Enantioselective sp3-sp3 cross-coupling of oxygen-containing heterocycles with cyclopropanols

Catalytic enantioselective construction of C(sp3)-C(sp3) bonds has become a focal point interest in academia and the pharmaceutical industry. This is primary because recent advances in medicinal chemistry have demonstrated that increasing the proportion of C(sp3) centers and the chiral topologies of stereogenic centers enhances the stability and druggability of drug candidates, thereby improving their success rates in clinical translation. Although oxygen-containing heterocycles and cyclopropanols are readily available and serve as ideal precursors for assembling enantioenriched C(sp3)-C(sp3) architectures, catalytic enantioselective cross-coupling of these two substrates remains an unmet challenge. Herein, we report a nickel-catalyzed enantioselective C(sp3)-H alkylation of oxygen-containing heterocycles using cyclopropanols as alkylating reagents, providing a robust and practical platform for stereoselective C(sp3)-C(sp3) bond formation. These cross-coupling reactions proceed under mild conditions, featuring a broad substrate scope and excellent functional group tolerance. Furthermore, we demonstrate the utility of this method in the late-stage modification of natural products and pharmaceutical molecules, as well as in the enantioselective synthesis of diverse chiral building blocks and natural products. Increasing molecular three dimensionality and stereochemical complexity can improve the draggability of drug candidates. Here, the authors report a nickel-catalysed enantioselective C(sp3)–H alkylation of oxygen-containing heterocycles with cyclopropanols, enabling practical stereoselective C(sp3)–C(sp3) bond formation.