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)协议的出现，最近出现了对用于EE的日益用户友好和快速分析的需求。许多研究需要数百次分析，但真正的高通量筛查必须适应每天数千次的分析。对于目前被广泛接受的用于ee分析的方法，这是不可能的。这一更新应用的一个主要目标是实现我们以前开发的高通量筛选方法，用于催化不对称反应筛选中的对映体过量(Ee)和反应产率。在这个项目中，我们将率先将光学HTS方法过渡到合成方法学化学家的工作实验室。我们对ee高温超导的研究结合了超分子化学和化学计量学。我们创造了非常简单的合成受体，这些受体针对一类手性官能团，并记录了非对映异构体或对映体络合物形成的吸光度或圆二色谱。LDA、PCA或ANN解释光学数据。分析是在微滴定板中进行的，根据特定的分析，可以在1分钟到2小时内读取96个粗反应混合物的ee值以及浓度(反应产率)。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)的分析，我们将设计一种手性仲醇的分析方法。其次，为了在现实生活中实现我们的分析，我们与合成方法论化学家建立了三个合作：张博士(罗格斯大学)、米勒博士(耶鲁大学)和克里什博士(德克萨斯大学奥斯汀分校)。这三个项目将在不对称催化反应的发现和优化中实现我们对伯胺、羧酸和仲醇的高温超导分析。因此，这项建议具有很高的翻译性。我们的合作努力将测试我们方法的实用性和通用性，同时也强调超分子化学和化学计量学的力量，以帮助合成有机化学的努力。 公共卫生相关性：在一定程度上依赖于药品。制造药物的合成过程包括形成右旋和左旋化学结构的几个步骤，这些结构被称为对映体。在这份NIH申请中描述的工作通过创造新的、更快的方法来分析药物开发过程中产生的对映体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.