New photocatalytic methods for the synthesis of complex heterocyclic scaffolds and base metal-catalysed cross-coupling

这个项目属于EPSRC合成有机化学的研究领域。自从它在大约十年前兴起以来，光氧化还原催化已经迅速发展成为合成有机化学中的一种强有力的工具，在放射性标记、聚合物制造和天然产物的全合成等领域有着广泛的应用。除了为传统的光化学方法提供一种温和的替代方法外，可见光催化剂提供的独特的反应模式正在从根本上改变有机化学家设计新反应和断开目标分子的方式。在这方面，可见光催化在有机合成中尚未开发的巨大潜力是一条重要的研究途径，特别是考虑到越来越需要“更绿色”的化学来确保大规模化学制造的长期可持续性。在这个项目中，我们的目标是利用可见光催化中几个未被开发的反应平台来开发新的、广泛适用于制药、农业化学和精细化工行业的合成方法。首先，我们的目标是开发能够提供进入以前未知的三维化学空间的新型光催化级联过程。这种方式快速产生的分子复杂性与小分子药物设计特别相关，在小分子药物设计中，包含高比例SP3杂化原子的临床候选药物比目前主导商业片段文库的“扁平”、富含Sp2的支架更有可能成功。我们预计，最近出现的强还原有机染料光催化剂将有助于在这种转化中使用顽固的底物，如芳基碘，这比基于贵金属的光催化剂具有显著的成本优势。此外，我们将未活化的有机卤化物引入氧化还原中性光催化循环的策略将克服目前涉及这些容易获得的化合物的最新转化的局限性，这些化合物通常是净还原的。我们还试图确定由铜和其他容易获得的过渡金属催化的新的可见光诱导的C-C和C-杂原子键形成反应。过渡金属催化是一种广泛的交叉偶联反应的成熟策略；然而，这种活化模式通常依赖于昂贵且不可持续的催化剂。因此，迫切需要温和和立体选择性的方法进行工业上相关的偶联反应，避免高温和钯等贵金属，以提高大规模化学过程的成本和能源效率。为了解决这个问题，我们试图开发由廉价的贱金属催化剂(如铜)催化的新的光化学方法，用于不同反应伙伴的偶联；原则上，这些反应可以在金属光氧化还原催化(光氧化还原和过渡金属催化的融合)下进行，或者通过直接激发光响应性的过渡金属络合物来进行，这是相对未被探索的。

This project falls within the EPSRC Synthetic Organic Chemistry research area.Since its rise to prominence roughly a decade ago, photoredox catalysis has rapidly evolved into a powerful tool in synthetic organic chemistry, with applications in fields as diverse as radiolabelling, polymer manufacture, and the total synthesis of natural products. In addition to providing a milder alternative to traditional photochemical methods, the unique modes of reactivity offered by visible light photocatalysts are fundamentally changing the ways in which organic chemists approach the design of new reactions and the disconnection of target molecules. In this respect, the vast untapped potential of visible light photocatalysis in organic synthesis represents an important avenue of research, especially considering the growing need for 'greener' chemistry to ensure the long-term sustainability of large-scale chemical manufacture. In this project, we aim to exploit several underexplored reactivity platforms in visible light photocatalysis to enable the development of new, broadly applicable synthetic methods of interest to the pharmaceutical, agrochemical and fine chemical industries.In the first instance, we aim to develop novel photocatalytic cascade processes capable of providing access to previously uncharted 3-D chemical space. The rapid generation of molecular complexity in this manner is particularly relevant to small-molecule drug design, where clinical candidates containing a high fraction of sp3-hybridized atoms are more likely to succeed than the 'flat', sp2-rich scaffolds that presently dominate commercial fragment libraries. We envisage that the use of recalcitrant substrates such as aryl iodides in such transformations will be facilitated by the recent advent of strongly reducing organic dye photocatalysts, which present significant cost advantages over their precious metal-based counterparts. Moreover, our strategy for engaging unactivated organyl halides in a redox-neutral photocatalytic cycle will overcome the current limitations of state-of-the-art transformations involving these readily available compounds, which are typically net-reductive.We also seek to identify new visible light-induced C-C and C-heteroatom bond-forming reactions catalysed by copper and other readily available transition metals. Transition metal catalysis is a well-established strategy for a wide range of cross-coupling reactions; however, this mode of activation typically relies on costly and unsustainable catalysts. Mild and stereoselective methods for industrially relevant coupling reactions that avoid high temperatures and precious metals such as palladium are therefore urgently needed to improve the cost and energy efficiency of large-scale chemical processes. We seek to address this problem by developing new photochemical methods catalysed by inexpensive base metal catalysts, such as copper, for the coupling of diverse reaction partners; in principle, these reactions could operate under metallaphotoredox catalysis (the fusion of photoredox and transition metal catalysis) or via the direct excitation of a photoresponsive transition metal complex, which is relatively unexplored.