Conformational Locking Induced Enantioselective Diarylcarbene Insertion into B-H and O-H Bonds Using a Cationic Rh(I)/Diene Catalyst.

Transition-metal-catalyzed enantioselective transformations of aryl/aryl carbene are inherently challenging due to the difficulty in distinguishing between two arene rings in the reaction process thus remain largely less explored. The few successful examples reported so far, without exception, have all been catalyzed by Rh(II)-complexes. Herein, we describe our successful development of a novel cationic Rh(I)/chiral diene catalytic system capable of efficient enantioselective B-H and O-H insertions with diaryl diazomethanes, allowing the access to a broad range of gem-diarylmethine boranes and gem-diarylmethine ethers in good yields with high enantioselectivities. Notably, previously unattainable asymmetric diarylcarbene insertion into the O-H bond was achieved for the first time. A remarkable feature of this newly designed Rh(I)/diene catalyst bearing two ortho-amidophenyl substitutents is that it can distinguish between two arene rings of the diaryl carbene through a stereochemically selective control of π-π stacking interactions. DFT calculations indicate that the rotation-restricted conformation of Rh(I)/diene complex played an important role in the highly enantioselective carbene transformations. This work provides an interesting and unprecedented stereocontrol mode in diaryl metal carbene transformations.

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.

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(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.

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.

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).

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%).

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.

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.

Recent advances in rhodium-catalyzed asymmetric synthesis of heterocycles.

Heterocycles are crucial structural motifs that are ubiquitously present in biologically active natural products and pharmaceutically important compounds. Over the past few decades, great attention has been paid to develop efficient methodologies for the construction of diverse enantioenriched heterocyclic frameworks. This review focuses on the recent impressive progress and advances in the asymmetric synthesis of heterocycles under rhodium catalysis.

Rhodium(I)-Catalyzed Highly Enantioselective Insertion of Carbenoid into Si-H: Efficient Access to Functional Chiral Silanes.

The first rhodium(I)-catalyzed enantioselective Si-H insertion reaction of α-diazoesters and α-diazophosphonates has been developed. The use of a C1-symmetric chiral diene ligand enabled the asymmetric reaction to proceed under exceptionally mild conditions and give versatile chiral α-silyl esters and phosphonates with excellent enantioselectivities (up to 99% ee). The mechanism and stereochemical pathway of this novel Rh(I)-carbene-directed Si-H insertion was investigated by deuterium kinetic isotope effect experiments and DFT calculations.

Access to Indole-Fused Polyheterocycles via Pd-Catalyzed Base-Free Intramolecular Cross Dehydrogenative Coupling.

A base-free process to access indole-fused polyheterocycles via a highly efficient and atom-economic palladium-catalyzed intramolecular cross dehydrogenetive coupling (CDC) reaction of 4-aniline substituted coumarins, quinolinones, and pyrones has been developed. A wide range of indolo[3,2-c]coumarins, indolo[3,2-c]quinolinones, and indolo[3,2-c]pyrones can be facilely afforded in good to excellent yields (up to 99%).

Rhodium(I)-catalyzed asymmetric carbene insertion into B-H bonds: highly enantioselective access to functionalized organoboranes.

A unique rhodium(I)-catalyzed asymmetric B-H insertion of α-diazo carbonyl compounds with easily available amine-borane adducts was achieved using a newly developed C1-symmetric chiral diene as ligand. This first Rh(I)-carbene-directed B-H insertion example represents an attractive and promising approach for synthesis of highly enantioenriched organoboron compounds, allowing for the efficient construction of α-boryl esters and ketones with excellent enantioselectivities (up to 99% ee) under exceptionally mild conditions.

Facile synthesis of acridines via Pd(0)-diphosphine complex-catalyzed tandem coupling/cyclization protocol.

A facile and efficient approach for the synthesis of a variety of acridines via the tandem coupling/cyclization of substituted 2-bromobenzaldehydes and anilines is described. The reaction can be accomplished with ease in the presence of a catalytic amount of Pd2(dba)3 and diphosphine ligand dppf, providing a broad range of substituted acridines in good to excellent yields (up to 99%). The Lewis acid, AlCl3, is required to promote the cyclization for less electron-rich anilines.

A highly diastereoselective Friedel-Crafts reaction of indoles with isatin-derived N-sulfinyl ketimines towards the efficient synthesis of chiral tetrasubstituted 3-indolyl-3-aminooxindoles.

A Lewis acid promoted highly diastereoselective asymmetric Friedel-Crafts alkylation of indoles with isatin-derived N-tert-butanesulfinyl ketimines is described. The reaction can be accomplished with ease in the presence of a catalytic amount of Bi(OTf)3, providing a series of 3-indolyl-3-aminooxindoles in excellent diastereoselectivities (up to 98% de) and yields (up to 99%).

Lewis acid promoted diastereoselective addition of TMSCN and TMSCF3 to isatin-derived N-sulfinyl ketimines: synthesis of optically active tetrasubstituted 3-aminooxindoles.

A practical and efficient method for preparation of highly enantiomerically enriched 3-cyano-3-aminooxindoles and 3-trifluoromethyl-3-aminooxindoles with up to 99% optical purity by a Lewis acid promoted diastereoselective Strecker reaction and trifluoromethylation of isatin-derived N-tert-butanesulfinyl ketimines has been developed. This protocol allows direct use of N-free isatin substrates under mild conditions.

Structure-activity relationship and interaction studies of new SIRT1 inhibitors with the scaffold of 3-(furan-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole.

SIRT1 is a NAD(+)-dependent deacetylase. It deacetylates a broad range of substrates and is involved in multiple diseases such as type 2 diabetes and cancer. Here we discovered a new class of SIRT1 inhibitors with the scaffold of 3-(furan-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole. The inhibitors up-regulate acetyl p53 level in human breast cells MCF-7. The docking simulations indicated that the scaffold and the R-substituents of the inhibitors bind in the C and D pocket of SIRT1, respectively, which was supported by the structure-activity relationship and SIRT1 mutagenesis studies. We propose that binding of the inhibitors repels the entering of the nicotinamide moiety of NAD(+) to the C pocket, prevents its transformation to the productive conformation and therefore inhibits the deacetylation catalyzed by SIRT1.

Clinical effects of soluble interleukin-6 receptor detection on autoimmune rheumatic disease patients.

UNLABELLED: Objective : This study aims to explore the effects of soluble interleukin-6 receptor (IL-6R) on the clinical diagnosis and treatment of autoimmune rheumatic disease (ARD) patients. METHODS: Sixty-eight ARD patients enrolled in our hospital recently were selected, the IL-6R levels of whom were detected by double-antibody sandwich ELISA method and compared with the IL-6 levels of normal subjects. The expressions of IL-6R in joint tissues were detected by section staining. The mechanism regarding the effects of IL-6R was postulated by administering the patients with blocking agent. RESULTS: The blood IL-6R level of ARD patients was 2-3 times higher than the IL-6 level of normal subjects with significant difference. The detection results of C-reactive protein and erythrocyte sedimentation rate show that both the indicators were significantly decreased (P=0.0098 and 0.0097 respectively). IL-6R was associated with autoimmunity based on the considerable expression in tissue sections, which was also verified by the alleviated symptoms after blocking IL-6R expression. CONCLUSION: Detecting soluble IL-6R is able to determine the patient's conditions and treatment effects. Meanwhile, soluble IL-6R detection can also serve as the inflammatory responses of ARD, as well as the determination index for abnormal immune responses and generated antibodies number, which is crucial for early diagnosis.

Simple branched sulfur-olefins as chiral ligands for Rh-catalyzed asymmetric arylation of cyclic ketimines: highly enantioselective construction of tetrasubstituted carbon stereocenters.

New, simple, sulfinamide-based branched olefin ligands have been developed and successfully used in Rh-catalyzed asymmetric arylations of cyclic ketimines, providing efficient and highly enantioselective access to valuable benzosultams and benzosulfamidates containing a stereogenic quaternary carbon center. This is the first example of applying a sulfur-olefin ligand in catalytic asymmetric addition of imines.