The development of optical methods for rapid asymmetric reaction screening : characterizing enantiomeric excess, diastereomeric excess and reaction yield




Herrera, Brenden Tate

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In the past twenty years, optical methods for asymmetric reaction characterization have had much success. Optical protocols allow for the determination of enantiomeric excess (ee) and reaction yield of transformations that are amenable to high-throughput experimentation. Chapter 1 highlights the advances of optical methods for determining ee and reaction yield. Despite the extensive success of these methods, few reports of optical assays for both enantiomers and diastereomers have been demonstrated. Such methods could be applied to an asymmetric reaction that sets two stereocenters in the same transformation, where the ee, diastereomeric excess (de) and reaction yield would be needed for complete asymmetric reaction characterization. Chapter 2 discusses the derivation of a mathematical relationship for relating the enantiomeric ratios of two individual stereocenters within a single chiral molecule to the diastereomeric ratio. Further, mathematical relationships are given for determining complete stereoisomer speciation with the knowledge of individual stereocenter ee values and a de value. Chapter 3 describes the first example of the use of optical methods for determining the ee, de, and total concentration of 2-aminocyclohexanol, where the complete stereoisomeric speciation was accomplished with an average absolute error of 4%. The procedure presented would allow for the total speciation of approximately 100 reactions in 30 minutes using a high-throughput experimentation routine. Chapter 4 details the progress made towards screening a stereodivergent biocatalytic transformation catalyzed by ketoreductases using optical methods. Chapter 5 describes workflows that have been developed for characterizing the success of transformations that set a single stereocenter, specifically a metalloenzyme-catalyzed aziridination and a ketoreductase-mediated reduction.



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