Department of Chemistry, University of Chicago, Chicago, IL, USA.
Discovery Chemistry, Merck & Co., Inc., Boston, MA, USA.
Science. 2022 Apr 29;376(6592):527-532. doi: 10.1126/science.abo4282. Epub 2022 Apr 28.
Discovery chemists routinely identify purpose-tailored molecules through an iterative structural optimization approach, but the preparation of each successive candidate in a compound series can rarely be conducted in a manner matching their thought process. This is because many of the necessary chemical transformations required to modify compound cores in a straightforward fashion are not applicable in complex contexts. We report a method that addresses one facet of this problem by allowing chemists to hop directly between chemically distinct heteroaromatic scaffolds. Specifically, we show that selective photolysis of quinoline -oxides with 390-nanometer light followed by acid-promoted rearrangement affords -acylindoles while showing broad compatibility with medicinally relevant functionality. Applications to late-stage skeletal modification of compounds of pharmaceutical interest and more complex transformations involving serial single-atom changes are demonstrated.
发现化学家通常通过迭代结构优化方法来鉴定有针对性的分子，但在化合物系列中制备每个连续的候选物时，很少能够以匹配其思维过程的方式进行。这是因为许多以直接方式修饰化合物核心所需的必要化学转化在复杂环境中并不适用。我们报告了一种方法，通过允许化学家直接在化学上不同的杂芳环骨架之间跳跃来解决这个问题的一个方面。具体来说，我们表明，用 390 纳米光选择性光解喹啉-氧化物，然后用酸促进重排，得到 -酰基吲哚，同时与具有医学相关性的功能具有广泛的兼容性。展示了对药物相关化合物后期骨架修饰的应用，以及涉及连续单原子变化的更复杂转化。
