Diastereomeric Iridium Catalysts for Enantioselective C(sp3)–H Borylation: Roles of Two Chiralities at the Metal Center and Ligand

The enantioselective functionalization of inert C(sp3)-H bonds is one of the most significant challenges in modern synthetic chemistry, especially when it is applied to structurally complex compounds. To achieve success, we require a comprehensive understanding of the mechanisms involved in controlling enantioselectivity, but such knowledge is currently limited. Herein, we systematically investigated the catalysis of chiral iridium complexes for the C(sp3)-H borylation of tetrahydroisoquinoline (THIQ) using DFT calculations with a careful conformational search of transition states. Our results reveal that the active species are iridium(III) tris(boryl) diastereomers bearing chiralities at both the Ir center (Λ or Δ) and (S,S)-pyridyl-boryl ligand (CBL). This reaction proceeds via enantioselective C(sp3)-H activation at the α-methylene position of THIQ, changes in hydride and boryl coordination sites, and B-C reductive elimination as the rate-determining step. R-product is calculated to be produced more than S-one, as experimentally observed. The difference in activation energy between Λ- and Δ-Ir catalysts is 3.60 kcal mol-1 (99% ee), which agrees with the experimentally observed ee value (94%). Crucially, neglecting Ir-centered Λ/Δ chirality leads to unrealistic 100% ee predictions regardless of CBL substituents, whereas incorporating both metal and ligand chiralities successfully reproduces the substituent-dependent ee trends observed experimentally. The greater selectivity of the R-product over the S-one is attributed to the larger reaction pocket of the transition state of the B-C reductive elimination in the R-product formation than that in the S-one. This work provides fundamental insights into the cooperative stereochemical roles of metal and ligand chiralities in asymmetric C-H borylation.