New Amine-Acid Couplings and Their Impact on Medicinal Properties

项目摘要。一种新的分子产品是当化学构件与一种 化学反应。药物发现的现状是获取大量的积木和缝合 它们通过少量的反应结合在一起。常见的构造块对传统地匹配到 通过模式识别的反应-酰胺偶联用于胺和羧酸，铃木 联轴器用于溴化物和硼酸盐。在这个已建立的范例中，构建块是 多样性。这种经典方法的成功依赖于构建块的商业可用性，以及 BEST引入了分子外围的多样性。在这里，我们探索一种新的范式，其中一个小的 使用大量的反应将多个构建块缝合在一起。在这个新的范式中， 反应原子是多样性的来源，是对经典方法的补充。在经典方法中，一个 胺和羧酸通过酰胺偶联的方式结合在一起。我们探讨了理论上和 有别于酰胺偶联的氨基酸-酸偶联反应的实验进展。我们专注于 关于形成碳-碳键的新的氨基酸-酸偶联反应。C-C债券在中国的流行 药品和天然产物表明有必要进行新的C-C键形成反应。一把钥匙 创新之处在于利用化学信息学证明高级化学物质中含有胺和酸。 多样性，通常比有机金属和有机卤化物建筑材料更具成本效益，通常安全和 情况稳定，可以处理。利用高通量实验确定特定的催化剂组合和 我们发现，我们能够发现胺-酸的C-C偶联反应。我们新的胺的问世- 毒品。要实现这些新型氨基酸-酸C-C偶联，需要鉴定和优化新的催化剂 和试剂系统，可实现广泛的底物范围、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 发明新的有效的胺酸偶联反应。虽然C-C债券是一个重点领域，但其他 复杂的生成反应也被考虑，以及胺-酸的C-N和C-O偶联。我们 通过复合体的后期多样化展示我们的方法在药物发现中的重要性 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.