A chiral ligand for the rhodium‐catalyzed asymmetric 1,4‐addition of an arylboronic acid to a coumarin substrate that could markedly reduce catalyst loading was developed using interplay between theoretical and experimental approaches. Evaluation of the transition states for insertion and for hydrolysis of intermediate complexes (which were emphasized in response to the experimental results) using DFT calculations at the B97D/6‐31G(d) level with the LANL2DZ basis set for rhodium revealed that: (i) the electron‐poor nature of the ligands and (ii) CH–π interactions between the ligand and coumarin substrates played significant roles in both acceleration of insertion and inhibition of ArB(OH)₂ decomposition (protodeboronation). The computationally‐designed ligand, incorporating the above information, enabled a decrease in the catalyst loading to 0.025 mol% (S/C=4,000), which is less than one one‐hundredth relative to past catalyst loadings of typically 3 mol%, with almost complete enantioselectivity. Furthermore, the gram‐scale synthesis of the urological drug, (R)‐tolterodine (l)‐tartrate, was demonstrated without the need of intermediate purification.

中文翻译：

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利用理论和实验之间的相互作用进行计算导向的配体修饰：受电子效应和CH-π相互作用控制的高活性手性铑催化剂

利用理论和实验方法之间的相互作用，开发了一种手性配体，用于铑催化的芳基硼酸不对称1,4加成到香豆素底物上，可以显着降低催化剂的负载量。使用在B97D / 6-31G（d）级别上的DFT计算以及铑的LANL2DZ基准，对中间体配合物的插入和水解的过渡态进行了评估（这是对实验结果的强调）。 ）配体的电子贫乏性质，以及（ii）配体与香豆素底物之间的CH–π相互作用在加速插入和抑制ArB（OH）_2方面均起着重要作用分解（原脱硼）。通过计算设计的配体，结合了以上信息，使催化剂负载量降低至0.025 mol％（S / C = 4,000），相对于以往催化剂负载量通常为3 mol％而言，降低了不到一百分之一。几乎完全对映选择性。此外，已证实无需中间纯化即可对泌尿科药物（R）-托特罗定（l）-酒石酸盐进行克级合成。