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

在英国的大学里，化学合成的研究传统上是一次进行一种反应，导致平均每人每天进行一种反应。因此，大量的时间、人力和耗材被投入到常规但必要的任务中，如反应优化、底物范围的探索和分子文库的合成。大量不成比例的时间花在低价值的活动上，如处理、准备和数据收集，而不是花在高价值的活动上，如实际反应和随后的结果分析和解释。使用自动化工作站将大大提高这些任务的效率、产出和质量，从而使宝贵的资源重新分配给解决问题、创新和应用。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，使复杂蛋白质和DNA/RNA低聚物能够常规制备和研究。这些类型的方法是如此有用，以至于它们被授予诺贝尔奖给发现者（Merrifield, 1984; Todd, 1957; Khorana, 1968）。我们计划采用最近在英国和世界范围内创建的强大方法，并在ISYNTH自动化工作站上调整其就业。这台全自动可编程工作站可以设置（分配固体和液体），运行，并一次检测多达96个反应（每个容器的容量高达8ml）。然后，工作站可以纯化产物（通过水萃取模块或过滤模块），并将其作为进一步反应的起始材料（通过自动蒸发和在新鲜溶剂中溶解），从而实现分子库的多步骤合成。反应可以在惰性气氛下，在高压反应气体下，在-70℃至+200℃的任何温度下进行，并将与超高效液相色谱/质谱（UHPLC-MS）相连接，用于快速和高通量在线（在线）分析反应混合物。因此，设想的装置能够使现代合成中使用的大多数类型的反应自动化。对于用户来说，它只需要加载原材料，输入一组命令，然后离开。即使是有机合成的一小部分也能以这种方式进行，它可能会产生与自动肽和寡核苷酸合成一样大的影响。有机反应的自动化优化和化合物库的自动化合成将显著提高效率和产量。此外，从优化反应中产生的高质量数据将用于多维计算，最终将用于设计和预测反应结果。高质量的反应装置、数据收集、分析和计算之间的协同作用将成为我们设施的关键组成部分，这将使这些预测变得有意义。

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.