Rhodium(I)-Catalyzed Direct Enantioselective C-H Functionalization of Indoles.

A highly regiospecific vinylogous carbene insertion protocol for direct asymmetric C-H functionalization of indoles with arylvinyldiazoacetates has been developed. Under the catalysis of simple Rh(I)/chiral diene complexes, the reaction occurs solely at the vinylogous position of the vinylcarbenoid with exceptional E selectivity and enantiocontrol. It provides an efficient way to obtain an interesting class of chiral indole scaffolds bearing an α,ß-unsaturated ester unit and a gem-diaryl carbon stereocenter in good yields (≤99%) with excellent enantioselectivities (≤96%) at room temperature.

Design of a Coumarin-Based Fluorescent Probe for Efficient In Vivo Imaging of Amyloid-ß Plaques.

Amyloid-ß (Aß) is the core constituent protein of senile plaques, which is one of the key pathological hallmarks of Alzheimer's disease (AD). Here we describe the design, synthesis, and evaluation of coumarin-derived small molecule fluorophores for Aß imaging. By embedding the aromatic coumarin framework into π bridge of a push-pull chromophore, a novel fluorescence probe XCYC-3 applicable to efficient Aß recognition was discovered. XCYC-3 displays higher fluorescent enhancement for aggregated Aß than monomeric Aß, and possesses good blood-brain barrier permeability. In vitro staining and in vivo imaging studies demonstrated that XCYC-3 could efficiently recognize Aß plaques in the brain of AD transgenic mice. These results suggest that XCYC-3 is a promising fluorescence imaging agent for Aß, which might provide important clues for the future development of potent NIR fluorescent probes for Aß diagnosis.

Low Coordination State RhI -Complex as High Performance Catalyst for Asymmetric Intramolecular Cyclopropanation: Construction of penta-Substituted Cyclopropanes.

A simple, broad-scope rhodium(I)/chiral diene catalytic system for challenging asymmetric intramolecular cyclopropanation of various tri-substituted allylic diazoacetates was successfully developed. The low coordination state RhI -complex exhibits an extraordinarily high degree of tolerance to the variation in the extent of substitution of the allyl double bond, thus allowing the efficient construction of a wide range of penta-substituted, fused-ring cyclopropanes bearing three contiguous stereogenic centers, including two quaternary carbon stereocenters, in a highly enantioselective manner with ease at catalyst loading as low as 0.1 mol %. The stereoinduction mode of this RhI -carbene-directed asymmetric intramolecular cyclopropanation was investigated by DFT calculations, indicating that π-π stacking interactions between the aromatic rings of chiral diene ligand and diazo substrate play a key role in the control of the reaction enantioselectivity.

Rhodium-Catalyzed Asymmetric 1,4-Addition of α/ß-(N-Indolyl) Acrylates.

A rhodium-catalyzed asymmetric 1,4-addition of α/ß-(N-indolyl) acrylates to access highly enantioenriched chiral N-alkylindoles promoted by chiral diene or sulfur-olefin ligands under mild reaction conditions has been developed, which provides an efficient and practical approach for constructing carbon stereocenters adjacent to the indole nitrogen. The reaction can be applied to various N-indolyl-substituted α,ß-unstaturated esters and arylboron reagents, providing access to a wide range of α- and ß-(N-indolyl) propionate derivatives in high yields with excellent enantioselectivities (≤99% ee).

Rhodium(I) Carbene-Promoted Enantioselective C-H Functionalization of Simple Unprotected Indoles, Pyrroles and Heteroanalogues: New Mechanistic Insights.

A rhodium(I)-diene catalyzed highly enantioselective C(sp2 )-H functionalization of simple unprotected indoles, pyrroles, and their common analogues such as furans, thiophenes, and benzofurans with arylvinyldiazoesters has been developed for the first time. This transformation features unusual site-selectivity exclusively at the vinyl terminus of arylvinylcarbene and enables a reliable and rapid synthetic protocol to access a distinctive class of diarylmethine-bearing α,ß-unsaturated esters containing a one or two heteroarene-attached tertiary carbon stereocenter in high yields and excellent enantioselectivities under mild reaction conditions. Mechanistic studies and DFT calculations suggest that, compared to the aniline substrate, the more electron-rich indole substrate lowers the C-C addition barrier and alters the rate-determining step to the reductive elimination, leading to different isotope effect.

Association of Killer Cell Immunoglobulin-like Receptor and Human Leukocyte antigen-C Genotype with HLA-B27 Associated Acute Anterior Uveitis and Idiopathic Acute Anterior Uveitis in a Chinese Han Population.

PURPOSE: whether killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigens C (HLA-C) are associated with HLA-B27 associated acute anterior uveitis (B27AAU) and idiopathic AAU (IAAU) remains unclear. METHODS: PCR with sequence-specific primers was used to analyze KIR genes and HLA-C alleles in a Chinese Han population of 196AAU patients and 210 control subjects. RESULTS: The higher frequencies of HLA-C2 and KIR2DL1/HLA-C2 (p = .009 and p = .044, respectively) and the lower frequencies of HLA-C1C1 and HLA-C1 (p = .034 and p = .009, respectively) were observed in B27AAU than control group. The higher frequencies of KIR2DL2 and KIR2DL2/HLA-C1 (p = .009 and p = .044, respectively) and the lower frequencies of KIR2DL3 and KIR2DL3/HLA-C1 (p = .000 and p = .001, respectively) were observed in IAAU than control group. CONCLUSIONS: HLA-C2 and KIR2DL1/HLA-C2, KIR2DL2, and KIR2DL2/HLA-C1 might be susceptible for B27AAU and IAAU, respectively. HLA-C1C1 and HLA-C1, KIR2DL3 and KIR2DL3/HLA-C1 might protect from B27AAU and IAAU, respectively.

Stereodivergent Synthesis of Enantioenriched 2,3-Disubstituted Dihydrobenzofurans via a One-Pot C-H Functionalization/Oxa-Michael Addition Cascade.

A one-pot rhodium-catalyzed C-H functionalization/organocatalyzed oxa-Michael addition cascade reaction has been developed. This methodology enables the stereodivergent synthesis of diverse 2,3-disubstituted dihydrobenzofurans with broad functional group compatibility in good yields with high levels of stereoselectivity under exceptionally mild conditions. The full complement of stereoisomers of chiral 2,3-disubstituted dihydrobenzofurans and 3,4-disubstituted isochromans could be accessed at will by appropriate permutations of the two chiral catalysts. The current work provides a rare example of two chiral catalysts independently controlling two contiguous stereogenic centers subsequently via a two-step reaction in a single operation.

Regiospecific and Enantioselective Arylvinylcarbene Insertion of a C-H Bond of Aniline Derivatives Enabled by a Rh(I)-Diene Catalyst.

Asymmetric insertion of an arylvinylcarbenoid into the C-H bond for direct enantioselective C(sp2)-H functionalization of aniline derivatives catalyzed by a rhodium(I)-diene complex was developed for the first time. The reaction occurred exclusively at the uncommon vinyl terminus site with excellent E selectivity and enantioselectivities, providing various chiral γ,γ-gem-diarylsubstituted α,ß-unsaturated esters with broad functional group compatibility under simple and mild conditions. It provides a rare example of the asymmetric C-H insertion of arenes with selective vinylogous reactivity. Synthesis applications of this protocol were featured by several versatile product transformations. Systematic DFT calculations were also performed to elucidate the reaction mechanism and origin of the uncommon enantio- and regioselectivity of the Rh(I)-catalyzed C(sp2)-H functionalization reaction. The measured and computed inverse deuterium kinetic isotope effect supports the C-C bond-formation step as the rate-determining step. Attractive interactions between the chiral ligand and substrates were also proposed to control the enantioselectivity.

Water as a Direct Proton Source for Asymmetric Hydroarylation Catalyzed by a Rh(I)-Diene: Access to Nonproteinogenic ß2/γ2/δ2-Amino Acid Derivatives.

A highly enantioselective rhodium-catalyzed intermolecular hydroarylation of α-aminoalkyl acrylates using water as a direct proton source has been realized by employing a chiral bicyclo[3.3.0] diene ligand, allowing efficient access to a broad range of α-aryl-methyl-substituted ß2-, γ2-, and δ2-amino esters with excellent enantioselectivities (up to 98% ee) under exceptionally mild conditions. By utilizing this method, a series of structurally interesting benzo-fused heterocyclic molecules and the corresponding ß2-, γ2-, and δ2-amino acids are facilely constructed.

Clinical study of different doses of atorvastatin combined with febuxostat in patients with gout and carotid atherosclerosis.

OBJECTIVE: To evaluate the efficacy of atorvastatin combined with febuxostat in the treatment of gout patients with carotid atherosclerosis and to observe the effects on serum tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and C-reactive protein (CRP) levels, carotid plaques, and the adverse reactions. METHODS: Seventy patients with gout and carotid atherosclerosis admitted to Affiliated Hospital of Hebei University from January 2014 to June 2017 were randomly divided into a treatment group and a control group. The treatment group received oral febuxostat 40 mg/day combined with atorvastatin 40 mg/day. The control group was given 40 mg/day febuxostat combined with 20 mg/day atorvastatin for 90 days. The effects of treatment on TNF-α, IL-1ß, and CRP levels and carotid plaques of the patients were observed. RESULTS: After 90 days of treatment, serum TNF-α, IL-1ß, and CRP levels, as well as HUA and total cholesterol (TC), decreased in both groups after treatment. There were significant differences observed (p < 0.05). The carotid artery plaques in the two groups were significantly smaller after treatment (P<0.05). There was no significant difference in adverse reactions between the two groups (P > 0.05). CONCLUSION: Double doses of atorvastatin combined with febuxostat can effectively reduce uric acid to improve the inflammatory state in patients and reduce carotid plaques without increasing the incidence of adverse reactions.

Development of Bisindole-Substituted Aminopyrazoles as Novel GSK-3ß Inhibitors with Suppressive Effects against Microglial Inflammation and Oxidative Neurotoxicity.

Development of glycogen synthase kinase-3ß (GSK-3ß) inactivation-centric agents with polypharmacological profiles is increasingly recognized as a promising therapeutic strategy against the multifactorial etiopathology of Alzheimer's disease (AD). In this respect, a series of disubstituted aminopyrazole derivatives were designed and synthesized as a new class of GSK-3ß inhibitors. Most of these derivatives possess GSK-3ß inhibitory activities with IC50 values in the micromolar ranges, among which bisindole-substituted aminopyrazole derivative 6h displayed moderate GSK-3ß inhibition (IC50 = 1.76 ± 0.19 µM), and alleviative effects against lipopolysaccharide (LPS)-induced glial inflammation in BV-2 cells and glutamate-induced oxidative neurotoxicity in HT-22 cells. Further in vivo studies indicated that compound 6h had potent anti-inflammatory effect, by showing markedly reduced microglial activation and astrocyte proliferation in the brain of LPS-injected mice. Overall, the simultaneous modulation of 6h on multiple dysfunctions of disease network highlights this structural distinctively bisindole-substituted aminopyrazole could be a useful prototype for the discovery of novel therapeutic agents to tackle AD and other GSK-3ß associated complex neurological syndromes.

Chiral diene-promoted room temperature conjugate arylation: highly enantioselective synthesis of substituted chiral phenylalanine derivatives and α,α-di(arylmethyl)acetates.

A highly enantiocontrolled room temperature rhodium-catalyzed conjugate arylation process was developed. The reaction proceeds through 1,4-addition of α-substituted acrylates followed by enantioselective protonation using a C1-symmetric chiral bicyclo[2,2,2] diene as the ligand and water as the proton source. This exceptionally simple protocol provides a reliable and practical access to structurally important phenylalanine derivatives and α,α-di(arylmethyl)acetates in high yields (up to 99%) with good to excellent ee values (up to 99%).

Pd(II)-Catalyzed Asymmetric Annulation toward the Synthesis of 2,3-Disubstituted Chiral Indenols.

An enantioselective asymmetric annulation of 2-formylboronic acids with internal alkynes has been realized using a chiral phosphinooxazoline/palladium(II) catalyst. The reaction tolerates a variety of alkynes including the relatively inert diaryl substituted internal ones. A wide range of optically active 2,3-disubstituted indenols was afforded in high yields with good to excellent enantioselectivities (up to 99% yield and 99% ee).

Rhodium-Catalyzed Enantioselective Addition of Arylboroxines to Isatin-Derived N-Boc Ketimines Using Chiral Phosphite-Olefin Ligands: Asymmetric Synthesis of 3-Aryl-3-amino-2-oxindoles.

An efficient rhodium-catalyzed enantioselective arylation of isatin-derived N-Boc ketimines with arylboroxines has been developed using H8-BINOL-derived phosphite-olefin as a chiral ligand. This method allows access to a broad variety of valuable tetrasubstituted 3-amino-2-oxindole derivatives in good yields (up to 98%) with excellent enantioselectivities (up to 98% ee).

Construction of Chiral 1,3-Diamines through Rhodium-Catalyzed Asymmetric Arylation of Cyclic N-Sulfonyl Imines.

A rhodium/sulfur-olefin complex catalyzed asymmetric 1,2-addition of arylboronic acids to six-membered 1,2,6-thiadiazinane 1,1-dioxide-type cyclic imines to access highly optically active sulfamides (95-99% ee) has been developed. By taking advantage of the simple functional group transformations, an interesting array of valuable chiral 1,3-diamines with different substitution patterns can be readily obtained in a highly enantioenriched manner.

Highly enantioselective synthesis of α-tertiary chiral amino acid derivatives through rhodium-catalyzed asymmetric arylation of cyclic N-sulfonyl α-ketimino esters.

By employing an easily available, exceptionally simple sulfur-olefin ligand, a highly enantioselective rhodium-catalyzed arylation of cyclic N-sulfonyl α-ketimino esters with arylboronic acids has been developed. The reaction allows facile access to a wide range of α,α-gem-diaryl substituted chiral amino esters in excellent yields with extremely high enantioselectivities (uniformly 98-99% ee). The synthetic utility of this approach was highlighted by the efficient synthesis of a series of interesting molecules including unique chiral spirocycles bearing 2,3-dihydrobenzofuran and 1H-isoindole skeletons.

Rhodium-Catalyzed Enantioselective Alkenylation of Cyclic Ketimines: Synthesis of Multifunctional Chiral α,α-Disubstituted Allylic Amine Derivatives.

By employing a simple open-chain chiral phosphite-olefin ligand, a highly enantioselective rhodium-catalyzed alkenylation of 1,2,5-thiadiazole 1,1-dioxide-type cyclic ketimines with diverse vinylboronic acids was achieved under mild conditions at room temperature. This protocol provides an efficient and practical access to multifunctional α,α-disubstituted chiral allylic amines bearing quaternary stereocenters in high yields (up to 99%) with good to excellent ee's (up to 99%).

Access to Spiroindolines and Spirodihydrobenzofurans via Pd-Catalyzed Domino Heck Spiroyclization through C-H Activation and Carbene Insertion.

A new palladium-catalyzed domino approach for the synthesis of attractive spirocyclic indolines and dihydrobenzofurans was developed. The reaction proceeds through a sequential intramolecular Heck spirocyclization, remote C-H activation, and diazocarbonyl carbene insertion. Various spiroindolines and spirodihydrobenzofurans containing two quartenary carbon stereocenters were readily obtained in good to excellent yields. A preliminary study of asymmetric spirocyclization using chiral monophosphoramidite as a ligand was also conducted, enabling access to highly valuable chiral spiroindolines with up to 80% ee.

Ligand-Controlled Rhodium-Catalyzed Site-Selective Asymmetric Addition of Arylboronic Acids to α,ß-Unsaturated Cyclic N-Sulfonyl Ketimines.

A site-selective rhodium-catalyzed asymmetric 1,4-/1,2-addition of arylboronic acids to challenging α,ß-unsaturated cyclic ketimines was realized through a ligand-controlled strategy. By employing different chiral olefin ligands, a ligand-controlled switch in the reaction regioselectivity was attained for the first time. The reactions allow the synthesis of highly valuable α,α-disubstituted chiral allylic amines and enantioenriched 1,4-adducts. Further product transformation provided easy access to various quaternary carbon-containing chiral amines and amino acid derivatives bearing multifunctional groups.

Enantioselective Synthesis of gem-Diaryl Benzofuran-3(2H)-ones via One-Pot Asymmetric Rhodium/Palladium Relay Catalysis.

An asymmetric dual-metal relay catalysis strategy that combines Rh/chiral sulfur-olefin-catalyzed enantioselective 1,2-addition with a Pd-catalyzed intramolecular C-O coupling has been developed. The method allows rapid and efficient synthesis of quaternary carbon-containing gem-diaryl benzofuran-3(2H)-ones in good yields in a highly enantioselective manner (up to 99% ee) through a simple one-pot cascade reaction.