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The selective introduction of fluorine atoms into drug candidates has long been used as a common strategy in drug discovery. Most methods used for the synthesis of tertiary aliphatic fluorides rely...

An exclusively regioselective hydrocyanation of monofluoroalkenes has been developed, with which a series of aliphatic quaternary α-fluoronitriles were synthesized in a facile and efficient manner. This novel method is featured with mild conditions, good functional groups compatibilities, and high reactivity.

The first example of copper-catalyzed ring-opening, enantioselective arylation of cyclic ketoxime esters to access ω,ω-diaryl alkyl nitriles has been developed in high yield (up to 92% yield) with excellent enantioselectivity (up to 91% ee). Side-arm bis(oxazoline) ligand plays a significant role in this asymmetric catalytic transformation, which provides an efficient route to construct diverse chiral ω,ω-diaryl alkyl nitriles. Synthetic utility has also been demonstrated in the further derivatization of the ω,ω-diaryl alkyl nitrile to the corresponding amide.

A novel method by a one-step introduction of axial chirality and sterically hindered group has been developed for facile synthesis of axially chiral styrene-type carboxylic acids. With the palladium-catalyzed C–H arylation and olefination of readily available cinnamic acid established, this transformation demonstrated excellent yield, excellent stereocontrol (up to 99% yield and 99% ee), and broad substrate scope under mild conditions. The axially chiral styrene-type carboxylic acids produced have been successfully applied to Cp*CoIII-catalyzed asymmetric C–H activation reactions, indicating their potential as chiral ligands or catalysts in asymmetric synthesis., Palladium-catalyzed asymmetric C–H functionalization to yield axially chiral styrene-type carboxylic acids is described, in which axial chirality and sterically hindered group were incorporated in one-step.

As an alternative approach to traditional C–H activation that often involved harsh conditions, and vicinal or primary C–H functionalization, radical relay offers a solution to these long-held problems. Enabled by 1,n (n = 5, 6)-hydrogen atom transfer (HAT), we use a most prevalent moiety, alkene, as the precursor to an sp3 C-centered radical to promote selective cleavage of inert C(sp3)–H bonds for the generation of azidotrifluoromethylated molecules. Mild conditions, broad scope and excellent regioselective control (>20 : 1) are observed in the reactions. Deuterium labelling studies disclose the kinetic characteristics of the transformations and verify a direct 1,n-HAT pathway. The key to this C-centered radical relay is that iron plays a dual role as a radical initiator and terminator to incorporate the azide functionality through radical oxidation via azido–ligand-transfer. The methods and the later derivatization promise expeditious synthesis of CF3-containing organic azides, γ-lactam and triazoles that are widely used in designing new fluorescent tags and functional materials.

Stress granules (SGs) form through phase separation of biomacromolecules to assist cells in resisting environmental stresses. Numbers of SG proteins contain Arg-Gly-Gly (RGG) motifs, indicating their RNA binding ability, and providing a substrate platform for asymmetric dimethylation of arginine (ADMA), whose roles in SG assembly remain unclear. Here, we demonstrated that Caprin1-mediated recruitment of PRMT1 asymmetrically dimethylates RGGs to provide multiple binding sites for TDRD3, a typical ADMA reader, which in turn bridges the multivalent interactions between RGG motifs and RNA to promote phase separation. This process was suppressed by a bivalent inhibitor of TDRD3, eventually inhibiting proliferation more effectively than arsenite treatment alone. Our work reveals the role of ADMA in SG assembly and the potential of targeting condensates for cancer therapy.

Summary: The direct functionalization of C(sp3)-H bonds has led to the development of methods to access molecules or intermediates from basic chemicals in an atom- and step-economic fashion. Nevertheless, achieving high levels of chemo-, regio-, and enantioselectivity in these reactions remains challenging due to the ubiquity and low reactivity of C(sp3)-H bonds. Herein, we report an unprecedented protocol for enantioselective cyanation of remote C(sp3)-H bonds. With chiral Box-Cu complex as the catalyst, the reaction of N-fluorosulfonamide furnishes the corresponding products in excellent yields and high enantiomeric excess (ee) under mild reaction conditions. A radical relay pathway involving 1,5-hydrogen atom transfer (1,5-HAT) of N-center radicals followed by enantioselective cyanation of the in situ-formed benzyl radicals is proposed. This enantioselective copper-catalyzed cyanation thus offers insights into an efficient way for the synthesis of bioactive molecules for drug discovery. : Catalysis; Organic Synthesis; Stereochemistry Subject Areas: Catalysis, Organic Synthesis, Stereochemistry

A nickel-catalyzed difluoroalkylation of α-C-H bonds of aryl ketones to furnish highly stereo-defined tetrasubstituted monofluoroalkenes or quaternary alkyl difluorides from secondary or tertiary ketones, respectively, has been established. Mechanistic investigations indicated that these C-H fluoroalkylations proceed via a Ni(i)/Ni(iii) catalytic cycle. An obvious fluorine effect was observed in the reaction, and this reaction has demonstrated high stereoselectivity, mild conditions, and broad substrate scopes, thus enabling the late-stage fluoroalkylation of bioactive molecules. This method offers a solution for expedient construction of monofluoroalkenes from readily available materials, and provides an efficient approach for the synthesis of bioactive fluorinated compounds for the discovery of lead compounds in medicinal chemistry.

As an alternative approach to traditional C–H activation that often involved harsh conditions, and vicinal or primary C–H functionalization, radical relay offers a solution to these long-held problems. Enabled by 1,n (n = 5, 6)-hydrogen atom transfer (HAT), we use a most prevalent moiety, alkene, as the precursor to an sp3 C-centered radical to promote selective cleavage of inert C(sp3)–H bonds for the generation of azidotrifluoromethylated molecules. Mild conditions, broad scope and excellent regioselective control (>20 : 1) are observed in the reactions. Deuterium labelling studies disclose the kinetic characteristics of the transformations and verify a direct 1,n-HAT pathway. The key to this C-centered radical relay is that iron plays a dual role as a radical initiator and terminator to incorporate the azide functionality through radical oxidation via azido–ligand-transfer. The methods and the later derivatization promise expeditious synthesis of CF3-containing organic azides, γ-lactam and triazoles that are widely used in designing new fluorescent tags and functional materials., Remote functionalization of inert C(sp3)–H bonds is described via iron-catalyzed sp3 C-centered radical relay.

The selective incorporation of gem-difluoroalkyl groups into biologically active molecules has long been used as an efficient strategy for drug design and discovery. However, the catalytic C(sp3)-CF2 bond-forming cross-coupling reaction for selective incorporation of difluoromethylene group into diverse alkyl chains, especially more sterically demanding secondary and tertiary functionalized alkanes, still remains as a major challenge. Herein, we describe a cobalt-catalyzed difluoroalkylation of tertiary aryl ketones for facile synthesis of quaternary alkyl difluorides, which exhibited high efficiency, broad scope and mild conditions. The synthetic utility of this method is demonstrated by late-stage difluoroalkylation of donepezil, a well-known acetylcholinesterase inhibitor used to treat the Alzheimer’s disease. Preliminary mechanistic investigations indicate that a difluoroalkyl radical is involved in a Co(I)/Co(III) catalytic cycle. This cobalt-catalyzed fluoroalkylation thus offers insights into an efficient way for the synthesis of fluoroalkylated bioactive molecules for drug discovery., The catalytic C(sp3)-CF2 bond formation is of high interest in drug design and discovery. Here, the authors report a cobalt-catalyzed difluoroalkylation of tertiary α-C-H bonds of aryl ketones for facile synthesis of quaternary alkyl difluorides and show the late-stage functionalization of marketed drugs.

An efficient nickel-catalyzed reductive relay cross-coupling of internal alkenes with alkyl (or aryl) halides has been developed. This method has demonstrated broad substrate scope, mild reaction conditions and excellent terminal-selectivity. Moreover, this efficient strategy could be applied to the terminal-selective alkylation of isomeric mixtures of internal alkenes.

The first example of copper-catalyzed direct formylation of alkenyl C–H bonds for the facile synthesis of α,β-unsaturated aldehydes has been developed. This transformation has demonstrated high reactivity, mild reaction conditions and a broad substrate scope. BrCHCl2 is expected to be developed as an efficient stoichiometric C1 building block in organic synthesis.

Copper-catalyzed selective coupling of C(sp3)–H bonds with C(sp2)–H bonds has been developed. An aniline module was used as a directing group to generate an aminyl radical, which selectively cleaves the secondary and tertiary C(sp3)–H bonds via a 1,5-HAT process to forge six-membered carbocyclic rings.

Ring-opening reaction via selective cleavage of C–C bond is known as a powerful strategy for construction of complex molecules. Complementary to the ionic process focusing on mostly small ring systems, radical-mediated C–C bond cleavage offers a solution for further diverse enantioselective functionalization benefited from its mild conditions, whereas such asymmetric transformations are still limited to three-membered rings so far. Herein, we describe radical-mediated ring-opening and enantioselective cyanation of four- and five-membered cycloketone oxime esters to access chiral 1,5- and 1,6-dinitriles. Employment of dual photoredox/copper catalysis is essential for the asymmetric ring-opening cyanation of cyclopentanone oxime esters. Both reactions proceed under mild conditions giving chiral dinitriles in high yields and enantioselectivity with low catalyst loading and broad substrate scope. The products dinitriles can be converted to valuable optically active diamides and diamines. Mechanistic studies indicate that the benzylic radical generated via C–C single bond cleavage is involved in the catalytic cycle., Ring-opening reaction via selective cleavage of C–C bond is a powerful strategy to increase molecular complexity. Here the authors present the facile synthesis of chiral 1,5- and 1,6-dinitriles via the radical-mediated ring-opening and enantioselective cyanation of cycloketone oxime esters.

A novel electrophilic trifluoromethylthiolation reaction system has been developed with AgSCF3 used directly as the SCF3 source, in the presence of KI/K2S2O8/I2. Various N-benzylindoles have been trifluoromethylthiolated successfully with this system, and the mechanism of investigation showed an electrophilic reagent was generated in situ.

Pd(II)-catalyzed enantioselective C–H activation of phenylacetic acids followed by an intramolecular C–O bond formation afforded chiral benzofuranones. This reaction provides the first example of enantioselecctive C–H functionalizations through Pd(II)/Pd(IV) redox catalysis.

Pd-catalyzed highly para-selective C-H arylation of monosubstituted arenes (including toluene) is developed for the first time using an F(+) reagent as a bystanding oxidant. This finding provides a new retrosynthetic disconnection for para-substituted biaryl synthesis via C-H/C-H cross-coupling.

Reductive elimination from partially or completely oxidized metal centers is a vital step in a myriad of carbon-carbon and carbon-heteroatom bond-forming reactions. One strategy for promoting otherwise challenging reductive elimination reactions is to oxidize the metal center using a two-electron oxidant (that is, from M((n)) to M((n+2))). However, many of the commonly used oxidants for this type of transformation contain oxygen, nitrogen, or halogen moieties that are subsequently capable of participating in reductive elimination, thus leading to a mixture of products. In this Minireview, we examine the use of bystanding F(+) oxidants for addressing this widespread problem in organometallic chemistry and describe recent applications in Pd(II) /Pd(IV) and Au(I) /Au(III) catalysis. We then briefly discuss a rare example in which one-electron oxidants have been shown to promote selective reductive elimination in palladium(II)-catalyzed C-H functionalization, which we view as a promising future direction in the field.

To evaluate the independent risk factors for failure of continuous veno-venous hemodialysis (CVVHD) in the treatment of acute kidney injury (AKI) following cardiac surgery.Adult patients without any prior pre-operative history of chronic renal disease suffering AKI following cardiac surgery and undergoing CVVHD at our center from January 2005 to December 2012 were recruited and divided into either a success group or a failure group. All pre-, intra- and post-operative data were collected and retrospectively analyzed.Ninety-three adult patients were enrolled. Among them, sixty-three patients survived with a failure rate of 32.2% and a mortality rate of 19.4%. Through univariate analysis and multivariate Logistic regression, independent risk factors for failure of CVVHD in the treatment of post-operative AKI included pre-operative LVEF (OR = 0.61, 95%CI 0.42-0.85) and duration of oliguria until dialysis (OR = 2.76, 95%CI 1.51-5.83).Pre-operative impaired left ventricular function is an important risk factor for failure of CVVHD in the treatment of AKI after cardiac surgery. The sooner the implementation of CVVHD, the better prognosis.

To evaluate the effect of atorvastatin on postoperative atrial fibrillation (AF) in patients undergoing coronary artery bypass grafting (CABG).A cohort of 140 consecutive patients without a history of documented AF or previous statin use, who were scheduled to undergo selective CABG, were enrolled. Included patients were randomly assigned to atorvastatin group (n = 71) who were administered atorvastatin 20 mg/d or to control group (n = 69). After CABG, subjects were monitored continuously by electrocardiographic monitors at least 7 days. During the initial postoperative 7 d, the incidence and duration of AF were recorded. And the levels of high-sensitivity C-reactive protein (hs-CRP) were measured before and 24 hours, 72 hours, 7 days after operation, respectively. The statistical software package SPSS (version 13.0) were used to analyze the data. The differences between groups were evaluated by chi(2)-test for discrete variables and student t-test for continuous variables. Multivariate logistic regression analysis was performed to determine the independent predictors of early postoperative AF.During initial postoperative 7 d, AF occurred at least once in 10 cases in atorvastatin group, with a prevalence of roughly 14%, and in 23 cases in control group, with a prevalence of approximately 34% (P = 0.009). The mean duration of single AF was 3.6 +/- 0.4 hours in atorvastatin group and 5.7 +/- 0.5 hours in control group (P0.01), respectively. The multivariate logistic analysis showed that perioperative atorvastatin administration was an independently risk factor for early postoperative AF (OR = 0.219, 0.076-0.633, P = 0.005). There was also statistical difference in hs-CRP after CABG between the two groups.Perioperative atorvastatin administration may inhibit inflammatory reaction, reduce the incidence and duration of postoperative AF, hence may prevent and treat postoperative AF.

To investigate the presence and severity of depression before and after operation in patients undergoing coronary artery bypass grafting (CABG) and the effect thereof on the quality of life.A validated Chinese version of Beck Depression Inventory (BDI) was used in 138 CABG patients that were divided into 2 groups according the fact if depression was present. 1 week before and 1, 3, and 6 months after operation, and SF-36 scale was used to evaluate the quality of life (QOL) one week before operation and 1 and 6 months after operation.Depressive disorders occurred in 42.7% of the patients preoperatively and in 23.1% of the patients 6 months after the operation. There were no significant differences in all the dimensions of the SF-36 scale before operation between the depression and non-depression groups. All the scores of the 36-F dimensions were improved 1 and 6 months after the operation. However, the SF-36 social functioning (SF), mental health (MH), role emotional (RE), and bodily pain (BP) subscale scores 6 months after operation of the depression group were all lower than those in the non-depressive groups (all P0.05).Depression symptoms at different degrees exist before CABG and can be improved post-operatively. The improvement of QOL of the depressive patients after operation is not so marked compared to the non-depressive patients, especially in SF, MH, RE, and BP dimensions.

To evaluate the effect and timing of continuous blood purification (CBP) in treatment of acute renal failure (ARF) following cardiac-vascular surgery.Twenty-five patients with ARF following cardiac-vascular surgery were divided into systematic inflammatory response syndrome (SIRS) Group (n = 13) and multiple organ dysfunction syndrome (MODS) Group (n = 12) according to the illness state prior to CBP and were divided into Group A (n = 5, with the APACHEIII score prior to CBPor= 60), Group B (n = 9, with the APACHEIII score 61 - 90), and Group C (n = 11, with the APACHEIII score90). All of the 25 patients underwent continuous veno-venous hemofiltration (CVVH). Before and 24h after the CVVH APACHEIII score was calculated and [peripheral; blood samples were collected to detect the levels of blood urea nitrogen (BUN) and serum creatinine (Scr) and the plasma levels of interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-alpha).The APACHEIII score, BUN, Scr, IL6, IL8, and TNFalpha 24 h after the CBP of the 25 patients were 61 +/- 15 mmol/L, (19 +/- 5) mmol/L, (312 +/- 87) micromol/L, (544 +/- 154) ng/L, (18 +/- 7) ng/L, and (43 +/- 15) ng/L respectively, all significantly lower than those before CBP (81 +/- 20, 26 +/- 5 mmol/L, 458 +/- 107 micromol/L, (842 +/- 132) ng/L, (25 +/- 8) ng/L, and (59 +/- 17) ng/L respectively, all P = 0.000). The survival rate of SIRS Group was 84.62%, significantly higher than that of MODS Group (41.67%, P0.05). The APACHEIII score, and the levels of BUN, Scr, IL6, IL8, and TNF-alpha of Group MODS were significantly higher than those of Group SIRS. The higher the level of Scr, IL6, IL8, and TNF-alpha and the APACHEIII score the lower the survival rate.CBP has a positive effect on ARF following cardiac-vascular surgery. The APACHEIII score 60 to 90 reflects an opportunity to treat the ARF following cardiac-vascular surgery using CBP.

To investigate the effect of pravastatin on blood lipids and serum high sensitive C-reactive protein (HsCRP) in patients undergoing conventional coronary artery bypass grafting under on-pump bypass (CCABG).Eighty-one patients underwent CCABG. Among which 40 took orally pravastatin 20 mg once daily to at least 28 days after operation, and 41 were used as control group. The serum levels of total cholesterol (TC), triglyceride (TG), HDL-C cholesterol (HDL-C), LDL-C cholesterol (LDL-C), and HsCRP were monitored before and 24 h, 72 h, 7 days, 10 days, 14 days, and 28 days postoperatively.In the control group the levels of different blood lipids after operation remarkably decreased after operation compared with those before operation (all P0.05), reached the lowest levels 24 h after operation, then gradually increased, however, still lower than those before operation (all P0.05), and recovered to the baseline level 28 hours after operation; and the HsCRP level increased 24 h after operation and peaked 72 h after, then gradually decreased, and recovered to the baseline level 28 days after operation. In the pravastatin group the TC level reached its lowest level 24 h after operation, then gradually increased, however, still lower than that before operation, and recovered to the baseline level 28 days after operation; and the TG level reached the lowest level 24 h after operation (P0.05), and then gradually increased 3 d after operation (P0.05). The TC, TG, and LDL-C levels 7, 10, 14, and 28 d after operation of the pravastatin group were all significantly lower than those of the control group (all P0.05). The HsCRP levels at different time points of the pravastatin group were all significantly lower than those of the control group (all P0.05).The use of pravastatin in the early stage of CCABG is safe and can decrease systemic inflammatory reaction.

A new, chiral phase transfer catalyst has been designed for the development of a general and useful procedure on the hitherto unknown, asymmetric conjugate additions of α-substituted-α-cyanoacetates to acetylenic esters with high enantioselectivity and moderate E/Z selectivity.

A Pd(II)-catalyzed C–H carbonylation protocol of phenethyl alcohols has been developed using amino acid ligands to promote the reaction. This transformation provides an expedient route to 1-isochromanone motifs, which are common structural elements in natural products and other biologically active compounds. A concise synthesis of a histamine release inhibitor showcases the utility of this transformation.