GOALI: Utilizing Rapid Assays for Determining Enantiomeric Excess and Catalyst Discovery in Pharma

开发新药仍然是对抗癌症和心脏病等疾病的主要战略。由于新的和现代的实验方法的出现，对于合成和快速评估用于制药工业的新分子的日益简单和快速的方法的需求已经出现。 药物开发过程需要每天进行数千次化学反应。不幸的是，验证合成分子的结构和纯度所需的标准分析方法通常很慢，无法以这样的速度运行。在这个项目中，Anslyn小组以前报告的新的快速光学技术正在用于全球制药公司默克进行的典型工作流程的现实生活中的筛选协议。德克萨斯大学-默克公司的这项合作测试了这些方法的实用性和通用性，同时也强调了它们在制药以外的应用中有益于工业相关的合成有机化学工作的能力。默克团队向Anslyn小组提供他们的反应，而Anslyn小组向默克提供他们的分析方法。Anslyn涉及学生团队在一个新生研究计划和先进的研究计划实验室在平行项目，与他的研究生研究相同的目标和可交付成果。 这些活动包括专门的实验室课程，教授大一学生科学发现的挑战和回报，同时提高这些学生在STEM课程中的保留率。在NSF化学部门的资助下，德克萨斯大学奥斯汀分校的Anslyn博士与默克公司合作设计和开发对映体过量（ee）的快速化学测定，包括三个阶段，称为筛选，训练和分析。筛选利用先前报道的Anslyn多组分组件，通过圆二色性（CD）报告ee值。训练是用手性分析物的对映体富集的样品进行的，并且根据需要涉及标准线性校准曲线或化学计量学分析。这一步创建了一个特定的分析方案，将产生的CD椭圆率与ee相关联。最后，分析步骤以真正高通量的方式确定ee值，与每小时数百个样品的速率相称。这些协议中的每一个都是针对制药界感兴趣的分析物类型而创建的。除了药物相关的化合物，显著的努力是针对解决工业使用的复杂基质中的样品。德克萨斯大学奥斯汀分校的研究生熟悉制药行业内支持高通量实验（HTE）所需的仪器和过程。通过每季度访问默克，这些学生通过与工业科学家的互动，了解与这种方法相关的实际挑战。在整个过程中，默克的科学家们确定了新的底物和反应类别，这些底物和反应类别最有可能对不对称合成产生积极影响。

The creation of new pharmaceuticals remains a primary strategy to combat disease, such as cancer and heart disease. The need for increasingly simple and rapid methods to synthesize and quickly evaluate new molecules for the pharmaceutical industry has arisen due to the advent of new and modern experimental methods. The drug development process requires thousands of chemical reactions to be conducted each and every day. Unfortunately, standard analytical methods needed to verify the structure and the purity of the molecules synthesized are often slow and unable to operate at such a pace. In this project, new and rapid optical techniques reported previously by the Anslyn group are being employed in real-life screening protocols typical of the workflow carried out at Merck, a global pharmaceutical company. This University of Texas-Merck collaboration tests the utility and generality of the methods, while also highlighting their power to benefit industrially-relevant, synthetic organic chemistry efforts in applications beyond pharmaceuticals. The Merck team provides their reactions to the Anslyn group, while the Anslyn group provides their analytical methods to Merck. Dr. Anslyn involves teams of students in a Freshman Research Initiative and Advanced Research Initiative laboratory in parallel projects, with the same goals and deliverables as his graduate research. These activities involve specialized laboratory courses that teach freshman college students the challenges and rewards of scientific discovery, while improving the retention rates of these students in STEM curricula.With funding from the NSF Chemistry Division, Dr. Anslyn of the University of Texas at Austin working with Merck to design and develop rapid chemical assays for enantiomeric excess (ee) that involve three stages referred to as screening, training, and analysis. The screening exploits the previously reported Anslyn multi-component assemblies that report ee values via circular dichroism (CD). The training is performed with enantioenriched samples of the chiral analyte, and involves standard linear calibration curves or chemometric analysis, as necessary. This step creates a protocol specific to a particular analyte, relating the resultant CD ellipticities to ee. Finally, the analysis step determines ee values in a truly high-throughput fashion, commensurate with a rate of hundreds of samples every hour. Each of these protocols is being created for the types of analytes that are of interest to the pharmaceutical community. In addition to the pharmaceutically-relevant compounds, significant effort is directed toward addressing samples in the complex matrices that industry uses. Graduate students at the University of Texas at Austin become familiar with the instrumentation required for and the processes undertaken to support high-throughput experimentation (HTE) within the pharmaceutical industry. Via quarterly visits to Merck, these students gain an understanding for the practical challenges associated with this approach through interaction with industrial scientists. Throughout the process, the scientists from Merck identify new substrates and reaction classes that have the greatest potential to positively impact asymmetric synthesis.