美国斯克利普斯研究所Baran, Phil S.团队报道了亲电卤化试剂N-X异构体酰胺的发现。相关研究成果发表在2024年5月20日出版的《自然—化学》。

亲电卤化是药物化学家广泛使用的一种工具，用于预功能化分子以获得进一步的多样性，或将卤素原子掺入药物或类药物化合物中以解决代谢问题或调节脱靶效应。目前增加卤化能力的方法依赖于新试剂的发明或用各种添加剂，如路易斯酸或布氏酸、路易斯碱和氢键活化剂活化市售试剂。对能够在温和条件下卤化其他不反应的化合物的新试剂有很高的需求。

该文中，研究人员报道了利用N–X异头酰胺金字塔化氮中储存能量，作为驱动力的一类基于异头酰胺的卤化试剂的发明。这些强有力的卤化方法与各种官能团和杂环相容，例如在50多种化合物上（包括13克规模的实例和1个流动化学放大）。

附：英文原文

Title: Discovery of N–X anomeric amides as electrophilic halogenation reagents

Author: Wang, Yu, Bi, Cheng, Kawamata, Yu, Grant, Lauren N., Samp, Lacey, Richardson, Paul F., Zhang, Shasha, Harper, Kaid C., Palkowitz, Maximilian D., Vasilopoulos, Aristidis, Collins, Michael R., Oderinde, Martins S., Tyrol, Chet C., Chen, Doris, LaChapelle, Erik A., Bailey, Jake B., Qiao, Jennifer X., Baran, Phil S.

Issue&Volume: 2024-05-20

Abstract: Electrophilic halogenation is a widely used tool employed by medicinal chemists to either pre-functionalize molecules for further diversity or incorporate a halogen atom into drugs or drug-like compounds to solve metabolic problems or modulate off-target effects. Current methods to increase the power of halogenation rely on either the invention of new reagents or activating commercially available reagents with various additives such as Lewis or Brnsted acids, Lewis bases and hydrogen-bonding activators. There is a high demand for new reagents that can halogenate otherwise unreactive compounds under mild conditions. Here we report the invention of a class of halogenating reagents based on anomeric amides, taking advantage of the energy stored in the pyramidalized nitrogen of N–X anomeric amides as a driving force. These robust halogenating methods are compatible with a variety of functional groups and heterocycles, as exemplified on over 50 compounds (including 13 gram-scale examples and 1 flow chemistry scale-up).

DOI: 10.1038/s41557-024-01539-4

Source: https://www.nature.com/articles/s41557-024-01539-4