Copper-Catalyzed Enantioselective Boron Conjugate Addition: DFT and AFIR Study on Different Selectivities of Cu(I) and Cu(II) Catalysts

We present a mechanistic survey on the LCu-catalyzed (L = chiral 2,2'-bipyridine ligand) enantioselective boron conjugate addition reaction, carried out using density functional theory (DFT) and artificial force induced reaction (AFIR) methods. The computed catalytic cycle for Cu(I)- and Cu(II)-based catalysts consists of three steps: (a) boron boron bond cleavage of B-2(pin)(2), (b) boron conjugate addition on the beta carbon of chalcone, and (c) protonation. The enantioselectivity of the reaction with LCuI or LCuII catalysts is solely governed at the boron conjugate addition step. The multicomponent(MC)-AFIR search and the subsequent DFT calculations for the LCuI catalyst determined transition states (TSs), which lead to Cu-I-O-enolate and Cu-I-C-enolate, and both equally contribute to the C-B bond formation with no enantioselectivity. On the other hand, a MC-AFIR search and the subsequent DFT calculations for the analogous LCuII catalyst showed that only the transition state (TS) leading to Cu-II-O-enolate contributes to the reaction. Furthermore, the TSs leading to the R and S forms of Cu-II-O-enolates are energetically well separated, with the R form being of lower energy, which is consistent with experimental observations. Our study provides important mechanistic insights for designing transition-metal catalysts for Cu-catalyzed enantioselective boron conjugate addition reactions.