N -Acyl Hemiperaminals: From Bioactive Skeleton Editing of Artemisinin to Programmable Handles for α-Amido Functionalization and Bioactive Peroxides

Abstract Late-stage molecular editing is vital for drug diversification and SAR studies. However, programmable peroxide-based editing handles for amides, α-amino acids, peptide- and drug-relevant scaffolds remain largely unexplored, particularly N-acyl hemiperaminals. Inspired by the molecular editing conception for the bioactive skeleton of artemisinin, we report herein efficient syntheses of structurally diverse N-acyl hemiperaminals via aerobic photocatalytic α-amido C–H oxidative functionalization and oxidative decarboxylative coupling of α-amino acids. Notably, the oxidative decarboxylative of dipeptides and tripeptides facilitates the late-stage modification of peptidomimetic drugs and drug-derived scaffolds. Investigations into the chemical properties of N-acyl hemiperaminals suggest their potential as programmable molecular editing handles for the facile construction of α-amido C–C bonds via Lewis acid-catalyzed nucleophilic substitution and titanocene-catalyzed radical cross-coupling. Importantly, as the derivatives, O-alkylated peroxides exhibit potent antimalarial activity, and 6-amido-1,2,4-trioxanes demonstrate powerful and broad-spectrum anticancer activities. This work will enhance the investigation and application of organic peroxides, advancing novel pharmaceuticals by establishing these peroxides as versatile editing linchpins.