Refining & Implementing Supramolecular Methods for HTS of EE & Concentration

精制

基本信息

批准号：
7987195
负责人：
Eric V. Anslyn
金额：
$ 32.42万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2014-08-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：最近出现了越来越多的用户友好型和快速测定的EE测定，这是由于高通量筛选（HTS）协议的出现，以进行不对称的反应发现和优化。许多研究需要数百个分析，但是真正的高通量筛查必须每天容纳数千种测定。目前广泛接受的EE分析方法是不可能的。这种更新应用的主要目的是实施我们先前开发的对对映体过量（EE）（EE）和催化不对称反应筛查中的反应产率的高通量筛选测定。在这个项目中，我们将率先将光学HTS方法的过渡到合成方法学化学家的工作实验室。我们对EE HTS的方法将超分子化学与化学计量学结合。我们创建了非常简单的合成受体，该受体针对的是手性官能团的类别，并记录对非对映异构体或对映体复合物形成的吸光度或圆形二分法光谱。 LDA，PCA或ANN解释光学数据。该分析是在微量滴定板中进行的，其中EE值以及浓度（反应产量），可在1分钟至2小时内根据特定的测定法读取96种粗反应混合物。在下一个资金期间，我们的第一个目标是为几乎是手术的手性官能团（原代胺，羧酸和酮）完成一些测定，我们将为手性二级醇设计一个测定法。其次，为了在现实生活环境中实施我们的测定法，我们已经与合成方法学化学家建立了三个合作：Drs。 Zhang（Rutgers），Miller（Yale）和Krische（UT Austin）。这三个项目将在非对称催化反应发现和优化中实施用于原代胺，羧酸和次生醇的HTS分析。因此，该提议是高度转化的。我们的协作努力将测试我们方法的效用和通用性，同时还强调了超分子化学和化学计量学对合成有机化学工作的力量。公共卫生相关性：部分依赖于药物。创建药物的合成程序涉及的步骤，这些步骤形成右手和左手的化学结构，称为对映异构体。 NIH应用程序中描述的工作通过创建新的，更快的方法来分析药物开发过程中创建的对映异构体的比率来改善公共卫生。