Xu Jingtong, Bloomer Brandon J, Brunn John N, Quest Andrew P, Chakraborty Sukriyo, Schneider Joseph E, Clark Douglas S, Hartwig John F
Department of Chemistry, University of California, Berkeley, California 94720, United States.
Department of Chemical and Biomolecular Engineering, University of California, Berkeley, California 94720, United States.
J Am Chem Soc. 2025 Aug 13;147(32):28875-28881. doi: 10.1021/jacs.5c06239. Epub 2025 Aug 1.
In the past decade, thousands of synthetic building blocks, intermediates, and drug candidates containing a spirocyclopropane core with at least one nitrogen atom have been investigated for a range of biological activities. These compounds create three-dimensional architectures that maintain the rigidity of their more sp-rich analogs. Most examples contain simple core structures with unsubstituted cyclopropyl moieties, and only one has been made enantioselectively. Therefore, a straightforward method to produce more complex spirocyclic amines with high stereoselectivity would be of great synthetic utility. Here, we report the stereoselective cyclopropanation of methylene-substituted saturated heterocycles catalyzed by an iridium-containing cytochrome. After just four rounds of mutagenesis, we identified a variant that forms spiroazetidines, spiropyrrolidines, and spiropiperidines with enantioselectivities up to 99%. These results demonstrate an expeditious route to valuable, rigid, sp-rich amino acid linchpins.
在过去十年中，人们对数千种含有至少一个氮原子的螺环丙烷核心的合成砌块、中间体和候选药物进行了一系列生物活性研究。这些化合物构建了三维结构，保持了其富含sp的类似物的刚性。大多数例子包含具有未取代环丙基部分的简单核心结构，并且只有一个是对映选择性合成的。因此，一种直接的方法来以高立体选择性生产更复杂的螺环胺将具有很大的合成实用性。在此，我们报道了含铱细胞色素催化的亚甲基取代饱和杂环的立体选择性环丙烷化反应。经过四轮诱变后，我们鉴定出一种变体，它能形成对映选择性高达99%的螺氮杂环丁烷、螺吡咯烷和螺哌啶。这些结果证明了一条通往有价值的、刚性的、富含sp的氨基酸关键结构的快速途径。
