Uncovering the Unwritten-Rules in Photoredox Catalysis for Late Stage Functionalisation

光氧化还原催化为药物和类铅化合物等本已复杂的分子构筑键提供了新的途径。这种反应总管使用可见光和光催化剂在温和得多的反应条件下生成活性中间体，从而避免使用强氧化剂和还原剂。这样的反应途径使官能团具有更广泛的兼容性，为分子设计开辟了新的选择，并加速了衍生物的合成。因此，光氧化还原催化作为新药发现的一种使能技术，在药物发现过程中具有巨大的应用潜力。尽管有潜力，但当代对光氧化还原催化过程的详细理解是有限的。众所周知，由于这种化学的技术性质以及这些光驱动反应涉及的变量数量，反应可能很难重现。关键因素，如反应温度，要么鲜有报道，要么控制不力，而且变量组合异常大，涉及：光催化剂、光源、波长、试剂浓度、溶剂、反应器设计和反应器材料。其中许多变量的相互作用，例如波长和温度的影响，还没有被研究过。本项目旨在研究间歇和连续流动过程中的这些因素，以加深对光氧化还原催化和支撑反应条件的理解。我们将从研究杂环的CH官能化反应开始-这是一个重要的挑战，无论是在学术上还是与制药相关的。通过使用间歇和流动光反应器，将有可能更详细地研究反应条件，产生更多关于因素的数据，并绘制出导致成功反应的“反应空间”。在Bull集团内部工作的基础上，我们的目标是开发新的间歇式光反应器，使反应温度能够精确控制。除此之外，我们将利用这一理解，通过使用基于连续流动液滴的微反应器来产生“丰富的数据”反应。这将使我们能够进行精确控制的大量反应，并提供比目前可能的更广泛的数据。这将允许对反应变量和底物进行广泛的探索，以绘制不同底物在不同条件下的反应性，并制定明确的选择性指南，以实现复杂分子的受控后期功能化。关键词：光氧化还原催化；杂环合成；流动化学；后期功能化。

Photoredox catalysis offers new ways to construct bonds to already complex molecules such as drugs and lead-like compounds. This reaction manifold uses visible light and a photocatalyst to generate reactive intermediates under much milder reactions conditions that circumvent the use of strong oxidants and reductants. Such reaction pathways enable broader functional group compatibility, open-up new options for molecular design and accelerate the synthesis of derivatives. Photoredox catalysis therefore has enormous potential to be broadly applied in the drug discovery process as an enabling technology for the discovery of new medicines. Despite its potential, a detailed contemporary understanding of photoredox catalytic processes is limited. Reactions can be notoriously difficult to reproduce owing to the technical nature of this chemistry and the number of variables involved for these light driven reactions. Crucial factors such as the reaction temperature are either rarely reported or poorly controlled, and the combination of variables is unusually large involving: photocatalyst, light source, wavelength, reagent concentration, solvent, reactor design and reactor material. The interplay of many of these variables, effect of wavelength and temperature for example, has not been studied. This project aims to study these multiple factors in batch and continuous flow processes in order to generate a greater understanding of photoredox catalysis and the underpinning reaction conditions. We will begin by investigating CH functionalization reactions of heterocycles - an important challenge both academically and relevant to pharma. By using batch and flow photo-reactors it will be possible to study the reaction conditions in greater detail, to generate much more data on the factors and to map out the 'reaction space' that will lead to successful reactions. Building on work within the Bull group we aim to develop new batch photoreactor that will enable the accurate control of reaction temperatures. Beyond this we will leverage this understanding to generate 'data rich' reactions through the use of a continuous flow droplet based micro reactors. This will enable us to perform large numbers of reactions with precise control and provide much more extensive data than is currently possible. This will allow wide exploration of reaction variables, and also substrates, to map reactivity of different substrates under different conditions and develop clear selectivity guides towards the controlled late stage functionalisation of complex molecules.Keywords: Photoredox catalysis; heterocycle synthesis; flow chemistry; late stage functionalisation.