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 B₂(pin)₂, (b) boron conjugate addition on the β carbon of chalcone, and (c) protonation. The enantioselectivity of the reaction with LCu^I or LCu^II catalysts is solely governed at the boron conjugate addition step. The multicomponent (MC)-AFIR search and the subsequent DFT calculations for the LCu^I 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 LCu^II 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.