New Amine-Acid Couplings and Their Impact on Medicinal Properties

项目摘要。一种新的分子产品成为真实的时，化学积木是结合在一起， 化学反应药物发现的现状是获得大量的积木和缝合 它们一起使用少量的反应。常见的构建块对通常匹配到 通过模式识别的反应-酰胺偶联用于胺和羧酸，Suzuki 偶联用于溴化物和硼酸盐。在这个既定的范例中，构建块是 多样性这种经典方法的成功依赖于构建模块的商业可用性， 在分子的外围引入多样性是最好的。在这里，我们探索了一个新的范式， 使用大量的反应将许多构建块缝合在一起。在这个新的范例中， 反应原子是多样性的来源，补充了经典方法。在经典方法中， 胺和羧酸结构单元将通过酰胺偶联结合。我们探索理论和 与酰胺偶联不同的胺-酸偶联反应的实验开发。我们专注 新的胺-酸偶联反应，形成碳-碳键。C-C债券的流行， 药物和天然产物的研究表明新的C-C键形成反应的必要性。一个关键 创新是使用化学信息学来证明胺和酸在高级化学品中是可用的。 多样性，通常比有机金属和有机卤化物结构单元更具成本效益，并且通常安全， 稳定处理。利用高通量实验来确定催化剂的特定组合， 配体，我们发现我们能够发现胺-酸C-C偶联反应。我们新胺的出现- 酸性C-C偶联反应允许将两种最丰富可用的结构单元再利用， 嵌段-胺和酸-用于合成最流行的原子排列- C-C键-在 毒品实现这些新的胺-酸C-C偶联需要鉴定和优化新的催化剂 和试剂系统，其能够实现宽的底物范围、用户友好性和潜在的引入 不对称利用现代高通量技术，我们寻找这样的反应条件，希望 发明新的和有影响力的胺-酸偶联反应。虽然C-C键是一个重点领域，但其他 复杂性生成反应也被认为是随着胺-酸C-N和C-O耦合。我们 展示我们的方法在药物发现通过复杂的后期多样化的重要性， 药物，并通过合成不同的化学库。

Project Summary. A new molecular product becomes real when chemical building blocks are united with a chemical reaction. The status quo in drug discovery is to acquire a large number of building blocks and stitch them together using a small number of reactions. Common building block pairs are classically matched to reactions through pattern recognition – the amide coupling is used for amines and carboxylic acids, the Suzuki coupling is used for bromides and boronates. In this established paradigm, building blocks are the source of diversity. The success of this classic approach relies on the commercial availability of the building blocks, and best introduces diversity around the periphery of the molecule. Here, we explore a new paradigm, where a small number of building blocks are stitched together using a large number of reactions. In this new paradigm, the reacting atoms are the source of diversity, complementing the classic approach. In the classic approach, an amine and carboxylic acid building block would be united by the amide coupling. We explore the theoretical and experimental development of amine–acid coupling reactions that are distinct from the amide coupling. We focus on new amine–acid coupling reactions that forge carbon–carbon bonds. The popularity of C–C bonds in pharmaceuticals and natural products suggests a necessity for new C–C bond-forming reactions. A key innovation is the use of chemoinformatics to demonstrate that amines and acids are available in high chemical diversity, typically more cost effective than organometal and organohalide building blocks and generally safe and stable to handle. Leveraging high-throughput experimentation to identify specific combinations of catalysts and ligands, we find that we are able to discover amine–acid C–C coupling reactions. The advent of our new amine– acid C–C coupling reactions allows for building block repurposing of the two most abundantly available building blocks – amines and acids – for the synthesis of the most popular atom arrangements – C–C bonds – found in drugs. Achieving these novel amine–acid C–C couplings requires identification and optimization of new catalyst and reagent systems that enable broad substrate scope, user-friendliness, and potentially introduction of asymmetry. Using modern high-throughput techniques, we search for such reaction conditions in the hopes of inventing new and impactful amine–acid coupling reactions. While C–C bonds are an area of focus, other complexity generating reactions are also considered, along with amine–acid C–N and C–O couplings. We showcase the significance of our approach in drug discovery through the late-stage diversification of complex pharmaceuticals, and through the synthesis of diverse chemical libraries.