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

创造新的药物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，出现了对用于制药工业的合成和快速评估新分子的日益简单和快速的方法的需求。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往往很慢，无法以这样的速度运行。在这个项目中，安斯林集团之前报告的新的快速光学技术正被用于全球制药公司默克公司执行的典型工作流程的真实筛选方案中。德克萨斯大学和默克公司的合作测试了这些方法的实用性和通用性，同时也突显了它们在制药以外的应用中造福于工业相关的合成有机化学努力的力量。默克团队向安斯林小组提供他们的反应，而安斯林小组向默克提供他们的分析方法。安斯林博士让新生研究计划和高级研究计划实验室的学生团队参与平行项目，他们的目标和交付成果与他的研究生研究相同。这些活动包括专门的实验室课程，向一年级大学生传授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。在美国国家科学基金会化学部的资助下，德克萨斯大学奥斯汀分校的安斯林博士与默克公司合作，设计和开发了对映体过量(Ee)的快速化学分析，包括筛选、培训和分析三个阶段。该筛查利用了先前报道的Anslyn多组分组件，这些组件通过圆二色谱(CD)报告ee值。训练是用手性分析物的对映体富集物样品进行的，必要时涉及标准线性校准曲线或化学计量学分析。这一步骤创建了特定分析物的特定方案，将得到的CD椭圆度与ee相关联。最后，分析步骤以真正的高通量方式确定ee值，与每小时数百个样本的速率相称。这些方案中的每一个都是为制药界感兴趣的分析物类型创建的。除了与药物相关的化合物外，还针对工业使用的复杂基质中的样品进行了重大努力。德克萨斯大学奥斯汀分校的研究生熟悉支持制药业高通量实验(HTE)所需的仪器和进行的过程。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最有可能对不对称合成产生积极影响的新底物和反应类别。

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.