Three-Component Reaction of Pentafluorosulfanyl Chloride, Alkenes and Diazo Compounds and Synthesis of Pentafluorosulfanylfurans.

We report herein the three-component radical addition reaction of SF5 Cl, alkene and diazo compounds for the selective formation of α-alkyl-α-SF5 carbonyl compounds. The three-component addition reaction proceeded through the first reaction of SF5 radical with the diazo compound followed by the addition of the in situ generated carbon radical to alkene. The synthetic useful α-allyl-α-SF5 carbonyl compounds were successfully prepared when allyl trimethylsilanes were used as the alkene substrates. Furthermore, the three-component adducts formed from SF5 Cl, α-diazoacetophenones and vinyl acetates were converted into pentafluorosulfanylfurans. This transformation provided a practical and efficeint method for the synthesis of pentafluorosulfanylfurans.

HIV induces synaptic hyperexcitation via cGMP-dependent protein kinase II activation in the FIV infection model.

Over half of individuals infected with human immunodeficiency virus (HIV) suffer from HIV-associated neurocognitive disorders (HANDs), yet the molecular mechanisms leading to neuronal dysfunction are poorly understood. Feline immunodeficiency virus (FIV) naturally infects cats and shares its structure, cell tropism, and pathology with HIV, including wide-ranging neurological deficits. We employ FIV as a model to elucidate the molecular pathways underlying HIV-induced neuronal dysfunction, in particular, synaptic alteration. Among HIV-induced neuron-damaging products, HIV envelope glycoprotein gp120 triggers elevation of intracellular Ca2+ activity in neurons, stimulating various pathways to damage synaptic functions. We quantify neuronal Ca2+ activity using intracellular Ca2+ imaging in cultured hippocampal neurons and confirm that FIV envelope glycoprotein gp95 also elevates neuronal Ca2+ activity. In addition, we reveal that gp95 interacts with the chemokine receptor, CXCR4, and facilitates the release of intracellular Ca2+ by the activation of the endoplasmic reticulum (ER)-associated Ca2+ channels, inositol triphosphate receptors (IP3Rs), and synaptic NMDA receptors (NMDARs), similar to HIV gp120. This suggests that HIV gp120 and FIV gp95 share a core pathological process in neurons. Significantly, gp95's stimulation of NMDARs activates cGMP-dependent protein kinase II (cGKII) through the activation of the neuronal nitric oxide synthase (nNOS)-cGMP pathway, which increases Ca2+ release from the ER and promotes surface expression of AMPA receptors, leading to an increase in synaptic activity. Moreover, we culture feline hippocampal neurons and confirm that gp95-induced neuronal Ca2+ overactivation is mediated by CXCR4 and cGKII. Finally, cGKII activation is also required for HIV gp120-induced Ca2+ hyperactivation. These results thus provide a novel neurobiological mechanism of cGKII-mediated synaptic hyperexcitation in HAND.

Chemoselective Hydro(Chloro)pentafluorosulfanylation of Diazo Compounds with Pentafluorosulfanyl Chloride.

Pentafluorosulfanyl chloride (SF5 Cl) is the most prevalent reagent for the incorporation of SF5 group into organic compounds. However, the preparation of SF5 Cl often relies on hazardous reagents and specialized apparatus. Herein, we described a safe and practical synthesis of a bench-stable and easy-to-handle solution of SF5 Cl in n-hexane under gas-reagent-free conditions. The synthetic application of SF5 Cl was demonstrated through the unprecedented reaction with diazo compounds. The chemoselective hydro- and chloropentafluorosulfanylations of α-diazo carbonyl compounds were developed in the presence of K3 PO4 or copper catalyst, respectively. These reactions provide a direct and efficient access to various α-pentafluorosulfanyl carbonyl compounds of high value for potential applications.

Rh(II)/Ag(I)-Cocatalyzed Three-Component Reaction via SN1/SN1'-Type Trapping of Oxonium Ylide with the Nicholas Intermediate.

A Rh(II)/Ag(I)-cocatalyzed three-component reaction of propargylic alcohol-Co2(CO)6 complexes with diazo compounds and benzyl alcohols is described, which represents the first trapping process of oxonium ylides with carbocations via the SN1/SN1'-type pathway. This transformation provides an efficient approach for construction of dicobalt hexacarbonyl-complexed 3,3-disubstituted oxindoles. Further derivatization of the product, initiated by the deprivation of the dicobalt species, gives the 3,3-disubstituted oxindoles with the ene alkynyl group and the privileged spirooxindole-vinyldihydropyran structure.

Synthesis of Hexafluoroisopropyl Aryl Ethers via Dual Photoredox/Nickel-Catalyzed C-O Coupling.

Herein we report a photoredox/nickel-catalyzed cross-coupling of aryl bromides with 1,1,1,3,3,3-hexafluoroisopropanol for the construction of hexafluoroisopropyl aryl ethers. The mild reaction conditions employed allow for the applicability of a wide range of aryl and heteroaryl bromides. Late-stage functionalization and preliminary mechanistic studies have been demonstrated.

trans-Trifluoromethyltetrafluorosulfanyl Chloride: Selective Synthesis and Reaction with Diazo Compounds.

trans-Trifluoromethyltetrafluorosulfanyl chloride (trans-CF3SF4Cl) is a unique reagent for the incorporation of the CF3SF4 group into organic compounds. However, CF3SF4Cl was prepared from hazardous reagents or formed as mixture of trans and cis isomers in low yield. Herein, a silver-promoted selective synthesis of trans-CF3SF4Cl under safe gas-reagent-free conditions is described. Furthermore, the synthetic application of trans-CF3SF4Cl is demonstrated through the new trifluoromethyltetrafluorosulfanylation of α-diazo carbonyl compounds.

Distinct Roles of GluA2-lacking AMPA Receptor Expression in Dopamine D1 or D2 Receptor Neurons in Animal Behavior.

Dopaminergic signaling in the central nervous system regulates several aspects of animal behavior. In the dopaminergic circuits, there are two classes of neurons that can be differentiated by their expression of dopamine receptors, D1 or D2 receptors (D1Rs or D2Rs). Notably, Ca2+-permeable GluA2-lacking glutamate AMPA receptors (CP-AMPARs) are important for gating synaptic plasticity and gene expression in neurons, and their expression particularly in the striatum affects various forms of animal behavior. However, differential effects of GluA2-lacking AMPARs in D1R or D2R neurons on animal behavior have not been addressed. Here, we employed the Cre-Lox recombination system to remove GluA2 selectively in D1R or D2R neurons to express CP-AMPARs and carried out multiple behavior assays. First, the open-field assay revealed that D2R GluA2 knockout (KO) mice showed hypoactivity, while GluA2 KO in D1R neurons had no effect on locomotor activity. We also revealed that D1R GluA2 KO mice showed delayed learning in the accelerating rotarod test compared with control animals, whereas D2R GluA2 KO animals exhibited complete loss of motor learning. In the sociability test, GluA2-lacking AMPAR expression in D1R neurons induced hypersociability, whereas D2R GluA2 KO mice elicited loss of sociability. Both D1R and D2R GluA2 KO mice consumed less food compared with control animals, while D1R GluA2 KO animals showed significantly more weight gain. Finally, D1R GluA2 KO induced anti-depressant effects, while GluA2-lacking AMPAR expression in D2R neurons promoted depression-like behavior. Taken together, GluA2-lacking CP-AMPAR expression in D1R and D2R neurons differentially affects animal behavior.

Co-activation of selective nicotinic acetylcholine receptors is required to reverse beta amyloid-induced Ca2+ hyperexcitation.

Beta-amyloid (Aß) peptide accumulation has long been implicated in the pathogenesis of Alzheimer's disease (AD). Hippocampal network hyperexcitability in the early stages of the disease leads to increased epileptiform activity and eventually cognitive decline. We found that acute application of 250 nM soluble Aß42 oligomers increased Ca2+ activity in hippocampal neurons in parallel with a significant decrease in activity in Aß42-treated interneurons. A potential target of Aß42 is the nicotinic acetylcholine receptor (nAChR). Three major subtypes of nAChRs (α7, α4ß2, and α3ß4) have been reported in the human hippocampus. Simultaneous inhibition of both α7 and α4ß2 nAChRs mimicked the Aß42 effects on both excitatory and inhibitory neurons. However, inhibition of all 3 subtypes showed the opposite effect. Importantly, simultaneous activation of α7 and α4ß2 nAChRs was required to reverse Aß42-induced neuronal hyperexcitation. We suggest co-activation of α7 and α4ß2 nAChRs is required to reverse Aß42-induced Ca2+ hyperexcitation.

Sucrose withdrawal induces depression and anxiety-like behavior by Kir2.1 upregulation in the nucleus accumbens.

Dieting induces depression and anxiety among other emotional symptoms. Animal models indicate that repeated access to palatable foods such as sugar induces depression and anxiety-like behavior when the food is no longer available. However, the neurobiological mechanisms of how dietary restriction influences mood have not been fully understood. We used the two-bottle sucrose choice paradigm as an overeating and withdrawal model. Withdrawal after lengthy sucrose overeating elicited depression and anxiety-like behavior, which was reversed by sucrose reinstatement. In the nucleus accumbens (NAc) of sucrose withdrawal animals, dopamine levels and cAMP response element binding protein (CREB) activity were significantly reduced, while the inwardly rectifying K+ channel, Kir2.1, was significantly elevated. In addition, overexpression of Kir2.1 selectively in neurons expressing dopamine D1 receptors was sufficient to induce negative mood-linked behavior in the absence of sucrose overeating experience. As elevated K+ channels reduce neuronal excitability, a sucrose withdrawal-induced increase in Kir2.1 expression is able to decrease NAc activity, which provides a cellular basis for depression and anxiety-like behavior in animals.

Enantioselective Trapping of Oxonium Ylides by 3-Hydroxyisoindolinones via a Formal SN1 Pathway for Construction of Contiguous Quaternary Stereocenters.

An enantioselective Rh(II)/chiral phosphoric acid co-catalyzed three-component reaction via trapping of oxonium ylides with 3-hydroxyisoindolinones by a formal SN1 pathway is described. This reaction allows for the efficient synthesis of isoindolinone derivatives with two contiguous quaternary stereogenic centers in high yields (up to 93%) with excellent enantioselectivities and moderate diastereoselectivities under mild reaction conditions.