Synthesis of chiral difluoromethyl cyclopropanes through desymmetric difluoromethylation of cyclopropenes enabled by enantioselective copper catalysis

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. General methods for the synthesis of chiral difluoromethyl cyclopropanes are challenging to develop, despite the increasing importance of this motif in pharmaceuticals. Now, a copper-catalysed desymmetric difluoromethylation method is reported for the modular synthesis of difluoromethyl cyclopropanes with high efficiency and enantioselectivity.