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.

惰性C(sp³)–H键的对映选择性官能化是现代合成化学中最具挑战性的课题之一，当该反应应用于结构复杂的化合物时尤为如此。要实现该类反应的成功应用，我们需要全面理解调控对映选择性的反应机理，但目前此类认知仍较为匮乏。本文中，我们借助密度泛函理论（Density Functional Theory，DFT）计算，并对过渡态进行了细致构象搜索，系统研究了手性铱配合物催化四氢异喹啉（tetrahydroisoquinoline，THIQ）的C(sp³)–H硼化反应。研究结果表明，活性催化物种为铱(III)三(硼基)非对映异构体，该类物种同时在铱(Ir)中心（Λ或Δ构型）与(S,S)-吡啶基-硼基配体（CBL）上具有手性。该反应通过以下路径进行：对THIQ的α-亚甲基位进行对映选择性C(sp³)–H活化、氢化物与硼基配位位点发生改变，以及以B–C还原消除作为决速步。计算结果显示，R构型产物的生成量多于S构型产物，这与实验观测结果一致。Λ型与Δ型铱催化剂之间的活化能差为3.60 kcal mol⁻¹，对应99%的对映体过量值（enantiomeric excess，ee），这与实验观测到的94% ee值相符。尤为关键的是，若忽略铱中心的Λ/Δ手性，则无论CBL取代基如何，都会得到不切实际的100% ee预测结果；而同时考虑金属中心与配体的手性时，则可成功复现实验中观测到的取代基依赖型ee变化趋势。R构型产物相较于S构型产物具有更高的选择性，这归因于R构型产物形成过程中B–C还原消除过渡态的反应空腔大于S构型产物形成过程中的对应空腔。本研究为不对称C–H硼化反应中金属中心与配体手性的协同立体化学作用提供了基础性认知。