This Perspective highlights the advances of optical methods for asymmetric reaction discovery. Optical analysis allows for the determination of absolute configuration, enantiomeric excess and reaction yield that is amenable to high-throughput experimentation. Thus, the synthetic organic community is encouraged to incorporate the methods discussed to expedite the development of high-yielding, enantioselective transformations.
Pyridoxal-5'-phosphate (PLP) is introduced to a biomimetic indicator displacement assay for simultaneous determination of the absolute configuration, enantiomeric composition and concentration of unprotected amino acids, amino alcohols and amines. The chiroptical assay is based on fast imine metathesis with a PLP aryl imine probe to capture the target compound for circular dichroism and fluorescence sensing analysis. The substrate binding yields characteristic Cotton effects that provide information about the target compound ee and the synchronous release of the indicator results in a nonenantioselective off-on fluorescence response that is independent of the enantiomeric sample composition and readily correlated to the total analyte concentration.
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.
A novel
approach to chiral recognition of small molecules using
the classical ninhydrin agent is introduced. Well-defined dynamic
covalent chemistry with amines and amino alcohols was developed and
applied to quantitative ee sensing with good accuracy
using a straightforward mixing protocol and subsequent circular dichroism
measurements. This chiroptical assay is fast, broadly useful, practical
and repurposes an inexpensive reagent known for more than 100 years
in a new application.
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