Copper-Catalyzed Asymmetric Arylation of α-Substituted Cyanoacetates Enabled by Chiral Amide Ligands.

The (S)-nobin-embodied picolinamide and L-hydroxyproline-derived amide are effective ligands for Cu-catalyzed enantioselective coupling reaction of (hetero)aryl iodides with α-alkyl substituted cyanoacetates. This arylation reaction gave α-(heteroaryl)-α-alkyl cyanoacetates in good to excellent enantioselectivities (up to 95 % ee). A variety of functionalized (hetero)aryl and alkyl groups could be introduced to the quaternary center and therefore provided a valuable tool for preparing enantioenriched compounds with an all-carbon quaternary center tethered with convertible functional groups. The size of both α-alkyl and ester groups was proven as the key factor for asymmetric induction.

Cu/Oxalic Diamide-Catalyzed Coupling of Terminal Alkynes with Aryl Halides.

N1-(2,6-Dimethylphenyl)-N2-(pyridin-2-ylmethyl)oxalamide (DMPPO) was revealed to be a more effective ligand for copper-catalyzed coupling reaction of (hetero)aryl halides with 1-alkynes than previously reported ones. Only 3 mol % CuCl and DMPPO are required to make the coupling complete at 100 °C (for bromides) and 80 °C (for iodides). Both (hetero)aryl and alkyl substituted 1-alkynes worked well under these conditions, leading to the formation of internal alkynes in great diversity.

Cu-Catalyzed Coupling Reactions of Sulfonamides with (Hetero)Aryl Chlorides/Bromides.

Direct N-arylation of sulfonamides is a very attractive approach for preparing pharmaceutically important N-(hetero)aryl sulfonamides because it avoids the potential genotoxic problem resulting from the previous condensation method. Most known catalytic methods suffer from limited reaction scope and inconveniency on metal catalyst and ligand availability. Here we described that the combination of copper and oxalamides (or 4-hydroxypicolinamides) offers a powerful catalytic system for N-arylation of sulfonamides. A wide range of primary and secondary sulfonamides were able to couple with a series of (hetero)aryl bromides in the presence of 2-5 mol % copper salts and oxalamides at 100 °C. Coupling of primary sulfonamides with (hetero)aryl chlorides worked well under the catalysis of Cu2 O and a 4-hydroxypicolinamide. The catalytic method enabled direct sulfonamidation of four chloro-containing marketed drugs and preparation of two sulfonamide drugs from the corresponding aryl halides.

Divergent Synthesis of Contorted Polycyclic Aromatics Containing Pentagons, Heptagon, and/or Azulene.

Divergent synthesis of four contorted aromatics containing pentagons, a heptagon, and/or an azulene from the same difluorenyl pentacenediene precursor were realized in one step. The subtle differences in molecular structure were confirmed by X-ray crystallography. The mechanisms for the control of different products, which involve a ring-expansion rearrangement, Scholl reactions, and/or Mallory cyclization were proposed on the basis of control experiments and DFT calculations. Such development adds good structure versatility and materials accessibility to the study of contorted aromatics.

Assembly of α-(Hetero)aryl Nitriles via Copper-Catalyzed Coupling Reactions with (Hetero)aryl Chlorides and Bromides.

α-(Hetero)aryl nitriles are important structural motifs for pharmaceutical design. The known methods for direct synthesis of these compounds via coupling with (hetero)aryl halides suffer from narrow reaction scope. Herein, we report that the combination of copper salts and oxalic diamides enables the coupling of a variety of (hetero)aryl halides (Cl, Br) and ethyl cyanoacetate under mild conditions, affording α-(hetero)arylacetonitriles via one-pot decarboxylation. Additionally, the CuBr/oxalic diamide catalyzed coupling of (hetero)aryl bromides with α-alkyl-substituted ethyl cyanoacetates proceeds smoothly at 60 °C, leading to the formation of α-alkyl (hetero)arylacetonitriles after decarboxylation. The method features a general substrate scope and is compatible with various functionalities and heteroaryls.

High Quality Pyrazinoquinoxaline-Based Graphdiyne for Efficient Gradient Storage of Lithium Ions.

N-doping of graphdiyne with atomic precision is very important for the study of heteroatom doping effect and the structure-properties relationships of graphdiyne. Here we report the bottom-up synthesis and characterizations of high-quality pyrazinoquinoxaline-based graphdiyne (PQ-GDY) film. First-principle studies of the layered structure were performed to examine the stacking mode, lithium binding affinity, and bulk lithium storage capacity. Three-stage insertion of 14 lithium atoms with binding affinities in the order of pyrazine nitrogen > diyne carbon > central aromatic ring were confirmed by both lithium-ion half-cell measurements and DFT calculations. More than half of the lithium atoms preferentially bind to pyrazine nitrogen, and a reversible capacity of 570.0 mA h g-1 at a current density of 200 mA g-1 after 800 cycles was achieved. Such a high capacity utilization rate of 97.2% provides a good case study of N-doped GDY with atomic precision.

Trelagliptin succinate: DPP-4 inhibitor to improve insulin resistance in adipocytes.

Trelagliptin inhibits the enzyme dipeptidyl-4 (DPP-4) to treat type 2 diabetes and it may possess the potential to improve insulin resistance. However, the molecular mechanism is not known. In this study, the effect of trelagliptin succinate in improving insulin resistance was investigated. The differentiation system of 3T3-L1 mouse preadipocytes was used to determine the content of adipokines and the content of GLUT4 in the outer membrane. The expression of AKT, P-AKT, IRS-1 and P-IRS-1 in differentiated 3T3-L1 adipocytes was determined by western blotting. Our results demonstrated that trelagliptin succinate increased the expression of AKT, P-AKT, IRS-1 and P-IRS-1 in the PI-3K/AKT insulin signaling pathway. These events promote the trans-membrane function of GLUT4 and concomitant glucose intake in adipocytes. In addition, the secretion of free fatty acids and resistin were decreased. In conclusion, our study suggested that trelagliptin succinate improved insulin resistance in adipocytes via regulation of PI-3K/AKT/GLUT4 insulin signaling pathway.

Effects and mechanisms of iridoid glycosides from Patrinia scabiosaefolia on improving insulin resistance in 3T3-L1 adipocytes.

Insulin resistance causes several adverse effects such as hypertension, diabetes and different aspects of cardiovascular diseases. Patrinia scabiosaefolia Fisch. ex Trev. is a traditional Chinese edible herbal, whose n-BuOH extract significantly increased glucose transportin 3T3-L1 adipocytes at the concentration of 12.5 µM. To determine its active constituent, its chemical components and bioactivities were investigated. Two compounds (1-2) could significantly improve insulin resistance in 3T3-L1 adipocytes at concentrations around 25.0 µM (P < 0.001). Compound 2 was more effective to lower the content of glucose content at 12.5 µM (P < 0.001). Compound 1 was a new compound identified by spectroscopic methods. Western-blot experiment demonstrated an upregulation of p-IRS-1, p-Akt, and GLUT4 induced by compounds 1 and 2. Hence, we speculated that compounds 1 and 2 could activate PI3K and Akt signaling by up-regulating of p-IRS-1 which resulted in the activation of PI3K before phosphorylating Akt, ultimately led to translocation of GLUT4. These events finally improve glucose transport. Our results may provide the scientific basis for the development and effective use of P. scabiosaefolia against type 2 diabetes.

The Mechanism of Phillyrin from the Leaves of Forsythia suspensa for Improving Insulin Resistance.

Three lignans, phillyrin, forsythia ester A, and rosin-ß-D-furan glucose, were isolated from Forsythia suspensa which is a famous Traditional Chinese Medicine used for clearing heat and detoxifying, reducing swelling and dispersing knot, and dispersing wind heat. In this study, the effects of phillyrin, forsythia ester A, and rosin-ß-D-furan glucose on insulin resistance of 3T3-L1 adipocytes were investigated by the method of glucose oxidase-peroxidase (GOD-POD) and the mechanism was assayed by the method of western blot. The results indicated that phillyrin, forsythia ester A, and rosin-ß-D-furan glucose could improve the glucose uptake in 3T3-L1 adipocytes under insulin resistance (IR). Among them, phillyrin showed significant activity in increasing glucose consumption at the concentrations of 100 µM and 200 µM (P < 0.001). The mechanism of improving insulin resistance may be that phillyrin could raise the protein phosphorylation of IRS-1 and Akt and the expression levels of GLUT4 protein.

Alizarin increase glucose uptake through PI3K/Akt signaling and improve alloxan-induced diabetic mice.

AIM: Alizarin (AZ), that can be isolated from Rubia cordifolia, has biological activities such as antioxidation and anti-inflammatory. This study aimed to investigate the effect of AZ on glucose and lipid metabolism disorders in alloxan-induced diabetic mice and also explored the effect of AZ on insulin resistance in 3T3-L1 adipocytes. RESULTS: The research showed that AZ could decrease fasting and postprandial blood glucose, TG, TC and MDA, and it could also increase liver glycogen levels and SOD activity in diabetic mice. AZ could significantly improve the glucose uptake of 3T3-L1 adipocytes under insulin resistance, and could also increase GLUT4 protein expression levels, IRS-1 and Akt protein phosphorylation. CONCLUSION: These results showed that AZ has the potential to reduce blood sugar and improve insulin resistance.

Polyelectrolyte Complex Nanoparticles Based on Methoxy Poly(Ethylene Glycol)-B-Poly (ε-Caprolactone) Carboxylates and Chitosan for Delivery of Tolbutamide.

In this study, a novel chitosan (CS)-modified nanoparticles (NPs) were developed to orally deliver tolbutamide (TOL). Methoxy poly(ethylene glycol)- b-poly(ε-caprolactone) carboxylates (mPEG2000-b-PCL4000) was synthesized via an esterification reaction. CS-modified mPEG2000-b-PCL4000-COOH NPs (CS@NPs) were fabricated by injecting mPEG2000-b-PCL4000-COOH NPs suspension (1.0 mg/mL) into CS solution (1.0 mg/mL, pH 5.0). Fourier transform infrared spectroscopy (FTIR) spectra were used to confirm the obtaining of mPEG2000-b-PCL4000-COOH. Transmission electron microscope (TEM) was carried out to observe morphology of all NPs. Nano ZS90 Malvern ParticleSizer were used to monitor the size distribution of obtained NPs. Thermogravimetry analysis (TGA) was performed to investigate the thermostability of CS@NPs. In vitro TOL release profiles were carried out in pH 1.2 and 7.4 buffers. FTIR spectra confirmed the obtaining of mPEG2000-b-PCL4000-COOH. TGA curves indicated that the protection of CS shells improved the thermostability of mPEG2000-b-PCL4000-COOH NPs. Cell tests indicated the CS@NPs had no obvious cytotoxicity, and they were easily taken up by 293T cells. In vitro release profiles showed that 91.0 ± 1.9% of encapsulated TOL were released from TOL-CS@NPs in pH 7.4 buffer. Therefore, the positive potential of CS@NPs could increase their combining capacity with intestinal mucosal cells. Finally, these NPs would improve the bioavailability of hydrophobic drugs.

Cp*Rh(iii) catalyzed ortho-halogenation of N-nitrosoanilines by solvent-controlled regioselective C-H functionalization.

We present a novel, efficient, and regioselective method for the rhodium-catalyzed direct C-H ortho-halogenation of anilines that involves a removable N-nitroso directing group. This method featured mild reaction conditions, wide substrate scope, good functional group tolerance and satisfactory yields. To maintain the high ortho-regioselectivity and conversion, increasing the steric hindrance of the solvent was critical. Preliminary mechanistic studies suggest that C-H activation may be involved in the rate-determining step.

Antithrombotic components of Malus halliana Koehne flowers.

Flowers of Malus halliana (M. halliana) Koehne have been used as a Chinese traditional medicine to treat metrorrhagia and in our study, its chemical composition and anticoagulant effect were investigated. Five compounds were isolated and identified from M. halliana flowers, including limocitrin-3-O-glucoside (1), baohuoside Ⅱ (2), kaempferol-3-O-α-L-furan arabinoside (3), phloretin-4'-O-glycosidase (4) and afzeloside (5). Compound 1-3 were isolated for the first time from this genus. The anticoagulant effect of the compounds and extracts of M. halliana flowers were evaluated by APTT, PT, TT and FIB on plasma of rabbit in vitro. The results indicated that several fractions of M. halliana flowers and compounds 2-5 exhibited anticoagulant activity in vitro. Subsequently, afzeloside (5), the abundant component in M. halliana flowers, was investigated further for its antithrombotic effect in vivo and its antithrombotic mechanisms were evaluated on rats acute blood-stasis model. The antithrombotic effect was evaluated by WBV, PV, HCT, ESR, APTT, PT, TT, FIB, 6-keto-PGF1α, TXB2, ET-1 and eNOS in vivo. Afzeloside demonstrated inhibitory effect of thrombus formation, and its underlying antithrombotic mechanism was found to be related to the regulation of vascular endothelium active substance, activating blood flow and anticoagulant effect. Hence, we postulate that flavonoids may be the active ingredients of the plant.

Access to 2-substituted-2H-indazoles via a copper-catalyzed regioselective cross-coupling reaction.

A CuCl catalyzed C-N cross-coupling reaction using commercially available 1H-indazoles with diaryliodonium salts is described. The methodology features ample structural versatility, affording 2-substituted-2H-indazole in good yields and complete N(2)-regiocontrol. Furthermore, the utility of the reaction was demonstrated in the synthesis of a known estrogen receptor ß agonist. Mechanistic studies using density functional theory calculations suggested that the complete regioselectivity can be attributed to the only weak base TfO- in our system which could not deprotonate indazoles, and the catalyst oxidation process would be the rate-determining step.

Rhodium(III)-Catalyzed Directed C-H Amidation of N-Nitrosoanilines and Subsequent Formation of 1,2-Disubstituted Benzimidazoles.

An efficient rhodium-catalyzed direct C-H amidation of N-nitrosoanilines with 1,4,2-dioxazol-5-ones as amidating agents has been developed. This method featured mild reaction conditions, a wide substrate scope and satisfactory yields. Besides, the amidated products could be readily converted to pharmaceutically valuable 1,2-disubstituted benzimidazoles via an HCl-mediated deprotection/cyclization process in one pot.

Pd-Catalyzed Dimethylation of Tyrosine-Derived Picolinamide for Synthesis of (S)-N-Boc-2,6-dimethyltyrosine and Its Analogues.

A short and efficient synthesis of (S)-N-Boc-2,6-dimethyltyrosine utilizing palladium-catalyzed directed C-H functionalization is described. This represents the first general method for the ortho-dimethylation of tyrosine derivatives and offers a practical approach for preparing this synthetically important building block. Notably, throughout the reaction sequence no racemization occurs at the susceptible α-chiral centers.

Rhodium-Catalyzed Regioselective C7-Olefination of Indazoles Using an N-Amide Directing Group.

A rhodium-catalyzed regioselective C-H olefination of indazole is described. This protocol relies on the use of an efficient and removable N,N-diisopropylcarbamoyl directing group, which offers facile access to C7-olefinated indazoles with high regioselectivity, ample substrate scope and broad functional group tolerance.

Iridium(III)-Catalyzed Regioselective C7-Amination of N-Pivaloylindoles with Sulfonoazides.

Direct C7-amination of N-pivaloylindoles has been achieved using a combination of [Cp*IrCl2]2, AgNTf2, and AgOAc as the catalyst and sulfonoazides as the nitrogen source. The reaction proceeded at room temperature to 80 °C to afford 7-sulfonamidoindoles in good to excellent yields. The reaction is broadly applicable to the C7-amination of a wide variety of 3-, 4-, 5-, and 6-substituted N-pivaloylindoles with either alkyl or aryl sulfonoazides.

Rhodium-Catalyzed Regioselective C7-Functionalization of N-Pivaloylindoles.

An efficient rhodium-catalyzed method for direct C-H functionalization at the C7 position of a wide range of indoles has been developed. Good to excellent yields of alkenylation products were observed with acrylates, styrenes, and vinyl phenyl sulfones, whereas the saturated alkylation products were obtained in good yield with α,ß-unsaturated ketones. Both the N-pivaloyl directing group and the rhodium catalyst proved to be crucial for high regioselectivity and conversion.

Assembly of substituted 3-aminoindazoles from 2-bromobenzonitrile via a CuBr-catalyzed coupling/condensation cascade process.

CuBr-catalyzed coupling reaction of 2-halobenzonitriles with hydrazine carboxylic esters and CuBr/4-hydroxy-l-proline-catalyzed coupling reaction of 2-bromobenzonitriles with N'-arylbenzohydrazides proceed smoothly at 60-90 °C to provide substituted 3-aminoindazoles through a cascade coupling/condensation (or coupling/deacylation/condensation) process. A wide range of 3-aminoindazoles with substituents at both the 1-position and the phenyl ring part can be prepared from the corresponding coupling partners.