Xiao Zheng

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.

N-Benzyl amides are important structural motifs in pharmaceuticals and natural products. The nucleophilic substitution reactions between aromatic nucleophiles and N-acyliminium ion precursors (N-acyl hemiaminal derivatives) represent one of the most common and powerful approaches. However, these protocols are typically limited by the scope of aromatic substrates or the requirement for air-sensitive reagents. Herein, we report a nickel-catalyzed reductive arylation reaction between N-acyl hemiaminals and readily available aryl halides, which enables the synthesis of a series of structurally diverse N-benzyl amide derivatives under mild conditions through simple operations. Mechanistic studies support a nickel-catalyzed cross-coupling pathway mediated by an N-acyliminium ion intermediate and exclude the participation of an N-acyl α-aminoalkyl radical.

A copper-catalyzed nitrogen radical-mediated cross-dehydrogenative coupling reaction has been developed for the synthesis of ynamides at room temperature.

A new prenylated indole alkaloid—Penicimutamide C N-oxide (1), a new alkaloid penicimutamine A (2), along with six known alkaloids were isolated from an endophytic fungus Pallidocercospora crystallina. A simple and accurate method was used to determine the N-O bond in the N-oxide group of 1. By using a β-cell ablation diabetic zebrafish model, compounds 1, 3, 5, 6 and 8 showed significantly hypoglycemic activities under the concentration of 10 μM. Further studies revealed that compounds 1 and 8 lowered the glucose level through promoting glucose uptake in zebrafish. In addition, all eight compounds showed no acute toxicity, teratogenicity, nor vascular toxicity in zebrafish under the concentrations range from 2.5 μΜ to 40 μM. Importantly, these results provide new lead compounds for the development of antidiabetes strategies.

A decarboxylative cross-coupling reaction of α-amino acids with nitrones via visible-light-induced photoredox catalysis has been established for easy access to β-amino hydroxylamines and vicinal diamines with structural diversity, which is featured with simple operation, mild conditions, readily available α-amino acids, and a broad scope of nitrone substrates. The application of this protocol can furnish efficient synthetic strategies for some valuable vicinal diamine-containing molecules.

The imino‐Nazarov cyclization of the polysubstituted pentan‐1,4‐diene‐3‐imines was realized. To this aim, a one‐pot procedure involving reductive alkenyliminylation of α,β‐unsaturated secondary amides with potassium organotrifluoroborates, followed by acid‐catalyzed imino‐Nazarov cyclization of the polysubstituted pentan‐1,4‐diene‐3‐imine intermediates, was studied systematically. This mild, operationally simple, flexible, and high‐yielding protocol efficiently affords polysubstituted pentan‐1,4‐diene‐3‐imines, cyclopentenimines, and α‐amino cyclopentenones, which are useful scaffolds in organic synthesis. The substituent effect at the C2 position of the polysubstituted pentan‐1,4‐diene‐3‐imines was studied by means of density‐functional theory calculations. Results suggested that the electron‐donating group facilitates the imino‐Nazarov cyclization process.

The imino‐Nazarov cyclization of the polysubstituted pentan‐1,4‐diene‐3‐imines was realized. To this aim, a one‐pot procedure involving reductive alkenyliminylation of α,β‐unsaturated secondary amides with potassium organotrifluoroborates, followed by acid‐catalyzed imino‐Nazarov cyclization of the polysubstituted pentan‐1,4‐diene‐3‐imine intermediates, was studied systematically. This mild, operationally simple, flexible, and high‐yielding protocol efficiently affords polysubstituted pentan‐1,4‐diene‐3‐imines, cyclopentenimines, and α‐amino cyclopentenones, which are useful scaffolds in organic synthesis. The substituent effect at the C2 position of the polysubstituted pentan‐1,4‐diene‐3‐imines was studied by means of density‐functional theory calculations. Results suggested that the electron‐donating group facilitates the imino‐Nazarov cyclization process.