Ding Decai, Chen Su, Yin Lingfeng, Ou Wei-Ting, Krause Jeanette A, Cheng Mu-Jeng, Liu Wei
Department of Chemistry, University of Cincinnati, Cincinnati, OH, USA.
Department of Chemistry, National Cheng Kung University, Tainan, Taiwan.
Nat Synth. 2025 May 22. doi: 10.1038/s44160-025-00809-4.
The incorporation of enantioenriched difluoromethyl cyclopropane (DFC) groups into drug candidates has garnered increasing attention in the pharmaceutical industry due to the unique ability of the DFC groups to serve as conformationally rigid hydrogen-bond donors. Despite their potential, the widespread use of chiral DFC groups has been limited by their challenging synthesis. Here we report the use of difluoromethyl-copper complexes for the development of a desymmetric difluoromethylation reaction, using enantioselective copper catalysis. Through desymmetric difluoromethylation of cyclopropenes and subsequent electrophilic functionalization, this method achieves high efficiency and enantioselectivity, enabling the modular construction of chiral DFC moieties. The synthetic utility of this strategy is demonstrated through the synthesis of a variety of chiral DFC-containing compounds, including analogues of pharmacologically relevant molecules. This reactivity of difluoromethyl-copper species opens opportunities for broader application in medicinal chemistry and the development of reactions for the construction of difluoromethyl-containing stereocentres.
由于对映体富集的二氟甲基环丙烷（DFC）基团具有作为构象刚性氢键供体的独特能力，将其引入候选药物在制药行业中受到越来越多的关注。尽管具有潜力，但手性DFC基团的广泛应用受到其合成挑战性的限制。在此，我们报道了使用二氟甲基铜配合物，通过对映选择性铜催化开发一种去对称二氟甲基化反应。通过环丙烯的去对称二氟甲基化和随后的亲电官能化，该方法实现了高效率和对映选择性，能够模块化构建手性DFC部分。通过合成多种含手性DFC的化合物，包括药理学相关分子的类似物，证明了该策略的合成实用性。二氟甲基铜物种的这种反应性为在药物化学中的更广泛应用以及构建含二氟甲基立体中心的反应开发提供了机会。
