Refining & Implementing Supramolecular Methods for HTS of EE & Concentration

描述（由申请人提供）：由于用于不对称反应发现和优化的高通量筛选（HTS）方案的出现，最近出现了对ee的日益用户友好和快速测定的需求。许多研究需要数百次分析，但真正的高通量筛选每天必须容纳数千次分析。这是不可能的方法，目前被广泛接受的ee分析。 本更新申请的主要目标是实现我们以前开发的高通量筛选分析对映体过量（ee）和催化不对称反应筛选中的反应产率。在这个项目中，我们将开创一个过渡的光学高温超导方法的合成方法化学家的工作实验室。 我们的方法结合了超分子化学和化学计量学的ee的高温超导。我们创建了非常简单的合成受体，其针对手性官能团的类别，并记录非对映体或对映体复合物形成的吸光度或圆二色性光谱。LDA、PCA或ANN解释光学数据。在微量滴定板中进行分析，其中96种粗反应混合物的ee值以及浓度（反应产率）可以在1分钟至2小时内读取，这取决于具体的测定。 在下一个资助期间，我们的第一个目标将是完成几个几乎可操作的手性官能团（伯胺，羧酸和酮）的测定，我们将设计一个手性仲醇的测定。其次，为了在真实的生活环境中实施我们的测定，我们与合成方法化学家建立了三个合作：Zhang博士（罗格斯大学），米勒（耶鲁大学）和Krische（UT奥斯汀）。这三个项目将在不对称催化反应发现和优化中实施我们对伯胺、羧酸和仲醇的HTS测定。 因此，这一建议是高度翻译的。我们的合作努力将测试我们的方法的实用性和通用性，同时也突出了超分子化学和化学计量学的力量，以协助合成有机化学的努力。 公共卫生相关性：部分依赖于药物。制造药物的合成过程涉及形成右手和左手化学结构的步骤，称为对映体。在NIH申请中描述的工作通过创建新的和更快的方法来分析药物开发过程中产生的对映异构体的比例来改善公共健康。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.