Visible-Light-Driven Redox Neutral Direct C-H Amination of Glycine Derivatives and Peptides with N-Acyloxyphthalimides.

A room temperature, visible-light-promoted and redox neutral direct C-H amination of glycine and peptides has been firstly accomplished by using N-acyloxyphthalimide or -succinimide as nitrogen-radical precursor. The present strategy provides ways to introduce functionalities such as N-acyloxyphthalimide or -succinimide specifically to terminal glycine segment of peptides. Herein, mild conditions and high functional-group tolerance allow the preparation of non-natural α-amino acids and modification of corresponding peptides in this way.

Photoinduced Olefin Diamination with Alkylamines.

Vicinal diamines are ubiquitous materials in organic and medicinal chemistry. The direct coupling of olefins and amines would be an ideal approach to construct these motifs. However, alkene diamination remains a long-standing challenge in organic synthesis, especially when using two different amine components. We report a general strategy for the direct and selective assembly of vicinal 1,2-diamines using readily available olefin and amine building blocks. This mild and straightforward approach involves in situ formation and photoinduced activation of N-chloroamines to give aminium radicals that enable efficient alkene aminochlorination. Owing to the ambiphilic nature of the ß-chloroamines produced, conversion into tetra-alkyl aziridinium ions was possible, thus enabling diamination by regioselective ring-opening with primary or secondary amines. This strategy streamlines the preparation of vicinal diamines from multistep sequences to a single chemical transformation.

Divergent Strain-Release Amino-Functionalization of [1.1.1]Propellane with Electrophilic Nitrogen-Radicals.

Herein we report the development of a photocatalytic strategy for the divergent preparation of functionalized bicyclo[1.1.1]pentylamines. This approach exploits, for the first time, the ability of nitrogen-radicals to undergo strain-release reaction with [1.1.1]propellane. This reactivity is facilitated by the electrophilic nature of these open-shell intermediates and the presence of strong polar effects in the transition-state for C-N bond formation/ring-opening. With the aid of a simple reductive quenching photoredox cycle, we have successfully harnessed this novel radical strain-release amination as part of a multicomponent cascade compatible with several external trapping agents. Overall, this radical strategy enables the rapid construction of novel amino-functionalized building blocks with potential application in medicinal chemistry programs as p-substituted aniline bioisosteres.

Photogenerated Neutral Nitrogen Radical Catalyzed Bifunctionalization of Alkenes.

Alkene bifunctionalizations are powerful tools for the rapid construction of structurally complex and valuable scaffolds, and such reactions typically involve the use of transition-metal catalysts or organocatalysts. Here, we report for the first time a photogenerated neutral nitrogen radical catalyzed intermolecular alkene bifunctionalization by using allyl sulfones as the source of both the carbon and the sulfone functionalities under mild conditions. The key to the success of this protocol involves the visible-light-mediated photocatalytic in situ generation of a nitrogen-centered radical from the N-(2-acetylphenyl) benzenesulfonamide catalyst, and its activation of the allyl sulfones to generate reactive species. The preliminary control experiments supported the postulated mechanism.

Reaction of Nitrogen-Radicals with Organometallics Under Ni-Catalysis: N-Arylations and Amino-Functionalization Cascades.

Herein, we report a strategy for the generation of nitrogen-radicals by ground-state single electron transfer with organyl-NiI species. Depending on the philicity of the N-radical, two types of processes have been developed. In the case of nucleophilic aminyl radicals direct N-arylation with aryl organozinc, organoboron, and organosilicon reagents was achieved. In the case of electrophilic amidyl radicals, cascade processes involving intramolecular cyclization, followed by reaction with both aryl and alkyl organometallics have been developed. The N-cyclization-alkylation cascade introduces a novel retrosynthetic disconnection for the assembly of substituted lactams and pyrrolidines with its potential demonstrated in the short total synthesis of four venom alkaloids.

Hydroxylamine Derivatives as Nitrogen-Radical Precursors in Visible-Light Photochemistry.

In recent years, hydroxylamines derivatives have been exploited as nitrogen-radical precursors in visible-light photochemistry. Their ability to serve as electrophores in redox chemistry has propelled the development of many novel transformations. Fundamental mechanistic aspects as well as the importance in the preparation of nitrogen-containing molecules will be highlighted.

Organophotocatalytic Generation of N- and O-Centred Radicals Enables Aerobic Oxyamination and Dioxygenation of Alkenes.

A cooperative TEMPO and photoredox catalytic strategy was applied for the first time to the direct conversion of N-H and O-H bonds into N- and O-centred radicals, enabling a general and selective oxidative radical oxyamination and dioxygenation of various ß,γ-unsaturated hydrazones and oximes. In the reaction, O2 was employed not only as a terminal oxidant but also as the oxygen source. This protocol provided efficient access to the synthesis of various synthetically and biologically important pyrazoline, pyridazine and isoxazoline derivatives under metal-free and mild reaction conditions. Mechanistic studies revealed that the cooperative organophotocatalytic system functions through two single-electron-transfer (SET) processes.

Some aspects of radical cascade and relay reactions.

The ability to create carbon-carbon bonds is at the heart of organic synthesis. Radical processes are particularly apt at creating such bonds, especially in cascade or relay sequences where more than one bond is formed, allowing for a rapid assembly of complex structures. In the present brief overview, examples taken from the authors' laboratory will serve to illustrate the strategic impact of radical-based approaches on synthetic planning. Transformations involving nitrogen-centred radicals, electron transfer from metallic nickel and the reversible degenerative exchange of xanthates will be presented and discussed. The last method has proved to be a particularly powerful tool for the intermolecular creation of carbon-carbon bonds by radical additions even to unactivated alkenes. Various functional groups can be brought into the same molecule in a convergent manner and made to react together in order to further increase the structural complexity. One important benefit of this chemistry is the so-called RAFT/MADIX technology for the manufacture of block copolymers of almost any desired architecture.

Protective effect of Sheng-Nao-Kang decoction on focal cerebral ischemia-reperfusion injury in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Sheng-Nao-Kang decoction (SNK), a modified traditional Chinese medicine (TCM), has been used clinically for the treatment of acute and chronic cerebrovascular related diseases. To evaluate the protective effect of SNK on focal cerebral ischemia-reperfusion (I/R) injury in rats and investigate the underlying mechanisms. MATERIALS AND METHODS: Focal cerebral I/R injury in rats was induced by middle cerebral artery occlusion (MCAO) for 2h followed by reperfusion for 24h. Adult male Sprague-Dawley (SD) rats were randomly divided into six kinds of groups: Sham group; I/R group; SNK-treated groups at doses of 0.7 g/kg, 1.4 g/kg and 2.8 g/kg; and nimodipine (NMP)-treated group. The recoveries of neurological function in rats were estimated by neurological defect scoring and 2,3,5-triphenyltetrazolium chloride (TTC) staining after 24h reperfusion. Various biochemical indexes in serum were assayed by colorimetry, including malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), inducible nitric oxide synthase (iNOS) and total nitric oxide synthase (TNOS). Histological structures of the brain in rats were observed by hematoxylin and eosin (H&E) staining. Immunohistochemistry was performed to detect the caspase-3 protein content in rats. RESULTS: SNK administration significantly reduced the neurological defect scores and lessened the cerebral infarction volume. The treatment of SNK lowered MDA content, up-regulated SOD and GSH-Px levels, down-regulated iNOS and TNOS levels in serum. Furthermore, histological examination indicated that dense neuropil and largely surviving neurons were seen in SNK-treated rats. SNK administration restrained the expression of caspase-3 positive protein significantly. CONCLUSION: The results suggest that SNK demonstrates a strong and ameliorative effect on cerebral I/R damage in rats. The protective mechanisms of SNK are associated with its properties of anti-apoptosis and anti-oxidation as well as regulation of iNOS and TNOS.