High-Throughput Determination of Enantiopurity by Microplate Circular Dichroism

Methods for the rapid determination of enantiomeric excess (ee) in asymmetric synthetic methodology development are increasingly in demand as high-throughput experimentation protocols in academia and industry are adopted. Optical approaches have been reported, many of which rely on the use of chemical derivatization or molecular assemblies, resulting in UV/vis, fluorescence, or circular dichroism (CD) signals that report the ee values. While UV/vis and fluorescence approaches benefit from readily available 96- and 384-well plate readers, until recently, no CD plate readers existed. Herein, we report the utility of using the EKKO CD plate reader to analyze a chlorocoumarin amine derivatization methodology for the ee determination of a diverse set of chiral amines with an error margin within ±7%. Linear calibration curves of ee versus CD responses for each amine were obtained, the minimum detectable and quantifiable ee values were calculated, the technique was applied to an asymmetric hydrogenation, and various interferents expected to be present in crude samples are explored. The technique described herein is found to be suitable for high-throughput experimentation that requires a parallel and rapid ee determination step.