Catalysing 3 routes to C-H Borylation using Earth-abundant Metals

快速构建新分子结构的能力在多个领域都是必不可少的。例如，药物开发需要构建模块库，以在药物发现的早期阶段最大限度地提高多样性。同样，材料科学是建立在聚合具有功能潜力的新结构单元的能力之上的。芳基硼酸和酯满足了这一需求，是一些最常用的结构单元。它们具有空气稳定性，易于操作，具有许多成熟的功能化路线。然而，目前形成芳基硼酸酯的途径依赖于超过50年历史的低效化学，或者需要使用有毒且稀缺（因此不可持续且昂贵）的贵金属催化剂。该提案试图用利用地球上丰富的铝和锌络合物的新方法来取代这些技术。更具体地，我们将使用铝和锌基催化剂来实现简单（早期阶段）和复杂（后期阶段）分子的直接（从简单前体的一步）硼基化。催化剂的使用对于确保工艺的可持续性至关重要，因为这可以最大限度地减少每次转化所需的能量输入要求和材料量。催化是确保化学合成可持续发展的唯一最适用的方法，地球上丰富的金属用于催化大大改善了这一前景。铝和锌的使用也是由于它们相对于直接硼基化中使用的许多其它催化剂（例如Co、Ir基催化剂）的低毒性。锌和铝具有较高的每日允许接触限值，使其能够在制药生产后期使用，而无需在使用贵金属催化剂时进行彻底的金属去除。该项目将专门针对芳烃C-H键的硼基化。芳烃是具有巨大结构多样性的商品化学品，但它们缺乏进一步功能化的手柄。我们将开发铝和锌催化剂能够引入硼功能处理这些基板。铝和锌受益于许多相似的性质，包括尺寸、底物（芳烃）亲和力、电负性和在一定程度上的配位偏好，但它们基于化合物中的电荷（价态）而不同（+3 VS +2）。我们将在共同的框架内利用这两种金属，使单位电荷变化的影响进行研究，以确定关键的结构活性关系。这种深刻的理解将使广泛的芳烃C-H键硼基化得以实现。芳基硼酸酯产品是学术界和工业界使用的最常见的合成结构单元之一，因此这将确保我们开发的方法的高影响力。我们将把我们最初的突破转移到操作简单的过程中，这些过程可以很容易地被最广泛的学术和工业合成社区使用。在整个过程中，我们将得到GSK和Andrew Dominey博士（GSK工艺化学，Stevenage）的支持，他们作为该项目的共同研究者，对于开发真正有用的工艺至关重要。GSK将定期举行会议和实习，以确保我们的新开发方法在GSK的一致进展、技术转移和嵌入。除此之外，GSK的实习机会还为我们新开发的方法的真实世界测试和基准测试提供了独特的机会。在Stevenage的职位将使我们的新反应能够应用于特定的药物靶点。

The ability to construct rapidly new molecular architectures is essential across multiple fields. For example, pharmaceutical development requires a library of building blocks to maximise diversity at the early stage of drug discovery. Likewise, materials science is built on the ability to polymerise new building blocks with functional potential. Aryl boronic acids and esters satisfy this need and are some of the most commonly used building blocks. They are air-stable and easy to manipulate with many well-established routes for functionalisation. However, the current routes to form aryl boronic esters rely on inefficient chemistry that is over 50 years old or require the use of toxic and scarce (thus unsustainable and expensive) precious metal catalysts. This proposal seeks to replace these technologies with new methods using Earth-abundant aluminium- and zinc-complexes. More specifically, we will use aluminium and zinc based catalysts to achieve the direct (one step from simple precursors) borylation of simple (early stage) and complex (late stage) molecules. The use of catalysis is essential in ensuring the sustainability of processes as this minimises the energy input requirements and amount of material needed for each transformation. Catalysis offers the single most applicable method to ensure a sustainable future for chemical synthesis and the use of Earth-abundant metals for catalysis greatly improves this prospect. The use of aluminium and zinc is also driven by their low-toxicity relative to many other catalysts used in direct borylation (e.g. Co, Ir based catalysts). Zinc and aluminium have high daily permitted exposure limits enabling their use late in pharmaceutical manufacturing without the need for exhaustive metal removal required when using precious metal catalysts. This project will specifically target the borylation of arene C-H bonds. Arenes are commodity chemicals with great structural diversity, but they lack handles for further functionalisation. We will develop aluminium- and zinc catalysts capable of introducing a boronic functional handle to these substrates. Aluminium and zinc benefit from many similar properties including, size, substrate (arene) affinity, electronegativity and, to some extent, coordination preferences, but they differ based on their charge (valency) in compounds (+3 Vs +2). We will utilise both metals within common frameworks to enable the effect of unit charge variation to be studied to determine key structure activity relationships. This deep understanding will enable broad scope borylation of arene C-H bonds to be achieved. The aryl boronic ester products are among the most common synthetic building blocks used by academia and industry so this will ensure the high impact of our developed methods. We will transfer our initial breakthroughs through to operationally simple processes that can be readily used by the broadest academic and industrial synthetic community. Throughout we will be supported by GSK and Dr Andrew Dominey (GSK Process Chemistry, Stevenage), who as a co-Investigator on this project will be essential to enable the development of a truly useful process. Regular meetings and placements at GSK will be carried out to ensure cohesive progression, technology transfer and imbedding of our new developed methods at GSK. Alongside this, the GSK placements offer a unique chance for real-world testing and benchmarking of our new developed methods. Placements at Stevenage will enable application of our new reaction to specific pharmaceutical targets.