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

快速构建新的分子结构的能力在多个领域都是必不可少的。例如，制药开发需要一个构造库，以便在药物发现的早期阶段最大限度地实现多样性。同样，材料科学建立在聚合具有功能潜力的新构件的能力之上。芳基硼酸和酯满足了这一需求，是一些最常用的构建块。它们空气稳定，易于操纵，有许多成熟的功能化路线。然而，目前形成芳基硼酸酯的方法依赖于已有50多年历史的低效化学物质，或者需要使用有毒和稀缺(因此不可持续和昂贵的)贵金属催化剂。这项提议寻求用地球上富含铝和锌的络合物的新方法来取代这些技术。更具体地说，我们将使用铝基和锌基催化剂来实现简单(早期)和复杂(后期)分子的直接(从简单前体一步)硼化反应。催化的使用对于确保过程的可持续性至关重要，因为这最大限度地减少了每次转化所需的能量投入和材料数量。催化提供了确保化学合成可持续未来的唯一最适用的方法，而使用地球上丰富的金属进行催化极大地改善了这一前景。铝和锌的使用也是因为它们相对于许多用于直接硼化反应的其他催化剂(如钴、Ir基催化剂)来说毒性较低。锌和铝具有较高的每日允许接触限值，使它们能够在制药制造后期使用，而不需要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键的硼化反应。芳烃是具有极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。我们将开发能够在这些底物上引入硼功能手柄的铝和锌催化剂。铝和锌具有许多相似的性质，包括大小、底物(芳烃)亲和力、电负性和某种程度上的配位偏好，但它们在化合物(+3vs+2)中的电荷(价态)不同。我们将在共同的框架内利用这两种金属来研究单位电荷变化的影响，以确定关键的结构活性关系。这种深入的理解将使芳烃C-H键的广泛的硼化反应得以实现。芳基硼酸酯产品是学术界和工业界使用的最常见的合成构件之一，因此这将确保我们开发的方法具有很高的影响力。我们将把我们最初的突破转化为操作简单的过程，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过程化学，Stevenage)的支持，他们作为该项目的联合调查员，将对开发真正有用的过程至关重要。葛兰素史克将定期举行会议和实习，以确保我们的新开发方法在葛兰素史克取得一致的进展、技术转让和植入。此外，葛兰素史克的入职为我们的新开发方法提供了一个独特的现实世界测试和基准测试机会。在Stevenage的安置将使我们的新反应能够应用于特定的药物靶标。

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.