Quantitative Chiral Analysis by Chiral Tag Rotational Spectroscopy

在化学系化学测量和成像项目的支持下，弗吉尼亚大学的布鲁克斯佩特教授和他的研究小组正在解决与含有不能与其镜像重叠的分子的样品的定量分析相关的挑战：即“手性”分子，类似于人的右手和左手。 手性分子（包括许多药物和大多数天然生物分子）的化学性质和相互作用敏感地依赖于它们的手性或“手性”。“例如，药物的不同手性形式可能具有根本不同的功效和副反应，尽管它们在其他方面具有相似的结构和性质。 因此，手性分析是至关重要的，尽管它通常是药物开发和制造中困难、耗时且通常昂贵的部分。 Pate集团正在开拓快速手性分析的新方法。 该工作使本科生和研究生接触到最先进的分析方法。这项工作的一个具体重点是开发一种化学测量技术，可以对具有多个手性中心的分子的立体异构体进行定量分析。 这个问题是具有挑战性的，因为它需要非对映异构体（具有不同分子几何形状的异构体）和每个非对映异构体（对映异构体）的不可重叠的镜像。 通常，需要不同的光谱和/或色谱技术来进行非对映异构体和对映异构体分析。 Pate小组正在开发一种更简单的方法，该方法基于使用手性标签的旋转光谱学-具有非共价连接到目标分析物的手性中心的小分子。 精确的量子化学计算可以确定测量中记录的每个光谱的基础对映体。 对映异构体的比例通过当使用手性标签的外消旋和对映体纯样品进行测量时观察到的光谱强度的变化来确定。 除了验证概念的原理验证测量外，该团队还在探索设计手性标签分子的化学想法，以提高分析速度、可靠性和应用范围。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

With support from the Chemical Measurement and Imaging Program in the Division of Chemistry, Professor Brooks Pate and his research group at the University of Virginia are addressing challenges associated with the quantitative analysis of samples containing molecules not superimposable on their mirror image: i.e. "chiral" molecules, analogous to a person's right and left hand. The chemistry and interactions of chiral molecules - including many pharmaceuticals and most natural biomolecules - can depend sensitively on their chirality or "handedness." For example, the different chiral forms of a drug can have radically different efficacy and side reactions, despite their otherwise similar structure and properties. As a result, analysis of chirality is critically important, although it is generally a difficult, time-consuming, and often costly part of drug development and manufacture. The Pate group is pioneering new methods for rapid chiral analysis. The work exposes undergraduate and graduate students to state-of-the-art analysis methods.A specific focus of this work is to develop a chemical measurement technique that can perform quantitative analysis of the stereoisomers of a molecule with multiple chiral centers. The problem is challenging because it entails both diastereomers (isomers with distinct molecular geometries) and the non-superimposable mirror images of each diastereomer (enantiomers). Conventionally, different spectroscopic and/or chromatographic techniques are needed to perform both diastereomer and enantiomer analysis. The Pate group is developing a much simpler approach based on rotational spectroscopy using chiral tags - small molecules with chiral centers attached non-covalently to the target analyte(s). Accurate quantum chemistry calculations make it possible to determine the base enantiomer responsible for each spectrum recorded in the measurement. The ratio of enantiomers is determined by changes in spectral intensity observed when the measurement is performed using racemic and enantiopure samples of the chiral tag. In addition to proof-of-principle measurements to validate the concept, the team is exploring chemical ideas for designing chiral tag molecules that can improve analysis speed, reliability, and scope of application.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.