Predictive modeling of optical enantiomeric excess determination assays for high-throughput asymmetric reaction screening

Howard, James Russell
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High-throughput screening (HTS) of asymmetric transformations is vital to the development of modern pharmaceuticals and fine chemicals. Enantiomeric excess (ee) determination of asymmetric transformations is accelerated through the use optical techniques such as circular dichroism (CD)-based ee determination assays. However, the implementation of these assays requires calibration experiments using enantioenriched materials, which ultimately hinder the use of these assays in real-world applications. We report the prediction of calibration curves used in ee determination assays for chiral amines using a data-driven approach. By leveraging density functional theory-based chemical descriptors, we have developed a model that predicts calibration curves without performing prior calibration experiments. This calibration curve prediction method was applied to a multicomponent ortho-iminoboronic acid assembly. The ee values measured with the predicted calibration curves were within 10% of those measured with the experimental calibration curves. The generality of this approach was demonstrated using an octahedral Fe(II) complex for the ee determination of chiral amines. A diverse library of analytes was created to elucidate the electronic and steric factors which influence the CD response of the Fe(II) complex. After assessing the scope and limitations of the assay, we generated a model of calibration curves which could be used to determine the ee of unknown solutions with less than 6% error. This computational approach circumvents the need for chiral resolution to perform calibration experiments, which will ultimately accelerate reaction discovery and optimization.