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Automating the Synthetic Chemistry Landscape in Bristol: Accelerating Impact and Application

布里斯托尔合成化学景观自动化：加速影响和应用

基本信息

批准号：
EP/R008795/1
负责人：
Varinder Aggarwal
金额：
$ 97.72万
依托单位：
University of Bristol
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FR008795%2F1
关键词：
Automating Synthetic Chemistry Landscape Bristol

项目摘要

In universities across the UK, research devoted to chemical synthesis is traditionally pursued one reaction at a time leading to an average of one reaction being conducted per day per person. Therefore, an unacceptably large portion of time, manpower and consumables is devoted to the routine yet necessary tasks of reaction optimisation, the exploration of substrate scope and the synthesis of molecular libraries. A large and disproportionate amount of time is spent low-value activities such as handling, preparation and data collection rather than on high-value activities such as the actual reaction and the subsequent analysis and interpretation of results. Access to an automated workstation would significantly increase the efficiency, output and quality of these tasks thus allowing valuable resource to be reallocated to problem-solving, innovation and application.The development of simple and robust automated methods for peptide and oligonucleotide (and to some extent oligosaccharide) synthesis revolutionised the field enabling complex proteins and DNA/RNA oligomers to be prepared routinely and studied. These types of methodology were so useful that they were recognised by the award of Nobel prizes to the discoverers (Merrifield, 1984; Todd, 1957, Khorana 1968). We plan to employ recently created robust methodology that has been created in the UK and world-wide and adapt its employment on an ISYNTH Automated Workstation. This fully automated and programmable workstation can setup (dispense solids and liquids), run, and workup as many as 96 reactions at a time (up to an 8 mL volume for each vessel). The workstation can then purify products (through an aqueous extraction module or through a filtration module) and subject them as starting materials for further reactions (through automated evaporation and dissolution in fresh solvent), thus enabling multistep synthesis of libraries of molecules. The reactions can be set up under an inert atmosphere, under high pressure of reactive gases, at any temperatures from -70 C to +200 C and will be interfaced with an ultra-high-performance liquid chromatography/mass spectrometry (UHPLC-MS) for rapid and high-throughput in-line (online) analysis of reaction mixtures. The envisaged set-up is thus capable of automating most types of reactions that are employed in modern synthesis. For the user, it involves just loading raw materials, keying in a set of commands and walking away. If, even a fraction of organic synthesis can be conducted in this way it could have as big an impact as automated peptide and oligonucleotide synthesis.Automating the optimisation of organic reactions and automating the synthesis of compound libraries will improve efficiency and throughput dramatically. Furthermore, the increased high-quality data that will emerge from optimisation reactions will feed into multi dimension computations that ultimately will be used to design and predict reaction outcomes. The synergy between high-quality reaction setup, data collection, analysis and computation, which will be key components of our facility, will enable such predictions to become meaningful.

在英国的大学里，致力于化学合成的研究传统上是一次进行一个反应，导致平均每人每天进行一个反应。因此，不可接受的大部分时间、人力和消耗品被用于反应优化、底物范围的探索和分子库的合成的常规但必要的任务。大量不成比例的时间花在低价值活动上，如处理、准备和数据收集，而不是花在高价值活动上，如实际反应和随后对结果的分析和解释。使用自动化工作站将显著提高这些任务的效率、产量和质量，从而使宝贵的资源重新分配到解决问题、创新和应用上。肽和寡核苷酸（以及某种程度上的寡糖）合成的简单而强大的自动化方法的发展彻底改变了该领域，使复杂的蛋白质和DNA/RNA寡聚体能够常规制备和研究。这些类型的方法是如此有用，他们被授予诺贝尔奖的发现者（梅里菲尔德，1984年;托德，1957年，Khorana 1968年）。我们计划采用最近创建的强大的方法，已在英国和世界范围内创建，并适应其就业ISYNTH自动化工作站。这款全自动可编程工作站可以一次设置（分配固体和液体）、运行和处理多达96个反应（每个容器最多8 mL体积）。然后，工作站可以纯化产物（通过水提取模块或通过过滤模块），并将其作为进一步反应的起始材料（通过自动蒸发和溶解在新鲜溶剂中），从而实现分子库的多步合成。反应可以在惰性气氛下、反应气体的高压下、在-70 ° C至+200 ° C的任何温度下进行，并将与超高效液相色谱/质谱（UHPLC-MS）连接，用于反应混合物的快速和高通量在线（在线）分析。因此，设想的设置能够自动化现代合成中使用的大多数类型的反应。对于用户来说，它只需要加载原材料，键入一组命令并走开。如果有机合成的一小部分可以通过这种方式进行，那么它可能会产生与自动化肽和寡核苷酸合成一样大的影响。自动优化有机反应和自动合成化合物库将大大提高效率和产量。此外，从优化反应中产生的高质量数据将输入多维计算，最终将用于设计和预测反应结果。高质量的反应设置，数据收集，分析和计算之间的协同作用，这将是我们设施的关键组成部分，将使这种预测变得有意义。