Strain-release amination

作者：Ryan Gianatassio, Justin M. Lopchuk, Jie Wang, Chung‐Mao Pan, Lara R. Malins, Liher Prieto, Thomas A. Brandt, Michael R. Collins, Gary M. Gallego, Neal W. Sach, Jillian E. Spangler, Huichin Zhu, JinJiang Zhu, Phil S. Baran · 发表于：Science · 年份：2016 · DOI：10.1126/science.aad6252 · 被引用次数：600 · 研究领域：Chemical Synthesis and Analysis、Synthesis and Catalytic Reactions、Click Chemistry and Applications

To optimize drug candidates, modern medicinal chemists are increasingly turning to an unconventional structural motif: small, strained ring systems. However, the difficulty of introducing substituents such as bicyclo[1.1.1]pentanes, azetidines, or cyclobutanes often outweighs the challenge of synthesizing the parent scaffold itself. Thus, there is an urgent need for general methods to rapidly and directly append such groups onto core scaffolds. Here we report a general strategy to harness the embedded potential energy of effectively spring-loaded C-C and C-N bonds with the most oft-encountered nucleophiles in pharmaceutical chemistry, amines. Strain-release amination can diversify a range of substrates with a multitude of desirable bioisosteres at both the early and late stages of a synthesis. The technique has also been applied to peptide labeling and bioconjugation.