Ligand engineering is one of the most important, but labor-intensive processes in the development of transition metal catalysis. Historically, this process has been streamlined by the invention of ligand descriptors such as Tolman’s electronic parameter and the cone angle. Analyzing reaction outcomes in terms of these parameters has enabled chemists to find important factors for designing optimal ligands. However, typical strategies for these analyses largely rely on regression approaches, which often requires many experimental data to understand non-intuitive trends. Here, we introduce the virtual ligand-assisted optimization (VLAO) method, a novel computational approach for ligand engineering. In this method, important features of ligands are identified by simple mathematical operations on equilibrium structures and/or transition states of interest, and derivative values of arbitrary objective functions with respect to ligand parameters are obtained. These derivative values are then used as a guiding principle to optimize ligands within the parameter space. The VLAO method was demonstrated in the optimization of monodentate and bidentate phosphine ligands including asymmetric quinoxaline-based ligands. In addition, we successfully found a highly selective ligand for the α-selective hydrogermylation of a terminal ynamide according to the suggested design principle by the VLAO method. These results would imply the potential utility of the VLAO method in optimizing wide variety of ligands in transition metal catalysis.

中文翻译：

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虚拟配体辅助优化：配体工程的合理策略

配体工程是过渡金属催化开发中最重要但劳动密集型的过程之一。从历史上看，这个过程已经通过配体描述符（例如托尔曼电子参数和锥角）的发明而简化。根据这些参数分析反应结果使化学家能够找到设计最佳配体的重要因素。然而，这些分析的典型策略很大程度上依赖于回归方法，这通常需要大量实验数据来理解非直观趋势。在这里，我们介绍虚拟配体辅助优化（VLAO）方法，这是一种新颖的配体工程计算方法。在该方法中，通过对感兴趣的平衡结构和/或过渡态进行简单的数学运算来识别配体的重要特征，并获得任意目标函数相对于配体参数的导数值。然后将这些导数值用作优化参数空间内的配体的指导原则。 VLAO 方法在单齿和双齿膦配体（包括不对称喹喔啉基配体）的优化中得到了证明。此外，我们根据VLAO方法建议的设计原理，成功找到了用于末端ynamide的α选择性氢甲酰化的高选择性配体。这些结果意味着 VLAO 方法在优化过渡金属催化中的各种配体方面具有潜在的用途。