The need for increasingly user-friendly and rapid assays for ee has arisen recently due the advent of high-throughput screening (HTS) protocols for asymmetric reaction discovery and optimization. Many studies require hundreds of analyses, but true high-throughput screening must accommodate thousands of assays per day. This is not possible with the methods that are currently widely accepted for ee analysis. A primary goal of this renewal application is to implement our previously developed high-throughput screening assays for enantiomeric excess (ee) and reaction yield in catalytic asymmetric reaction screening. In this project we will pioneer a transition of optical HTS methods to the working laboratories of synthetic methodology chemists. Our approach to the HTS of ee combines supramolecular chemistry with chemometrics. We create very simple synthetic receptors that are targeted to classes of chiral functional groups, and record absorbance or circular dichroism spectra for diastereomeric or enantiomeric complex formation. LDA, PCA, or ANN interprets the optical data. The analysis is performed in microtiter plates where the ee values, as well as concentration (reaction yield), of 96 crude reaction mixtures can be read within 1 minute to 2 hrs depending upon the particular assay. During the next funding period our first goal will be to complete a few assays for chiral functional groups that are almost operational (primary amines, carboxylic acids, and ketones), and we will devise an assay for chiral secondary alcohols. Second, to implement our assays in real life settings we have established three collaborations with synthetic methodology chemists: Drs. Zhang (Rutgers), Miller (Yale), and Krische (UT Austin). These three projects will implement our HTS assays for primary amines, carboxylic acids, and secondary alcohols, in asymmetric catalytic reaction discovery and optimization. Hence, this proposal is highly translational. Our collaborative efforts will test the utility and generality of our methods, while also highlighting the power of supramolecular chemistry and chemometrics to assist synthetic organic chemistry efforts.
is in part reliant upon pharmaceuticals. The synthetic procedures that create pharmaceuticals involve steps, which form right- and left-handed chemical structures, called enantiomers. The work described in this NIH application improves public health by creating new and faster methods for analyzing the ratios of enantiomers created during pharmaceutical development.
|Lin, Chung-Yon; Giuliano, Michael W; Ellis, Bryan D et al. (2016) From Substituent Effects to Applications: Enhancing the Optical Response of a Four-Component Assembly for Reporting EE Values. Chem Sci 7:4085-4090|
|Chen, Xuan-Xuan; Jiang, Yun-Bao; Anslyn, Eric V (2016) A racemate-rules effect supramolecular polymer for ee determination of malic acid in the high ee region. Chem Commun (Camb) 52:12669-12671|
|Wu, Weilong; Liu, Shaodong; Duan, Meng et al. (2016) Iridium Catalysts with f-Amphox Ligands: Asymmetric Hydrogenation of Simple Ketones. Org Lett 18:2938-41|
|Brittain, William D G; Chapin, Brette M; Zhai, Wenlei et al. (2016) The Bull-James assembly as a chiral auxiliary and shift reagent in kinetic resolution of alkyne amines by the CuAAC reaction. Org Biomol Chem 14:10778-10782|
|Lin, Chung-Yon; Lim, Stephanie; Anslyn, Eric V (2016) Model Building Using Linear Free Energy Relationship Parameters-Eliminating Calibration Curves for Optical Analysis of Enantiomeric Excess. J Am Chem Soc 138:8045-7|
|Giuliano, Michael W; Lin, Chung-Yon; Romney, David K et al. (2015) A Synergistic Combinatorial and Chiroptical Study of Peptide Catalysts for Asymmetric Baeyer-Villiger Oxidation. Adv Synth Catal 357:2301-2309|
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|Dragna, Justin M; Gade, Alexandra M; Tran, Lee et al. (2015) Chiral amine enantiomeric excess determination using self-assembled octahedral Fe(II)-imine complexes. Chirality 27:294-8|
|Jo, Hyun Hwa; Edupuganti, Ramakrishna; You, Lei et al. (2015) Mechanistic Studies on Covalent Assemblies of Metal-Mediated Hemi-Aminal Ethers. Chem Sci 6:158-164|
|Zhao, Qingyang; Wen, Jialin; Tan, Renchang et al. (2014) Rhodium-catalyzed asymmetric hydrogenation of unprotected NH imines assisted by a thiourea. Angew Chem Int Ed Engl 53:8467-70|
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