Boronic Acid-Catalysed Dehydrative Synthesis

制药、农用化学品、化学生物学和材料科学的进步是由我们有选择性地创造分子的能力所支撑的。例如，所有的药物都含有有机分子，因此，有机合成是所有未来发展的核心。然而，最近的分析表明，药物化学目前只探索了化学可达空间的一小部分，并且依赖于有限数量的合成反应。因此，合成化学往往是新药开发的瓶颈。此外，面对珍贵的元素资源和化学原料不断变化的供应，传统的有机合成必须适应以确保未来的可持续性。催化是同时推进有机合成和解决可持续性挑战的最有效的方法。该提案将开发一系列清洁和高效的催化方法，用于使用硼基催化剂对简单，易于获得的含有羟基（OH）基团的起始材料进行功能化。新的反应将通过催化去除羟基以形成反应中间体并释放水作为唯一的副产物而引发。这种反应性明显比传统方法更有效和环保，传统方法需要对羟基进行额外的转化，并产生大量的有机废物副产品。该项目将侧重于开发新的催化脱水反应，用于制备在现代药物中广泛存在的有价值的小分子基元。例如，据报道，85%的生物活性实体含有至少一个杂环，但在所有可能的环系统中，已制成的还不到2%。我们将利用催化脱水来探索新的反应性，用于制备没有一般合成方法的杂环靶标，以增强可接近的药物样化学空间。我们还将把这些方法应用于目前在药物化合物中发现的其他常见杂环的制备，为目前的合成方法提供更可持续的催化替代品。另一个目标是开发新的催化反应，直接激活N-OH键，促进重排成受保护的胺，再次释放水作为副产物。由于超过80%的候选药物含有胺功能，新开发的反应将提供更可持续和有效的方法来获取这些重要的基序。新的合成方法的发展将得到新的双功能硼基催化剂的制备和获得基本认识的工作的支持。我们将探索现成的硼体系作为Bronsted酸催化剂与拴系路易斯碱的结合。双功能酸/碱体系可以稳定反应中间体，从而提高整体反应活性和/或选择性。机理研究将用于阐明催化剂在溶液中的结构和动态行为，所获得的知识将用于帮助进一步的催化剂开发和支持新的合成方法的优化。总的来说，新的催化技术的发展，以及对该过程的基本理解的增加，将为工业界和学术界提供一个增强的工具箱，用于可持续合成有价值的有机分子。

Progress in the development of pharmaceuticals and agrochemicals, chemical biology, and materials science is underpinned by our ability to create molecules selectively. For example, all pharmaceuticals contain organic molecules and, consequently, organic synthesis is central to all future developments. However, recent analysis has shown that medicinal chemistry currently explores only a fraction of chemically accessible space and is reliant on a limited number of synthetic reactions. Therefore, synthetic chemistry is often a bottleneck in the development of new medicines. Furthermore, traditional organic synthesis must adapt to ensure future sustainability in the face of the changing availability of both precious elemental resources and chemical feedstocks. Catalysis represents the single most effective way of simultaneously advancing organic synthesis and addressing the challenges in sustainability. This proposal will develop a range of clean and efficient catalytic methods for the functionalisation of simple, readily available starting materials containing hydroxyl (OH) groups using boron-based catalysts. The new reactions will be initiated by the catalytic removal of an hydroxy group to form a reactive intermediate and release water as the only by-product. Such reactivity is significantly more efficient and environmentally friendly than traditional methods, which require additional transformations of the hydroxy group and generate large amounts of organic waste by-products. The project will focus on the development of new catalytic dehydrative reactions for the preparation of valuable small molecule motifs that are widely found in modern pharmaceuticals. For example, 85% of all biologically active entities are reported to contain at least one heterocycle, yet less than 2% of all possible ring systems have been made. We will use catalytic dehydration to explore new reactivity for the preparation of heterocyclic targets for which no general synthetic method exists to enhance accessible drug-like chemical space. We will also apply these methods to the preparation of other common heterocycles currently found in drug compounds to provide more sustainable catalytic alternatives to current synthetic methods. Another aim is to develop new catalytic reactions for the direct activation of N-OH bonds to promote rearrangement into protected amines, again releasing water as the by-product. As over 80% of drug candidates contain amine functionality, the new reactions developed will provide more sustainable and effect methods of accessing these important motifs. The development of the new synthetic methods will be supported by work to prepare and gain fundamental understanding of new bifunctional boron-based catalysts. We will explore readily available boron systems as Bronsted acid catalysts in combination with a tethered Lewis base. The bifunctional acid/base system will allow for stabilisation of reaction intermediates that may enhance overall reactivity and/or selectivity. Mechanistic studies will be used to elucidate the structure and dynamic behaviour of the catalysts in solution, with the knowledge gained used to aid further catalyst development and support the optimisation of the new synthetic methods. Overall, the new catalytic technology developed, alongside increased fundamental understanding of the processes will provide both industry and academia with an enhanced toolbox for the sustainable synthesis of valuable organic molecules.