Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.
Data Science and Modelling, Pharmaceutical Sciences, R&D, AstraZeneca Gothenburg, Pepparedsleden 1, Mölndal SE-431 83, Sweden.
J Org Chem. 2022 Sep 16;87(18):12334-12341. doi: 10.1021/acs.joc.2c01553. Epub 2022 Sep 6.
Ferrocene derivatives have a wide range of applications, including as ligands in asymmetric catalysis, due to their chemical stability, rigid backbone, steric bulk, and ability to encode stereochemical information via planar chirality. Unfortunately, few of the available molecular mechanics force fields incorporate parameters for the accurate study of this important building block. Here, we present a MM3* force field for ferrocenyl ligands, which was generated using the quantum-guided molecular mechanics (Q2MM) method. Detailed validation by comparison to DFT calculations and crystal structures demonstrates the accuracy of the parameters and uncovers the physical origin of deviations through excess energy analysis. Combining the ferrocene force field with a force field for Pd-allyl complexes and comparing the crystal structures shows the compatibility with previously developed MM3* force fields. Finally, the ferrocene force field was combined with a previously published transition-state force field to predict the stereochemical outcomes of the aminations of Pd-allyl complexes with different amines and different chiral ferrocenyl ligands, with an of ∼0.91 over 10 examples.
二茂铁衍生物具有广泛的应用，包括作为不对称催化中的配体，因为它们具有化学稳定性、刚性骨架、空间位阻和通过平面手性编码立体化学信息的能力。然而，可用的分子力学力场中很少有参数可以准确研究这个重要的结构单元。在这里，我们提出了一种用于二茂铁配体的 MM3力场，该力场是使用量子引导的分子力学（Q2MM）方法生成的。通过与 DFT 计算和晶体结构的详细比较验证表明，参数的准确性和通过过剩能分析揭示偏差的物理起源。将二茂铁力场与 Pd-烯丙基配合物的力场相结合，并比较晶体结构表明与先前开发的 MM3力场具有兼容性。最后，将二茂铁力场与先前发表的过渡态力场相结合，预测不同胺和不同手性二茂铁配体与 Pd-烯丙基配合物的胺化的立体化学结果，在 10 个实例中，的平均值为 0.91。
