Reactivity and Selectivity Controlling Factors in the Pd/Dialkylbiarylphosphine-Catalyzed C–C Cleavage/Cross-Coupling of an N‑Fused Bicyclo α‑Hydroxy-β-Lactam

Density functional theory was employed in order to elucidate the mechanism and factors that lead to the observed regioselectivity in the dialkylbiarylphosphine (Phos)/Pd-catalyzed C–C cleavage/cross-coupling of an N-fused bicyclo α-hydroxy-β-lactam, 1. We have identified that (a) a complex [(1)­(Cs₂CO₃)]-PdL­(PhBr) forms prior to a “base-mediated oxidative addition”; (b) Cs-carbonate (rather than a halide) deprotonates the alcohol substrate in the lowest energy pathway en route to Pd-alcoholate formation; (c) reactions using Phos ligands bearing OCF₃ and OCF₂H substituents on the “B”-ring are predicted to be selective toward proximal ring opening of 1; (d) steric repulsion between the bottom “B”-ring of the Phos ligand and the piperidine moiety of 1 controls the regioselectivity of the C–C cleavage followed by cross-coupling; and (e) the α- vs β-selective functionalization of the piperidine moiety in 1 is influenced by the bulkiness of the R²-substituent of the coupling partner. These studies will aid in the design of selective functionalizations of the piperidine moiety in 1.