Ligand Evolution-Enabled Enantioselective C(sp ³ )–H Azidation

Chiral azides constitute a versatile class of compounds that are ubiquitous in the spectrum of biologically active substances. These compounds serve as valuable precursors for synthesizing various nitrogen-based drug scaffolds, biologically active natural products, and functional molecules. Nevertheless, the inherent high reactivity and elusive nature of azides have limited the reporting of methods for direct asymmetric azidation of carbon–hydrogen (C–H) bonds. Herein, we present a photoinduced copper-catalyzed enantioselective radical α-C(sp 3 )–H azidation of carbonyl compounds via a 1,5-hydrogen atom transfer (HAT) strategy. A novel binary bisphosphine and N, N, N -tridentate anionic chiral ligand system functions both as a photosensitizer and a chiral catalyst for azidation. This practical method exhibits excellent chemo-, regio-, and enantioselectivity in the efficient azidation of the α-carbonyl C–H bond within complex functional group environments. The versatility of this method is further showcased through diverse postazidation manipulations, facilitating the synthesis of non-natural α-amino acid derivatives and the straightforward installation of azide groups in complex bioactive compounds as ligation platforms for click chemistry. DFT studies reveal a remote S H 2 mechanism and demonstrate that the ligand-evolution strategy combining ligand modification and ligand self-assembly is critical for tuning the active chiral space of the catalyst as well as improving the enantioselectivity.