Ruthenium-catalyzed asymmetric hydrogenation of aromatic and heteroaromatic ketones using cinchona alkaloid-derived NNP ligands

A series of cinchona alkaloid-based NNP ligands, including a new one, have been employed for the asymmetric hydrogenation of ketones. By combining ruthenium complexes, various aromatic and heteroaromatic ketones were smoothly reacted, yielding valuable chiral alcohols with extremely high 99.9% ee. Moreover, a proposed reaction mechanism was discussed and verified by NMR.

A series of cinchona alkaloid-based NNP ligands including a new one has been employed for the asymmetric hydrogenation of ketones. By combining ruthenium complexes, various ketones were smoothly reacted with up to 99.9% ee.

Since the well-known failure of using racemic thalidomide, attention has been paid to the manufacture of optically pure compounds as effective components in pharmaceuticals and agrochemicals. Asymmetric hydrogenation of ketones, especially heteroaromatic ketones, has emerged as a popular facile route to approach enantiopure secondary alcohols as essential intermediates for the construction of biologically active molecules.^1–4 Knowles et al.⁵ pioneered the production of enantioenriched chiral compounds in 1968, and Noyori and co-workers^6–8 laid the cornerstone of asymmetric hydrogenation in 1990s. Subsequently, numerous catalytic systems have been developed. Ru-BICP-chiral diamine-KOH was developed and proved to be effective for asymmetric hydrogenation of aromatic ketones by Xumu Zhang.⁹ Cheng-yi Chen reported asymmetric hydrogenation of ketone using trans-RuCl₂[(R)-xylbinap][(R)-daipen] and afforded secondary alcohol in 92–99% ee.¹⁰ Mark J. Burk and Antonio Zanotti-Gerosa disclosed Phanephos-ruthenium-diamine complexes catalyzing the asymmetric hydrogenation of aromatic and heteroaromatic ketones with high activity and excellent enantioselectivity.¹¹ Qi-Lin Zhou et al. designed and synthesized chiral spiro diphosphines as a new chiral scaffold applied in the asymmetric hydrogenation of simple ketones with extremely high activity and up to 99.5% ee.^12–15 Similarly, Kitamura and co-workers have developed a set of tridentate binan-Py-PPh₂ ligands for the asymmetric hydrogenation of ketones affording excellent results.¹⁶ Recently, chiral diphosphines and tridentate ligands based on ferrocene have been developed for the asymmetric hydrogenation of carbonyl compound with a remarkable degree of success.^17–21 Despite many ligands for asymmetric hydrogenation of ketones have been reported, expensive reagent and multistep complicated reactions were employed to synthesize most of them.^22–24 In light of increasing industrial demand, easily obtained, cheap and practical chiral ligands are still highly desirable. In addition to chiral ligands, the selection of metals was essential for asymmetric hydrogenation.^25–27 Although Mn,^28–30 Fe,^31–34 Co,^35–37 Ni^38,39 and Cu^40,41 metals were proved to be effective for asymmetric hydrogenation in recent years, Rh,^42–44 Ir^45,46 and especially Ru remained the most preferred metals. Ruthenium^47–51 was chosen owing to its superior performances in terms of low price, selectivity and activity. Takeshi Ohkuma,⁵² Hanmin Huang^53,54 and Johannes G. de Vries⁵⁵ all successfully used ruthenium catalysts for asymmetric hydrogenation of ketones. Admittedly, there is a continuing interest in the development of cheaper, simpler and more efficient catalysts for the asymmetric hydrogenation of ketones under mild conditions to access corresponding secondary alcohols. Recently, we developed new NNP chiral ligands derived from cinchona alkaloid for the asymmetric hydrogenation of various ketones in extremely excellent results using a iridium catalytic system.⁵⁶ Prompted by these encouraging results, we were interested in exploring a ruthenium-catalyzed asymmetric hydrogenation of ketones with NNP chiral ligands derived from cinchona alkaloid. Here, we showed that changing from iridium to ruthenium, with the same simple synthetic ligands, delivered a catalyst catalyzed asymmetric hydrogenation of ketones to give the industrially important chiral alcohols with up to 99.9% ee. Although the catalytic activity of ruthenium catalyst was not as high as that of the iridium catalyst, the enantioselectivity could be maintained, and even showed higher enantioselectivity in the hydrogenation of some substrates.Chiral tridentate ligand NNP (L1–L10) were synthesized and characterized as reported in our previous publication. With tridentate ligands in hand, we began to evaluate the catalytic performance in benzylidene-bis(tricyclohexylphosphine) dichlororuthenium-catalyzed asymmetric hydrogenation of acetophenone employed as a standard substrate (Fig. 2). MeOH was found to be a better one as the conversion and enantioselectivity were 99.9% and 98.2%, respectively. Bases screening showed that Ba(OH)₂ was superior to the others, giving >99.9% conversion and 98.8% ee in the present catalytic system (Fig. 1). Ligand screening revealed that the configuration of chiral centers of cinchona alkaloids of the ligand markedly affected the catalytic performance. NNP ligands derived from cinchonine and quinidine appeared to benefit both the reaction rate and enantioselectivity, while those derived from cinchonidine and quinine had the opposite effect. Further, different NNP ligands that bearing different substituents on the phenyl rings were evaluated. Similar to our previous research, ligands with electron-withdonating substituents showed better catalytic performance than those with electron-withdrawing substituents. However, it was noted that the more electron-withdonating substituents furnished lower activity but same enantioselectivity. The optimal ligand L5 derived from quinidine with one methoxy group on benzene ring provided the corresponding chiral alcohol with 99.9% conversion and 98.8% ee. Considering that L3 derived from cinchonine had similar catalytic performance to L4 derived from quinidine, new ligand L10 similar to L5 with one methoxy group on benzene ring was synthesized and applied to the asymmetric hydrogenation of template substrate. 99.6% conversion and 97.6% ee was obtained. Hence, L5 was employed as better ligand in subsequent experiments.Open in a separate windowFig. 1The effect of different bases for the asymmetric hydrogenation of acetophenone (substrate/Ru/L5 = 500/1/2, ketones: 0.429 mol L⁻¹, base: 0.15 mol L⁻¹, MeOH: 2 mL, 30 °C, 6 MPa, 2 h.).Open in a separate windowFig. 2The effect of different solvents for the asymmetric hydrogenation of acetophenone. (substrate/Ru/L5 = 1000/1/2, ketones: 0.858 mol L⁻¹, Ba(OH)₂: 0.15 mol L⁻¹, solvent: 2 mL, 30 °C, 6 MPa, 2 h.).The effect of different ligand for the asymmetric hydrogenation of acetophenone^a

Structural and functional biomarkers of the insula subregions predict sex differences in aggression subscales

Aggression is a common and complex social behavior that is associated with violence and mental diseases. Although sex differences were observed in aggression, the neural mechanism for the effect of sex on aggression behaviors remains unclear, especially in specific subscales of aggression. In this study, we investigated the effects of sex on aggression subscales, gray matter volume (GMV), and functional connectivity (FC) of each insula subregion as well as the correlation of aggression subscales with GMV and FC. This study found that sex significantly influenced (a) physical aggression, anger, and hostility; (b) the GMV of all insula subregions; and (c) the FC of the dorsal agranular insula (dIa), dorsal dysgranular insula (dId), and ventral dysgranular and granular insula (vId_vIg). Additionally, mediation analysis revealed that the GMV of bilateral dIa mediates the association between sex and physical aggression, and left dId–left medial orbital superior frontal gyrus FC mediates the relationship between sex and anger. These findings revealed the neural mechanism underlying the sex differences in aggression subscales and the important role of the insula in aggression differences between males and females. This finding could potentially explain sexual dimorphism in neuropsychiatric disorders and improve dysregulated aggressive behavior.     

高效毛细管电泳法同时测定尿液清蛋白和肌酐

目的建立同时测定尿液清蛋白和肌酐的高效毛细管电泳法。方法对缓冲系统、pH值、缓冲液的离子强度、检测波长、表面活性剂、电压及电流和进样方法等进行研究,建立同时测定清蛋白和肌酐的毛细管电泳法。结果选择20mmol/L、pH9.3硼砂-NaOH(含6mmol/LSDS)缓冲液作为毛细管区带电泳运行液,利用外标法定量,检测波长214nm,同时测定肌酐和清蛋白。非涂层毛细管有效长度47.5cm,内径75μm;电流79μA,压力进样1psi、4s,电泳时间为12min。肌酐和清蛋白的线性范围分别为4.32～8840μmol/L和1.95～1000mg/L,肌酐和清蛋白最低检出限分别为0.977μmol/L和0.285mg/L。本法的日内和日间变异系数均小于4.8%。肌酐和清蛋白的平均回收率分别为99.6%和102.4%。结论建立的方法线性范围宽,测定简单快速,可用于临床检测。     

气功对顽固性失眠的治疗措施

目的：介绍气功对顽固性失眠的治疗措施。方法：从失眠的病因病机、周天功及六字诀治疗失眠的功理等入手详细分析了治疗的原理和原则。结果：将周天功与六字诀相配合可以有效地取长补短,达到心火下降,肾水上滋,心肾相交的效果。结论：气功对于顽固性失眠具有良好的治疗效果。     

Functional utilization of biochar derived from Tenebrio molitor feces for CO2 capture and supercapacitor applications

Biochar has attracted great interest in both CO₂ capture and supercapacitor applications due to its unique physicochemical properties and low cost. Fabrication of eco-friendly and cost-effective biochar from high potential biomass Tenebrio molitor feces can not only realize the functional application of waste, but also a potential way of future carbon capture and energy storage technology. In this study, a novel KOH activation waste-fed Tenebrio molitor feces biochar (TMFB) was developed and investigated in terms of CO₂ capture and electrochemical performance. When activated at 700 °C for 1 h, the specific surface area of the feces biochar (TMFB-700A) increased significantly from 232.1 to 2081.8 m² g⁻¹. In addition, well-developed pore distribution facilitates CO₂ capture and electrolyte diffusion. TMFB-700A can quickly adsorb a large amount of CO₂ (3.05 mol kg⁻¹) with excellent recycling performance. TMFB-700A also exhibited promising electrochemical performance (335.8 F g⁻¹ at 0.5 A g⁻¹) and was used as electrode material in a symmetrical supercapacitor. It provided a high energy density of 33.97 W h kg⁻¹ at a power density of 0.25 kW kg⁻¹ with 90.47% capacitance retention after 10 000 charge–discharge cycles. All the results demonstrated that TMFB could be a potential bifunctional material and provided valuable new insights for Tenebrio molitor feces high-value utilization.

Biochar has attracted great interest in both CO₂ capture and supercapacitor applications due to its unique physicochemical properties and low cost.     

Lucentamycins A-D, cytotoxic peptides from the marine-derived actinomycete Nocardiopsis lucentensis

Four new 3-methyl-4-ethylideneproline-containing peptides, lucentamycins A-D (1-4), have been isolated from the fermentation broth of a marine-derived actinomycete identified by phylogenetic methods as Nocardiopsis lucentensis (strain CNR-712). The planar structures of the new compounds were assigned on the basis of 1D and 2D NMR spectroscopic techniques, while the absolute configurations of the amino acid residues were determined by application of the advanced Marfey method. Lucentamycins A (1) and B (2) showed significant in vitro cytotoxicity against HCT-116 human colon carcinoma.     

Regulation of PPAR-γ activity in lipid-laden hepatocytes affects macrophage polarization and inflammation in nonalcoholic fatty liver disease

BACKGROUNDLipid metabolism disorder and inflammatory-immune activation are vital triggers in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Various studies have shown that PPAR-γ exerts potent anti-inflammatory and immunomodulatory properties. However, little is known about the regulation of PPAR-γ activity in modulating cell crosstalk in NAFLD.AIMTo investigate whether the regulation of PPAR-γ activity in lipid-laden hepatocytes affects macrophage polarization and inflammation.METHODSPrimary hepatocytes were isolated from wild-type C57BL6/J mice or hepatocyte-specific PPAR-γ knockout mice and incubated with free fatty acids (FFAs). Macrophages were incubated with conditioned medium (CM) from lipid-laden hepatocytes with or without a PPAR-γ agonist. Wild-type C57BL/6J mice were fed a high-fat (HF) diet and administered rosiglitazone.RESULTSPrimary hepatocytes exhibited significant lipid deposition and increased ROS production after incubation with FFAs. CM from lipid-laden hepatocytes promoted macrophage polarization to the M1 type and activation of the TLR4/NF-κB pathway. A PPAR-γ agonist ameliorated oxidative stress and NLRP3 inflammasome activation in lipid-laden hepatocytes and subsequently prevented M1 macrophage polarization. Hepatocyte-specific PPAR-γ deficiency aggravated oxidative stress and NLRP3 inflammasome activation in lipid-laden hepatocytes, which further promoted M1 macrophage polarization. Rosiglitazone administration improved oxidative stress and NLRP3 inflammasome activation in HF diet-induced NAFLD mice in vivo.CONCLUSIONUpregulation of PPAR-γ activity in hepatocytes alleviated NAFLD by modulating the crosstalk between hepatocytes and macrophages via the reactive oxygen species-NLRP3-IL-1β pathway.     

天冬天精的合成

本文通过全新的合成路线,以L-苯丙氨酸为起始化合物,经过甲酯化、游离、成内酐、缩合、水解、精制等6步反应得到天冬天精,总收率达到45．85％,较文献收率提高了8％,质量符合标准。     

百令胶囊在肾移植术后早中期的应用研究

为研究百令胶囊在肾移植术后早,中期的免疫抑制作用,将肾移植患者分为３组,Ａ组为百令胶囊＋Ｐｒｅｄ＋ＣｓＡ,Ｂ组为百令胶囊＋Ｐｒｅｄ＋ＣｓＡ＋ＡｚａＣ组为Ｐｒｅｄ＋ＣｓＡ＋Ａｚａ。结果：１．急性排斥发生情况：Ａ组１６．５％（３３／２００）,Ｂ组１１．７９％（３３／２８０）,Ｃ组１６％（１６／１００）,２．肝功能损害情况;Ａ组１８．５％,Ｂ组为２１．０７％,Ｃ组２５％,３．白细胞下降,Ａ组无,Ｂ组１２