Synthesis of Polysubstituted Enamides by Hydrogen Atom Transfer Alkene Isomerization Using Dual Cobalt/Photoredox Catalysis.

M-HAT isomerization is a highly reliable method to access thermodynamically stable alkenes with high functional group tolerance. However, synthesis of heteroatom-substituted alkenes by M-HAT isomerization reaction is still underdeveloped. Herein, we report an enamide synthesis using M-HAT via a combination of cobalt and photoredox catalysis. This method tolerates a variety of functional groups including haloarenes, heteroarenes, free hydroxy groups, non-protected indoles, and drug derivatives. Furthermore, this method can isomerize styrene derivatives in good yield and E/Z selectivity.

1,5-Anhydro-D-Fructose Exhibits Satiety Effects via the Activation of Oxytocin Neurons in the Paraventricular Nucleus.

1,5-Anhydro-D-fructose (1,5-AF) is a bioactive monosaccharide that is produced by the glycogenolysis in mammalians and is metabolized to 1,5-anhydro-D-glucitol (1,5-AG). 1,5-AG is used as a marker of glycemic control in diabetes patients. 1,5-AF has a variety of physiological activities, but its effects on energy metabolism, including feeding behavior, are unclarified. The present study examined whether 1,5-AF possesses the effect of satiety. Peroral administration of 1,5-AF, and not of 1,5-AG, suppressed daily food intake. Intracerebroventricular (ICV) administration of 1,5-AF also suppressed feeding. To investigate the neurons targeted by 1,5-AF, we investigated c-Fos expression in the hypothalamus and brain stem. ICV injection of 1,5-AF significantly increased c-Fos positive oxytocin neurons and mRNA expression of oxytocin in the paraventricular nucleus (PVN). Moreover, 1,5-AF increased cytosolic Ca2+ concentration of oxytocin neurons in the PVN. Furthermore, the satiety effect of 1,5-AF was abolished in oxytocin knockout mice. These findings reveal that 1,5-AF activates PVN oxytocin neurons to suppress feeding, indicating its potential as the energy storage monitoring messenger to the hypothalamus for integrative regulation of energy metabolism.

Photocatalytic Deuterium Atom Transfer Deuteration of Electron-Deficient Alkenes with High Functional Group Tolerance.

Due to its mild reaction conditions and unique chemoselectivity, hydrogen atom transfer (HAT) hydrogenation represents an indispensable method for the synthesis of complex molecules. Its analog using deuterium, deuterium atom transfer (DAT) deuteration, is expected to enable access to complex deuterium-labeled compounds. However, DAT deuteration has been scarcely studied for synthetic purposes, and a method that possesses the favorable characteristics of HAT hydrogenations has remained elusive. Herein, we report a protocol for the photocatalytic DAT deuteration of electron-deficient alkenes. In contrast to the previous DAT deuteration, this method tolerates a variety of synthetically useful functional groups including haloarenes. The late-stage deuteration also allows access to deuterated amino acids as well as donepezil-d2 . Thus, this work demonstrates the potential of DAT chemistry to become the alternative method of choice for preparing deuterium-containing molecules.

Naturally occurring 3RS, 7R, 11R-phytanic acid suppresses in vitro T-cell production of interferon-gamma.

BACKGROUND: Among the eight stereoisomers of phytanic acid (PA), the 3RS, 7R, 11R-isomer is naturally occurring and is present in foods and the human body. PA is considered to have possible health benefits in the immune system. However, it remains undetermined whether these effects are elicited by the 3RS, 7R, 11R-PA isomer, because previous studies used a commercially available PA whose isomer configuration is unknown. In this study, we synthesized a preparation of 3RS, 7R, 11R-PA, and investigated its in vitro immunomodulatory effects, especially the T-cell production of interferon (IFN)-γ, which is associated with various autoimmune diseases. This study also investigated the effects of 3RS, 7R, 11R-PA on NF-κB activity in order to address the mechanism of its immunomodulatory effects. METHODS: Mouse splenocytes and purified T-cells were stimulated with T-cell mitogens and incubated with 3RS, 7R, 11R-PA, followed by evaluation of IFN-γ production. The effect of 3RS, 7R, 11R-PA on NF-κB activity was also investigated using an A549 cell line with stable expression of an NF-κB-dependent luciferase reporter gene. RESULTS: 3RS, 7R, 11R-PA significantly reduced in vitro IFN-γ production at both the protein and mRNA levels, and was accompanied by decreased expression of T-bet, a key regulator of Th1 cell differentiation. The results indicated that NF-κB-mediated transcriptional activity was significantly decreased by 3RS, 7R, 11R-PA and that GW6471, an antagonist of peroxisome proliferator activated receptor α (PPARα), abrogated the inhibitory effect of 3RS, 7R, 11R-PA on NF-κB activity. CONCLUSIONS: The present study suggests that 3RS, 7R, 11R-PA is a functional and bioactive fatty acid, and has a potentially beneficial effect for amelioration of T-cell mediated autoimmune diseases. This study also indicates that interference in the NF-κB pathway via PPARα activation is a potential mechanism of the immunomodulatory effects of 3RS, 7R, 11R-PA.

Cobalt/Photoredox Dual-Catalyzed Cross-Radical Coupling of Alkenes via Hydrogen Atom Transfer and Homolytic Substitution.

Cobalt-catalyzed metal hydride hydrogen atom transfer (MHAT) in combination with photoredox catalysis has emerged as a powerful synthetic method, owing to its redox nature and applicability to various radical precursors. Herein, we describe a cross-radical coupling reaction under cobalt/photoredox dual catalysis. MHAT and homolytic substitution (SH2) processes enabled Markovnikov-selective hydrobenzylation of di/trisubstituted alkenes, affording products with a quaternary carbon center in a redox-neutral manner.

Intramolecular Hydrogen Atom Transfer Hydroarylation of Alkenes toward δ-Lactams Using Cobalt-Photoredox Dual Catalysis.

Intramolecular hydroarylation of alkenes through hydrogen atom transfer (HAT) represents a robust method to prepare benzo-fused heterocycles. However, the reported methods have limitations in a variety of accessible cyclic scaffolds. Here we report a dual cobalt- and photoredox-catalyzed HAT hydroarylation of alkenes that is characterized by higher efficiency in the synthesis of a δ-lactam compared to established protocols. The proposed mechanism is supported by experiments and DFT calculations.

Silane- and peroxide-free hydrogen atom transfer hydrogenation using ascorbic acid and cobalt-photoredox dual catalysis.

Hydrogen atom transfer (HAT) hydrogenation has recently emerged as an indispensable method for the chemoselective reduction of unactivated alkenes. However, the hitherto reported systems basically require stoichiometric amounts of silanes and peroxides, which prevents wider applications, especially with respect to sustainability and safety concerns. Herein, we report a silane- and peroxide-free HAT hydrogenation using a combined cobalt/photoredox catalysis and ascorbic acid (vitamin C) as a sole stoichiometric reactant. A cobalt salophen complex is identified as the optimal cocatalyst for this environmentally benign HAT hydrogenation in aqueous media, which exhibits high functional-group tolerance. In addition to its applicability in the late-stage hydrogenation of amino-acid derivatives and drug molecules, this method offers unique advantage in direct transformation of unprotected sugar derivatives and allows the HAT hydrogenation of unprotected C-glycoside in higher yield compared to previously reported HAT hydrogenation protocols. The proposed mechanism is supported by experimental and theoretical studies.

Protein adsorption behaviors onto Mn(II)-doped calcium hydroxyapatite particles with different morphologies.

Fundamental experiments on the adsorption behaviors of proteins onto plate-like and rod-like manganese-doped calcium hydroxyapatite particle (abbreviated as MnHAp) were examined. All of the obtained adsorption isotherms of bovine serum albumin (BSA) and lysozyme (LSZ) in a 1 × 10-4 mol/dm3 KCl solution were of the Langmuirian type. We found that the saturated amounts of the adsorbed BSA (nsBSA) increased with the increase in Mn/(Ca + Mn) atomic ratio (abbreviated as XMn) of the plate-like MnHAp, while the saturated amounts of adsorbed LSZ (nsLCZ) decreased. This result is explained by plate shape of the particles; the large fraction of positively charged adsorbing sites produced on the ac and bc faces (C sites) of these particles is advantageous to the adsorption of negatively charged BSA. In this case, however, the fraction of negatively charged adsorbing sites produced on the ab faces (P sites) decreased, and the (nsLCZ) values therefore decreased. In the case of the rod-like MnHAp, (nsBSA) decreased until XMn = 0.08, while the (nsLCZ) values were almost constant (ca. 0.2 mg/m2) over the whole range of XMn. This decrease in (nsBSA) values is explained by the increase in the specific surface area of rod-like particles as XMn increased. However, since the fraction of P sites on the ab faces does not depend on the particle length, the (nsLCZ) values were nearly constant. The binding effect of the Mn2+ and Ca2+ ions dissolved from rod-like particles caused the increase in (nsBSA) at XMn ≥ 0.1. The adsorption behavior of proteins onto MnHAp is therefore strongly dependent on the morphology of these particles.