Carbene-Catalyzed Addition/Lactonization of Azides and Enedials

The azide moiety, as a bioactive structural unit, is found in a wide range of drugs and pharmaceutical compounds. Currently, the predominant method for synthesizing azide-containing chiral molecules involves SN2-type reactions. Therefore, developing diverse and efficient methodologies for the synthesis of chiral azide-containing molecules is of great significance. However, the direct addition of azide anions to aryl aldehydes and ketones remains difficult and typically requires strong Bro̷nsted acid catalysts to proceed. Moreover, achieving high enantioselectivity in such addition reactions via asymmetric catalysis remains a challenge. Herein, we report an N-heterocyclic carbene (NHC)-catalyzed strategy for the asymmetric synthesis of chiral azide-containing lactones. The reaction between enedials and sodium azide proceeds with chemo- and enantioselectivity, affording optically enriched azide-containing lactones. These azide-containing lactones can be further converted into various functional molecules, and their antibacterial activities are also investigated. In addition, density functional theory (DFT) calculations, along with noncovalent interaction (NCI) and natural bond orbital (NBO) analyses, demonstrate that the chemo- and enantioselectivity of the azide anion can be effectively modulated by the n→π* interactions involving the acylazolium intermediate. These findings may enrich the synthetic strategies of chiral azide-containing compounds.