A copper-catalyzed reaction of alpha-azidocarbonyl compounds under an oxygen atmosphere is reported where nitriles are formed via C-C bond cleavage of a transient iminyl copper intermediate. The transformation is carried out by a sequence of denitrogenative formation of iminyl copper species from alpha-azidocarbonyl compounds and their C-C bond cleavage, where molecular oxygen (1 atm) is a prerequisite to achieve the catalytic process and one of the oxygen atoms of O(2) was found to be incorporated into the beta-carbon fragment as a carboxylic acid.

A copper-catalyzed synthesis of phenanthridine derivatives was developed starting from biaryl-2-carbonitriles and Grignard reagents. The present transformation is carried out by a sequence of nucleophilic addition of Grignard reagents to biaryl-2-carbonitriles to form N-H imines and their Cu-catalyzed C-N bond formation on the aromatic C-H bond, where molecular oxygen is a prerequisite to achieve the catalytic process.

Copper-catalyzed benzylic C-H oxygenation under an oxygen atmosphere was developed starting from carbonitriles and Grignard reagents via N-H imine intermediates. The present process is characterized by the following two-step sequence in a one-pot manner: (1) addition of Grignard reagents to carbonitriles to form N-H imines and (2) benzylic C-H oxygenation (C═O bond formation) triggered by 1,5-hydrogen atom transfer with transient iminyl copper species.

Tumor metastasis is the main cause of death in cancer patients. Anoikis resistance is one critical malefactor of metastatic cancer cells to resist current clinical chemotherapeutic treatments. Although endoperoxide-containing compounds have long been suggested as anticancer drugs, few have been clinically employed due to their instability, complex synthesis procedure or low tumor cell selectivity. Herein, we describe a one-pot strategy to synthesize novel amino endoperoxides and their derivatives with good yields and stabilities. In vitro cell-based assays revealed that 4 out of the 14 amino endoperoxides selectively induce metastatic breast carcinoma cells but not normal breast cells to undergo apoptosis, in a dose-dependent manner. Mechanistic studies showed that the most potent amino endoperoxide, 4-Me, is selective for cancer cells expressing a high level of Nox4. The anticancer effects are further shown to be associated with reduced O2−:H2O2 ratio and increased ·OH level in the cancerous cells. Animal study showed that 4-Me impairs orthotopic breast tumor growth as well as tumor cell metastasis to lymph nodes. Altogether, our study suggests that anticancer strategies that focus on redox-based apoptosis induction in tumors are clinically viable.

No abstract