Chen Si-Jie, He Cyndi Qixin, Kong May, Wang Jun, Lin Shishi, Krska Shane W, Stahl Shannon S
Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, WI, USA.
Department of Discovery Chemistry, Merck & Co., Inc., South San Francisco, CA, USA.
Nat Synth. 2023 Oct;2(10):998-1008. doi: 10.1038/s44160-023-00332-4. Epub 2023 Jun 1.
Pharmaceutical and agrochemical discovery efforts rely on robust methods for chemical synthesis that rapidly access diverse molecules. Cross-coupling reactions are the most widely used synthetic methods, but these methods typically form bonds to C()-hybridized carbon atoms (e.g., amide coupling, biaryl coupling) and lead to a prevalence of "flat" molecular structures with suboptimal physicochemical and topological properties. Benzylic C()-H cross-coupling methods offer an appealing strategy to address this limitation by directly forming bonds to C()-hybridized carbon atoms, and emerging methods exhibit synthetic versatility that rivals conventional cross-coupling methods to access products with drug-like properties. Here, we use a virtual library of >350,000 benzylic ethers and ureas derived from benzylic C-H cross-coupling to test the widely held view that coupling at C()-hybridized carbon atoms affords products with improved three-dimensionality. The results show that the conformational rigidity of the benzylic scaffold strongly influences the product dimensionality. Products derived from flexible scaffolds often exhibit little or no improvement in three-dimensionality, unless they adopt higher energy conformations. This outcome introduces an important consideration when designing routes to topologically diverse molecular libraries. The concepts elaborated herein are validated experimentally through an informatics-guided synthesis of selected targets and the use of high-throughput experimentation to prepare a library of three-dimensional products that are broadly distributed across drug-like chemical space.
药物和农用化学品的研发工作依赖于强大的化学合成方法，以便快速获得各种不同的分子。交叉偶联反应是应用最广泛的合成方法，但这些方法通常是与sp²杂化的碳原子形成键（例如酰胺偶联、联芳基偶联），导致具有次优物理化学和拓扑性质的“平面”分子结构普遍存在。苄基C(sp³)-H交叉偶联方法提供了一种有吸引力的策略来解决这一局限性，即通过直接与sp³杂化的碳原子形成键，并且新兴方法展现出的合成通用性可与传统交叉偶联方法相媲美，从而获得具有类药性质的产物。在此，我们使用一个由超过350,000种源自苄基C-H交叉偶联的苄基醚和脲组成的虚拟库，来检验一种广泛持有的观点，即在sp³杂化的碳原子处进行偶联可得到具有改善的三维结构的产物。结果表明，苄基骨架的构象刚性强烈影响产物的三维结构。源自柔性骨架的产物通常在三维结构上几乎没有改善，除非它们采取更高能量的构象。这一结果在设计通往拓扑多样的分子库的路线时引入了一个重要的考虑因素。本文阐述的概念通过对选定目标进行信息学指导的合成以及使用高通量实验来制备广泛分布于类药化学空间的三维产物库，在实验上得到了验证。
