abstract

We use first principles quantum mechanics (density functional theory) to report a detailed reaction mechanism of the asymmetric Tsuji allylation involving prochiral nucleophiles and non-prochiral allyl fragments, which is consistent with experimental findings. The observed enantioselectivity is best explained with an inner-sphere mechanism involving the formation of a 5-coordinate Pd species that undergoes a ligand rearrangement, which is selective with regard to the prochiral faces of the intermediate enolate. Subsequent reductive elimination generates the product and a Pd0 complex. The reductive elimination occurs via an unconventional seven-centered transition state that contrasts dramatically with the standard three-centered C–C reductive elimination mechanism. Although limitations in the present theory prevent the conclusive identification of the enantioselective step, we note that three different computational schemes using different levels of theory all find that inner-sphere pathways are lower in energy than outer-sphere pathways. This result qualitatively contrasts with established allylation reaction mechanisms involving prochiral nucleophiles and prochiral allyl fragments. Energetic profiles of all reaction pathways are presented in detail.

Congested C–C Bonds by Pd-Catalyzed Enantioselective Allyl–Allyl Cross-Coupling, a Mechanism-Guided Solution

“…22 Extensive computational studies on the 3,3'-reductive elimination pathway for simple unsubstituted systems with achiral monodentate phosphine ligands were completed by Echavarren and Espinet. 23 We focused our analysis on the portion of the reaction coordinate essential to regio- and stereodefinition during formation of the branched ( S )-enantiomer of 3a rather than ( R )- 3a or the linear isomer (the Si-, Re- or linear -pathways, respectively).…”

Advances in Stereoconvergent Catalysis from 2005 to 2015: Transition-Metal-Mediated Stereoablative Reactions, Dynamic Kinetic Resolutions, and Dynamic Kinetic Asymmetric Transformations

“…12,13,14 Preliminary studies (Scheme 1) suggested that an internal mechanism (i.e. reductive elimination) is a lower-energy pathway than the corresponding external mechanism involving attack of the enolate onto an η 3 -allyl complex; it was later discovered that η 1 -allylpalladium carboxylate 5 was found to be the resting state of the catalyst and that decarboxylation was likely rate-limiting.…”

Asymmetric Dearomatization/Cyclization Enables Access to Polycyclic Chemotypes

“…A similar hydrogen bond was observed in Lloyd-Jones’ transition state calculations of cesium malonate with an L2 -Pd-η3-allyl complex, giving rise to a quasi-inner sphere transition state wherein enantioselectivity is governed by pre-coordination of the nucleophile to the ligand rather than the Pd atom. [14] …”