Clinical Evidence and Potential Mechanisms of Complementary Treatment of Ling Gui Zhu Gan Formula for the Management of Serum Lipids and Obesity.

Objective: This study aims to evaluate the clinical effects of Ling Gui Zhu Gan formula (LGZG), a famous TCM formula, for the management of serum lipids and obesity and preliminarily elucidates the bioactive components and the potential mechanism. Methods: Cluster analysis was adopted to investigate the TCM herbs and their frequency of occurrence for treating hyperlipidemia and obesity in an academic experience database of Chinese famous TCM doctors (http://www.gjmlzy.com:83). Then, relevant randomized controlled trials (RCTs) about LGZG supplementation in improving lipid levels and obesity were retrieved and analyzed. Lastly, the integration of network pharmacology, as well as greedy algorithms, which are theoretically well founded for the set cover in computer science, was exploited to identify the bioactive components of LGZG and to reveal potential mechanisms for attenuation or reversal of hyperlipidemia and obesity. Results: Based on the cluster analysis of 104 cases in TCM academic experience database, four TCM herbs in LGZG showed high-use frequency for treating hyperlipidemia and obesity. Meta-analysis on 19 randomized controlled trials (RCTs) with 1716 participants indicated that LGZG supplementation significantly decreased the serum levels of total triglycerides, total cholesterol, low-density lipoprotein cholesterol, BMI, and body weight and increased high-density lipoprotein cholesterol, compared with clinical control groups. No serious adverse effect was detected in all studies. Twenty-one bioactive components of LGZG, mainly flavonoids (i.e., naringenin, kaempferol, and kumatakenin), saponins (i.e., hederagenin), and fatty acids (i.e., eicosenoic acid), had the potential benefits possibly by regulating multiple targets such as PTPN1, CYP19A1, and ESR2, as well as a few complex pathways including the TNF signaling pathway, PPAR signaling pathway, arachidonic acid metabolism, fat digestion, and absorption. Conclusion: The present study has proved the clinical value of LGZG as a complementary treatment for attenuation or reversal of hyperlipidemia and obesity. More high-quality clinical and experimental studies in the future are demanded to verify its effects and the precise mechanism of action.

Enantioselective Mannich Reactions of 3-Fluorooxindoles with Cyclic N-Sulfamidate Aldimines.

Both the 3-fluorooxindole and cyclic sulfamidate frameworks are important in medicinal chemistry owing to their associated biological activities. We report an approach accessing 3-fully substituted 3-fluorooxindoles, containing a benzo-fused sulfamidate subunit through highly enantioselective Mannich-type reactions between 3-fluorooxindoles and cyclic benzo-fused N-sulfamidate aldimines. These reactions are promoted by a commercially available cinchona alkaloid catalyst, accommodate a broad substrate scope, and deliver the desired products in a yield of up to 99% with an enantiomeric excess of up to 94%. A plausible reaction pathway is also presented.

Organocatalytic asymmetric Michael addition between 3-subsituted oxindoles and enals catalyzed by camphor sulfonyl hydrazine.

Organocatalytic asymmetric Michael addition between 3-substituted oxindoles and enals catalyzed by chiral camphor sulfonyl hydrazines (CaSHs) has been developed. A wide range of 3-substituted oxindoles and enals were successfully used, giving the corresponding 3,3-disubstituted oxindoles containing vicinal stereogenic carbon centers in good yields with good to excellent enantioselectivities and moderate to good diastereoselectivities (up to 89% yield, 99% ee and 99 : 1 dr).

Organocatalytic asymmetric syntheses of 3-fluorooxindoles containing vicinal fluoroamine motifs.

An organocatalytic Mannich reaction of 3-fluorooxindoles has been developed. Using a commercially available cinchona alkaloid catalyst, a wide range of 3-fluorooxindoles was successfully reacted with N-sulfonyl aldimines to give biologically important 3-fluorooxindoles containing vicinal fluoroamine motifs with high efficiency and good enantioselectivity. This protocol uses readily available reactants and cheap organocatalysts, and it is operationally simple.

Diastereoselective Mannich Reactions Using Fluorinated Ketones: Synthesis of Stereogenic Carbon-Fluorine Units.

A diastereoselective Mannich reaction of simple α-fluoro ketones with N-tert-butylsulfinylimines was developed. This method provides a concise route to a variety of structurally diverse α-fluoro-ß-amino ketones containing fluorinated stereogenic carbon centers; good yields and high diastereoselectivities were achieved. This method uses readily accessible starting materials and has a broad substrate scope: cyclic and linear α-fluoro ketones and fluoromethyl ketones are all suitable substrates.

Diastereoselective Addition of Metal α-Fluoroenolates of Carboxylate Esters to N-tert-Butylsulfinyl Imines: Synthesis of α-Fluoro-ß-amino Acids.

We report a diastereoselective addition reaction of fluoroacetate and α-alkylated fluoroacetate to N-tert-butylsulfinyl imines. This method provides a concise route to α-fluoro-ß-amino acids containing fluorinated quaternary stereogenic carbon centers with very good yields and high diastereoselectivities. This protocol has the benefit of using abundant and readily accessible starting materials and is operationally simple. Additionally, the stereochemical outcome of the present reaction was different from that of the previously known addition of comparable nonfluorinated, brominated, and chlorinated enolates to N-sulfinyl imines, suggesting that an open transition state (rather than a closed one) is involved in the current fluoroalkylation reaction.

Crystal structure of 4-chloro-2-[(5-eth-oxy-1,3,4-thia-diazol-2-yl)meth-yl]-5-(piperidin-1-yl)pyridazin-3(2H)-one.

In the title mol-ecule, C14H18ClN5O2S, the six atoms of the 1,6-di-hydro-pyridazine ring are essentially coplanar (r.m.s. deviation = 0.008 Å), and the dihedral angle between this and the 1,3,4-thia-diazole ring is 62.06 (10)°. In the crystal, centrosymmetrically related mol-ecules are linked by inter-molecular C-H-O hydrogen bonding to form a supra-molecular dimer. The terminal ethyl group is statistically disordered over two positions.

Double-addition reaction of aryl methyl sulfones with N-tert-butylsulfinyl imines: diastereoselective and concise synthesis of 2-sulfonylated 1,3-diamines.

We report a double-addition reaction of methyl phenyl sulfone and methyl 2-pyridyl sulfone with N-tert-butylsulfinyl imines. This method provides concise access to 2-sulfonylated 1,3-anti diamines with good to excellent diastereoselectivities. This protocol has the benefit of using readily accessible starting materials and is operationally simple.

Selective arylation and vinylation at the α position of vinylarenes.

In intermolecular Heck reactions of styrene and vinylarenes, the aryl and vinyl groups routinely insert at the ß position. However, selective insertion at the α position has been very rare. Herein, we provide a missing piece in the palette of Heck reaction, which gave >20:1 α selectivity. The key to our success is a new ferrocene 1,1'-bisphosphane (dnpf) that carries 1-naphthyl groups. Our mechanistic studies revealed that the high α selectivity is partly attributable to the steric effect of dnpf. The rigid and bulky 1-naphthyl groups of dnpf sterically disfavor ß insertion.

1,1'-Bis[bis-(4-meth-oxy-phen-yl)phosphan-yl]ferrocene.

In the crystal structure of the title substituted ferrocene complex, [Fe(C19H18O2P)2], the Fe(II) atom lies on a twofold rotation axis, giving an eclipsed cyclo-penta-dienyl conformation with a ring centroid separation of 3.292 (7) Šand an Fe-C bond-length range of 2.0239 (15)-2.0521 (15) Å. In the ligand, the cyclo-penta-dienyl ring forms dihedral angles of 60.36 (6) and 82.93 (6)° with the two benzene rings of the diphenyl-phosphine group, while the dihedral angle between the benzene rings is 67.4 (5)°.

An efficient, overall [4+1] cycloaddition of 1,3-dienes and nitrene precursors.

Intermolecular cycloadditions of conjugated dienes and nitrene precursors usually produce aziridines. A generally useful method was lacking to directly provide the [4+1] cycloadducts, 3-pyrrolines. We have realized this transformation by using an uniquely active catalyst, copper(II) 1,1,1,5,5,5-hexafluoroacetylacetonate ([Cu(hfacac)(2)]). The method is applicable to a wide array of dienes with good yields. When 1,4-disubstituted dienes are used as substrates, good-to-excellent cis or trans selectivity can be obtained. Interestingly, the cis or trans preference depends on the nature of the substituents, rather than diene geometry. Mechanistic studies reveal that the [4+1] cycloaddition proceeds through diene aziridination and subsequent ring expansion. Among common copper catalysts, only [Cu(hfacac)(2)] can efficiently catalyze both steps, which explains the unique efficiency of the catalyst.