Iron(I) Complex Bearing an Open-Shell Diazenido Ligand.

Low-valent transition-metal diazenido species are important intermediates in transition-metal-mediated dinitrogen reduction reactions. Isolable complexes of the type unanimously feature closed-shell diazenido ligands. Those bearing open-shell diazenido ligands have remained elusive. Herein, we report the synthesis, characterization, and reactivity of a d7 iron(I) complex featuring an open-shell silyldiazenido ligand, [(ICy)Fe(NNSiiPr3)(η2:η2-dvtms)] (1, ICy = 1,3-dicyclohexylimidazole-2-ylidene, dvtms = divinyltetramethyldisiloxane). Complex 1 is prepared in good yield by silylation of the iron(-I)-N2 complex [K(18-crown-6)][(ICy)Fe(N2)(η2:η2-dvtms)] with iPr3SiOTf and has been fully characterized by various spectroscopic methods. Theoretical studies, in combination with characterization data, established an S = 1/2 ground spin-state for 1 that can best be described as a quartet iron(I) center featuring an antiferromagnetically coupled triplet silyldiazenido ligand. The diazenido and alkene ligands in 1 are labile, as indicated by the facile disproportionation reaction of 1 at ambient temperature to transform into the iron(II) bis(diazenido) species [(ICy)(NNSiiPr3)2Fe(dvtms)Fe(NNSiiPr3)2(ICy)] (2) and the iron(0) species [(ICy)Fe(η2:η2-dvtms)] and also the alkene-exchange reaction of 1 with PhCH═CHBC8H14 to form [(ICy)Fe(NNSiiPr3)(η2-trans-PhCH═CHBC8H14)] (3). Complex 1 is light-sensitive. Upon photolysis, it undergoes a SiiPr3 radical-transfer reaction to yield [(ICy)Fe(σ:η2-MeCHSiMe2OSiMe2CH═CHSiiPr3)] (4) and N2. The reactions of 1 with the trityl radical and organic bromides yield iron(II) complexes, which indicates its reducing nature. Moreover, 1 is a weak hydrogen-atom abstractor, as indicated by its inertness toward HSi(SiMe3)3 and cyclohexa-1,4-diene and the low calculated N-H bond dissociation energy (48 kcal/mol) of its corresponding iron(II) iso-hydrazenido species.

Iridium-Catalyzed Enantioselective Transfer Hydrogenation of 1,1-Dialkylethenes with Ethanol: Scope and Mechanism.

Despite half a century's advance in the field of transition-metal-catalyzed asymmetric alkene hydrogenation, the enantioselective hydrogenation of purely alkyl-substituted 1,1-dialkylethenes has remained an unmet challenge. Herein, we describe a chiral PCNOx-pincer iridium complex for asymmetric transfer hydrogenation of this alkene class with ethanol, furnishing all-alkyl-substituted tertiary stereocenters. High levels of enantioselectivity can be achieved in the reactions of substrates with secondary/primary and primary/primary alkyl combinations. The catalyst is further applied to the redox isomerization of disubstituted alkenols, producing a tertiary stereocenter remote to the resulting carbonyl group. Mechanistic studies reveal a dihydride species, (PCNOx)Ir(H)2, as the catalytically active intermediate, which can decay to a dimeric species (κ3-PCNOx)IrH(µ-H)2IrH(κ2-PCNOx) via a ligand-remetalation pathway. The catalyst deactivation under the hydrogenation conditions with H2 is much faster than that under the transfer hydrogenation conditions with EtOH, which explains why the (PCNOx)Ir catalyst is effective for the transfer hydrogenation but ineffective for the hydrogenation. The suppression of di-to-trisubstituted alkene isomerization by regioselective 1,2-insertion is partly responsible for the success of this system, underscoring the critical role played by the pincer ligand in enantioselective transfer hydrogenation of 1,1-dialkylethenes. Moreover, computational studies elucidate the significant influence of the London dispersion interaction between the ligand and the substrate on enantioselectivity control, as illustrated by the complete reversal of stereochemistry through cyclohexyl-to-cyclopropyl group substitution in the alkene substrates.

Associations of blood lead, cadmium, and mercury with resistant hypertension among adults in NHANES, 1999-2018.

BACKGROUND: Resistant hypertension (RHTN), a clinically complex condition with profound health implications, necessitates considerable time and allocation of medical resources for effective management. Unraveling the environmental risk factors associated with RHTN may shed light on future interventional targets aimed at reducing its incidence. Exposure to heavy metal has been linked to an increased risk of hypertension, while the relationship with RHTN remains poorly understood. METHODS: Using the 1999-2018 National Health and Nutrition Examination Survey (NHANES) data, we examined the association of blood lead (Pb), cadmium (Cd), and mercury (Hg) with RHTN using a multinomial logistic regression model. The combined effects of the metals and the contribution of each metal were assessed using a weighted quantile sum (WQS) analysis. RESULTS: A total of 38281 participants were included in the analysis. Compared with no resistant hypertension (NRHTN), per 1 µg/dL increase in blood Pb concentration, the proportion of RHTN increased by 16% [adjusted odds ratio (aOR), 1.16; 95% confidence interval (CI) 1.01-1.32]. When analyzed by quartiles (Q), the aOR [95% CI] for Pd was 1.30[1.01,1.67] (Q4 vs. Q1); there was a significant dose-response relationship (p < 0.05). Likewise, as a continuous variable, each 1 µg/dL increase in blood Cd level was associated with a 13% increase in the proportion of RHTN (aOR: 1.13; 95%CI: [1.00,1.27]); when analyzed as quartile, aOR [95% CI] for Cd were 1.30[1.01,1.69] (Q3 vs. Q1), and 1.35[1.03,1.75] (Q4 vs. Q1); the dose-response relationship was significant (p < 0.05). WQS analysis showed a significant combined effects of Pb, Cd, and Hg on RHTN, with Pb as the highest weight (0.64), followed by Cd (0.25) and Hg (0.11). Stratified analysis indicated that the associations for the two heavy metals were significant for participants who were male, ≼ 60 years old, and with kidney dysfunction. CONCLUSION: Findings of this study with national data provide new evidence regarding the role of environmental heavy metal exposure in RHTN. The prevention strategies aimed at reducing heavy metal exposure should particularly focus on Americans who are middle-aged, male, and afflicted with kidney dysfunction.

A Triplet Iron Carbyne Complex.

Tuning the spin state of metal carbynes, which have broad applications in organic synthesis and material science, presents a formidable challenge for modern chemists as the strong field nature of carbyne ligands dictates low-spin ground spin states (S = 0 or 1/2) for known metal carbynes. Through the oxidative addition reaction of a low-coordinate iron(0) N-heterocyclic carbene complex with the C-S bond of a thioazole-2-ylidene, we synthesized the first triplet (S = 1) metal terminal carbyne, an iron cyclic carbyne complex. Different from the classical metal carbynes, the triplet complex features an LXZ-type carbyne ligand and a weak Fe≡C triple bond, which endow it with the unique reactivity pattern of facile carbyne coupling, weak affinity toward nucleophiles, and facial addition reactions with electrophiles.

Association between dietary intake of omega-3 polyunsaturated fatty acids and all-cause and cardiovascular mortality among hypertensive adults: Results from NHANES 1999-2018.

BACKGROUND: Hypertensive adults are at a higher risk of cardiovascular morbidity and mortality. Dietary omega-3 polyunsaturated fatty acids (N3-PUFA) intake has been associated with cardiovascular benefits. However, few studies have specifically investigated whether dietary intake of N3-PUFA is associated with lower risk of all-cause and cardiovascular mortality among hypertensive adults in the U.S. METHODS: This prospective cohort study included 26,914 hypertensive individuals 18 years or older who participated in 10 NHANES cycles from 1999 to 2018. Dietary levels of N3-PUFA were obtained from the 24-hour dietary recalls. The dietary data were linked to mortality records from the National Death Index through December 31, 2019. The associations between dietary N3-PUFA levels and mortality were evaluated by constructing the Multivariable Cox Proportional Hazards models. RESULTS: We observed an increasing trend of dietary N3-PUFA intake levels over the years, mainly driven by alpha-linolenic acid (ALA). Lower all-cause mortality risk was observed among hypertensive adults with higher consumption of total N3-PUFA [adjusted hazards ratio, 95% confidence interval: 0.91 (0.86, 0.97)], plant-based ALA [0.88 (0.83, 0.93)], fish oil-based eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) [0.91 (0.83, 0.99)], EPA [0.93 (0.88, 0.98)], docosapentaenoic acid (DPA) [0.73 (0.58, 0.91)], or DHA [0.95 (0.90, 0.99)]. Hypertensive adults were at lower risk of cardiovascular mortality if their diet contained higher levels of total N3-PUFA [0.68 (0.53, 0.88)], ALA [0.89 (0.80, 0.99)], EPA [0.87 (0.79, 0.97)] or DPA [0.86 (0.78, 0.95)]. Weighted quantile sum analysis showed that ALA, EPA, and DPA were the main contributors of the N3-PUFA benefits against mortality among hypertensive adults. CONCLUSIONS: Dietary intake of N3-PUFA, particularly ALA, EPA, and DPA, was associated with lower risk of all-cause and cardiovascular mortality among U.S. hypertensive adults. These findings suggest that increasing dietary intake of N3-PUFA may serve as a potential strategy to lower hypertension-associated mortality risk.

A current and future perspective on T cell receptor repertoire profiling.

T cell receptors (TCR) play a vital role in the immune system's ability to recognize and respond to foreign antigens, relying on the highly polymorphic rearrangement of TCR genes. The recognition of autologous peptides by adaptive immunity may lead to the development and progression of autoimmune diseases. Understanding the specific TCR involved in this process can provide insights into the autoimmune process. RNA-seq (RNA sequencing) is a valuable tool for studying TCR repertoires by providing a comprehensive and quantitative analysis of the RNA transcripts. With the development of RNA technology, transcriptomic data must provide valuable information to model and predict TCR and antigen interaction and, more importantly, identify or predict neoantigens. This review provides an overview of the application and development of bulk RNA-seq and single-cell (SC) RNA-seq to examine the TCR repertoires. Furthermore, discussed here are bioinformatic tools that can be applied to study the structural biology of peptide/TCR/MHC (major histocompatibility complex) and predict antigenic epitopes using advanced artificial intelligence tools.

Diimidazolium Salt HBDIM: An Easily Available, Low-Cost, CageCarbene Precursor with Broad Applications in Transition Metal-Catalyzed Reactions.

The preparation of diimidazolium salt HBDIM 1, a precursor for a di-NHCs ligand, from cheap and easily available agent hexabenzylhexaazaisowurtzitane (HBIW) is reported. Under basic conditions, HBDIM undergoes facile deprotonation to in situ generate CageCarbene, which could efficiently coordinate to transition-metals, such as, Au, Cu or Pd, to give the corresponding bimetallic complexes 2-4. These complexes were isolated and fully characterized, including X-ray diffraction of their single crystals. It was found that the steric hinderance of CageCarbene is similar to that of SIMes but smaller than that of IPr, and electronically, CageCarbene is a strong σ-donator similar to SIMes and a stronger σ-donator than IPr. Further studies showed that complexes 2-4 were highly reactive to catalyze up to 17 reactions. Control experiments utilizing a N-benzyl-substituted monoimidazolium salt showed much lower catalytic reactivity when it was bound to Au or Cu, but exhibited similar reactivity for the Pd complex. Kinetic studies showed that the low reactivity of the monodentate carbene-ligated Au or Cu complex was due to the low stability of the complex under the reaction conditions.

Signet-Ring-Shaped Octaphosphorus-Cobalt Complexes: Synthesis, Structure, and Functionalization Reactions with Carbene Analogs.

White phosphorus activation with low-valent metal species has proved to be very effective in converting P4 into small Pn-containing molecules with n ≤ 4. Much less developed are metal-mediated P4-coupling reactions that can yield selectively large polyphosphorus clusters. Herein, we report P4-activation reactions with three-coordinate N-heterocyclic carbene(NHC)-cobalt(0)-alkene complexes, which produce the P8 complexes of cobalt [(NHC)2Co2(µ-η6:η6-P8)] (NHC = 1,3-dimesitylimidazol-2-ylidene (IMes), 1; 1,3-bis(2,6-diethylphenyl)imidazol-2-ylidene (IDep), 2) in high yields. The P8 ligand in 1 and 2 exhibits a signet-ring type structure that was predicted by theoretical study but has never been obtained in synthetic molecules. Theoretical studies suggest that [(NHC)2Co2(µ-η6:η6-P8)] is best described as a Co0-[P8]0-Co0 complex featuring a Co-Co σ-bond and discernible Co-to-P8 back-donation. By treating with N-heterocyclic silylene, phosphinidene precursor, organic azides, and NHCs, complex 1 was transformed into [(IMes)2Co2(µ-η6:η6-P8X)] (X = 1,3-bis(tert-butyl)-1,3-diaza-2-silacyclopent-4-en-2-ylidene, 3; PNMe2, 4), [(IMes)2Co2(σ:(µ-η4:η6)-RNPPP6)] (R = SO2-C6H4-p-Me, 5; C(CF3)2Ph, 6), and [(IMes)2Co2(µ-η2:η2-cyclo-P4P(IPri2))(µ-η3:η3-P3)] (7), respectively. Complexes 3-7 can be viewed as the adducts of 1 with the corresponding carbene analogous SiR2, PR, NR, and CR2, but their core structures are distinct. Under similar conditions, white phosphorus is inert toward these reagents. These cage functionalization reactions showcase the enhanced reactivity of the P8 ligand in [(NHC)2Co2(µ-η6:η6-P8)] over that of P4, and indicate the amphiphilicity of the P8 ligand toward electrophiles and nucleophiles.

[Ph4 P]+ [Cu(CF2 H)2 ]- : A Powerful Difluoromethylating Reagent Inspired by Mechanistic Investigation.

The quest of the active species in copper-mediated difluoromethylation of aryl halides led to the discovery of a powerful difluoromethylating reagent [Ph4 P]+ [Cu(CF2 H)2 ]- 2. Complex 2 was able to difluoromethylate a variety of electrophiles including electron-deficient and electron-rich aryl iodides, heteroaryl iodides, activated heteroaryl bromides, chloride and aryl bromides with a directing group, as well as other electrophiles such as alkenyl iodide, benzyl bromides, allyl bromides, alkyl iodide, allyl carbonates and acid chloride. In addition, in the presence of an oxidant, complex 2 reacted with various lithium nbutyl arylboronic acid pinacol esters, alkyne and heteroarene. Moreover, complex 2 could transmetalate the difluoromethyl reagent to other metals such as [Ph4 P]+ [CuCl2 ]- and [(DPPF)PdCl2 ].

MicroRNA-29a attenuates CD8 T cell exhaustion and induces memory-like CD8 T cells during chronic infection.

CD8 T cells mediate protection against intracellular pathogens and tumors. However, persistent antigen during chronic infections or cancer leads to T cell exhaustion, suboptimal functionality, and reduced protective capacity. Despite considerable work interrogating the transcriptional regulation of exhausted CD8 T cells (TEX), the posttranscriptional control of TEX remains poorly understood. Here, we interrogated the role of microRNAs (miRs) in CD8 T cells responding to acutely resolved or chronic viral infection and identified miR-29a as a key regulator of TEX. Enforced expression of miR-29a improved CD8 T cell responses during chronic viral infection and antagonized exhaustion. miR-29a inhibited exhaustion-driving transcriptional pathways, including inflammatory and T cell receptor signaling, and regulated ribosomal biogenesis. As a result, miR-29a fostered a memory-like CD8 T cell differentiation state during chronic infection. Thus, we identify miR-29a as a key regulator of TEX and define mechanisms by which miR-29a can divert exhaustion toward a more beneficial memory-like CD8 T cell differentiation state.

Synthesis, Characterization, and Reactivity of a Hydrido- and Imido-Bridged Dinuclear Ytterbium(III) Complex.

The trivalent rare-earth metal hydrido and imido complexes are of versatile reactivity, and many such complexes have been synthesized. However, no example of a rare-earth metal complex bearing both hydrido- and imido-ligands has been reported. Herein, we report the first rare-earth metal complex bearing both hydrido- and imido-ligands, namely a hydrido- and imido-bridged dinuclear ytterbium(III) complex. The complex was synthesized via an unprecedented redox reaction of divalent rare-earth metal hydrido complex with azido compound. DFT calculation indicated that the N2 release from azido compound in the presence of ytterbium(II) is a kinetically facile process because of the cooperative effects of the two metal centers. The reactivity of the hydrido- and imido-bridged dinuclear ytterbium(III) complex was also explored, which showed the redox, addition and σ-bond metathesis reactivities.

Regio- and enantioselective umpolung gem-difluoroallylation of hydrazones via palladium catalysis enabled by N-heterocyclic carbene ligand.

The enantioselective construction of C-CF2R (R: alkyl or fluoroalkyl) bonds has attracted the attention of synthetic chemists because of the importance of chiral fluorinated compounds in life and materials sciences. Catalytic asymmetric fluoroalkylation has mainly been realized under organocatalysis and Lewis acid catalysis, with substrates limited to carbonyl compounds. Few examples using transition-metal catalysis exist, owing to side reactions including decomposition and isomerization of fluoroalkylating reagents. Herein we report umpolung asymmetric difluoroallylation of hydrazones with 3-bromo-3,3-difluoropropene (BDFP) under palladium catalysis. Difluoroallylation products having quaternary chiral carbon centers are afforded in good yields with high α/γ- and enantioselectivities. The usefulness of the reaction products is demonstrated and an inner-sphere mechanism of the reaction is proposed. The use of chiral N-heterocyclic carbene as ligand is the key for the selectivities as well as the productivity of the reaction.

Catalytic Method for the Synthesis of Deuterium-Labeled N-Heterocyclic Carbenes Enabled by a Coordinatively Unsaturated Ruthenium N-Heterocyclic Carbene Catalyst.

The wide usage of N-heterocyclic carbenes (NHCs) has raised the quest for their deuterated molecules. Effective synthesis method to obtain them, however, has remained elusive. We present here a catalytic method for the preparation of deuterated NHCs, namely, the catalytic hydrogen-deuterium exchange reaction between NHCs and deuterated benzene using a coordinatively unsaturated Ru NHC catalyst. The catalytic system enables selective deuteration of the C(sp3)-H bonds of the alkyl groups on N-substituents, as well as the sterically nonhindered C(sp2)-H bonds of NHCs as demonstrated by the preparation of 16 deuterium-labeled NHCs that have a deuteration ratio on specified sites higher than 90%. The gram-scale synthesis of deuterated IMes indicated the applicability of this catalytic method. Mechanistic studies revealed that the high regio-selectivity toward those C(sp3)-H bonds on NHCs originates from the regio-selectivity of cyclometalation reactions of coordinatively unsaturated Ru NHC species.

Markovnikov Hydrosilylation of Alkynes with Tertiary Silanes Catalyzed by Dinuclear Cobalt Carbonyl Complexes with NHC Ligation.

Metal-catalyzed hydrosilylation of alkynes is an ideal atom-economic method to prepare vinylsilanes that are useful reagents in the organic synthesis and silicone industry. Although great success has been made in the preparation of ß-vinylsilanes by metal-catalyzed hydrosilylation reactions of alkynes, reported metal-catalyzed reactions for the synthesis of α-vinylsilanes suffer from narrow substrate scope and/or poor selectivity. Herein, we present selective Markovnikov hydrosilylation reactions of terminal alkynes with tertiary silanes using a dicobalt carbonyl N-heterocyclic carbene (NHC) complex [(IPr)2Co2(CO)6] (IPr = 1,3-di(2,6-diisopropylphenyl)imidazol-2-ylidene) as catalyst. This cobalt catalyst effects the hydrosilylation of both alkyl- and aryl-substituted terminal alkynes with a variety of tertiary silanes with good functional group compatibility, furnishing α-vinylsilanes with high yields and high α/ß selectivity. Mechanistic study revealed that the stoichiometric reactions of [(IPr)2Co2(CO)6] with PhC≡CH and HSiEt3 can furnish the dinuclear cobalt alkyne and mononuclear cobalt silyl complexes [(IPr)(CO)2Co(µ-η2:η2-HCCPh)Co(CO)3], [(IPr)(CO)2Co(µ-η2:η2-HCCPh)Co(CO)2(IPr)], and [(IPr)Co(CO)3(SiEt3)], respectively. Both dicobalt bridging alkyne complexes can react with HSiEt3 to yield α-triethylsilyl styrene and effect the catalytic Markovnikov hydrosilylation reaction. However, the mono(NHC) dicobalt complex [(IPr)(CO)2Co(µ-η2:η2-HCCPh)Co(CO)3] exhibits higher catalytic activity over the di(NHC)-dicobalt complexes. The cobalt silyl complex [(IPr)Co(CO)3(SiEt3)] is ineffective in catalyzing the hydrosilylation reaction. Deuterium labeling experiments with PhC≡CD and DSiEt3 indicates the syn-addition nature of the hydrosilylation reaction. The absence of deuterium scrambling in the hydrosilylation products formed from the catalytic reaction of PhC≡CH with a mixture of DSiEt3 and HSi(OEt)3 hints that mononuclear cobalt species are less likely the in-cycle species. These observations, in addition to the evident of nonsymmetric Co2C2-butterfly core in the structure of [(IPr)(CO)2Co(µ-η2:η2-HCCPh)Co(CO)3], point out that mono(IPr)-dicobalt species are the genuine catalysts for the cobalt-catalyzed hydrosilylation reaction and that the high α selectivity of the catalytic system originates from the joint play of the dicobalt carbonyl species to coordinate alkynes in the Co(µ-η2:η2-HCCR')Co mode and the steric demanding nature of IPr ligand.

Mechanistic Insight into Copper-Mediated Trifluoromethylation of Aryl Halides: The Role of CuI.

The synthesis, characterization, and reactivity of key intermediates [Cu(CF3)(X)]-Q+ (X = CF3 or I, Q = PPh4) in copper-mediated trifluoromethylation of aryl halides were studied. Qualitative and quantitative studies showed [Cu(CF3)2]-Q+ and [Cu(CF3)(I)]-Q+ were not highly reactive. Instead, a much more reactive species, ligandless [CuCF3] or DMF-ligated species [(DMF)CuCF3], was generated in the presence of excess CuI. On the basis of these results, a general mechanistic map for CuI-promoted trifluoromethylation of aryl halides was proposed. Furthermore, on the basis of this mechanistic understanding, a HOAc-promoted protocol for trifluoromethylation of aryl halides with [Ph4P]+[Cu(CF3)2]- was developed.

An Isolable Mononuclear Palladium(I) Amido Complex.

Mononuclear Pd(I) species are putative intermediates in Pd-catalyzed reactions, but our knowledge about them is limited due to difficulties in accessing them. Herein, we report the isolation of a Pd(I) amido complex, [(BINAP)Pd(NHArTrip)] (BINAP = 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene, ArTrip = 2,6-bis(2',4',6'-triisopropylphenyl)phenyl), from the reaction of (BINAP)PdCl2 with LiNHArTrip. This Pd(I) amido species has been characterized by X-ray crystallography, electron paramagnetic resonance, and multiedge Pd X-ray absorption spectroscopy. Theoretical study revealed that, while the three-electron-two-center π-interaction between Pd and N in the Pd(I) complex imposes severe Pauli repulsion in its Pd-N bond, pronounced attractive interligand dispersion force aids its stabilization. In accord with its electronic features, reactions of homolytic Pd-N bond cleavage and deprotonation of primary amines are observed on the Pd(I) amido complex.

Divalent Ytterbium Hydrido Complex Supported by a ß-Diketiminato-Based Tetradentate Ligand: Synthesis, Structure, and Reactivity.

While the chemistry of trivalent rare-earth metal hydrido complexes has been well developed in the past 40 years, that of the divalent rare-earth metal hydrido complexes remains in its infancy because of the synthetic challenge of such complexes. In this paper, we report the synthesis and structural characterization of a divalent ytterbium hydrido complex supported by a bulky ß-diketiminato-based tetradentate ligand. This hydrido complex is a dimer containing two µ-hydrogen ligands, and it easily undergoes a hydrido shift reaction to form a new divalent ytterbium hydrido complex that contains only one hydrido bridge. Furthermore, this hydrido complex reacts with pyridine and pyridine derivatives, showing versatile reactivity [Yb-H addition to pyridine, hydrido shift to ancillary ligand, and ytterbium(II)-center-induced redox reaction with bipyridine]. This hydrido complex reacts with Ph3P═O, resulting in a P-CPh cleavage of Ph3P═O and an elimination of C6H6; on the other hand, the reaction with Ph3P═S is a hydrido coupling-based redox reaction. The reactions of this hydrido complex with 1 and 2 equiv of PhSSPh clearly indicate that the hydrido coupling-based redox reaction is prior to the ytterbium(II) oxidation-based redox reaction.

Treatment with the Immunomodulator AIC649 in Combination with Entecavir Produces Antiviral Efficacy in the Woodchuck Model of Chronic Hepatitis B.

As current interventions for chronic hepatitis B (CHB) rarely induce cure, more effective drugs are needed. Short-term treatment of woodchucks with the novel immunomodulator AIC649, a parapoxvirus-based stimulator of toll-like receptor 9 dependent and independent pathways, has been shown to reduce viral DNA and surface antigen via a unique, biphasic response pattern. The present study evaluated long-term AIC649 treatment in combination with Entecavir for potency and safety in woodchucks. AIC649 monotreatment induced modest reductions in serum viral DNA and surface and e antigens that were associated with the same biphasic response pattern previously observed. Entecavir monotreatment reduced transiently viremia but not antigenemia, while AIC649/Entecavir combination treatment mediated superior viral control. Undetectability of viral antigens and elicitation of antibodies in AIC649/Entecavir-treated woodchucks correlated with the expression of interferons and suppression of viral replication in liver. Combination treatment was well tolerated, and liver enzyme elevations were minor and transient. It was concluded that the AIC649-mediated effects were most likely based on an improvement and/or reconstitution of antiviral immune responses that are typically deficient in CHB. As a combination partner to Entecavir, the antiviral efficacy of AIC649 was markedly enhanced. This preclinical study supports future evaluation of AIC649 for treatment of human CHB.

An Amine-Assisted Ionic Monohydride Mechanism Enables Selective Alkyne cis-Semihydrogenation with Ethanol: From Elementary Steps to Catalysis.

The selective synthesis of Z-alkenes in alkyne semihydrogenation relies on the reactivity difference of the catalysts toward the starting materials and the products. Here we report Z-selective semihydrogenation of alkynes with ethanol via a coordination-induced ionic monohydride mechanism. The EtOH-coordination-driven Cl- dissociation in a pincer Ir(III) hydridochloride complex (NCP)IrHCl (1) forms a cationic monohydride, [(NCP)IrH(EtOH)]+Cl-, that reacts selectively with alkynes over the corresponding Z-alkenes, thereby overcoming competing thermodynamically dominant alkene Z-E isomerization and overreduction. The challenge for establishing a catalytic cycle, however, lies in the alcoholysis step; the reaction of the alkyne insertion product (NCP)IrCl(vinyl) with EtOH does occur, but very slowly. Surprisingly, the alcoholysis does not proceed via direct protonolysis of the Ir-C(vinyl) bond. Instead, mechanistic data are consistent with an anion-involved alcoholysis pathway involving ionization of (NCP)IrCl(vinyl) via EtOH-for-Cl substitution and reversible protonation of Cl- ion with an Ir(III)-bound EtOH, followed by ß-H elimination of the ethoxy ligand and C(vinyl)-H reductive elimination. The use of an amine is key to the monohydride mechanism by promoting the alcoholysis. The 1-amine-EtOH catalytic system exhibits an unprecedented level of substrate scope, generality, and compatibility, as demonstrated by Z-selective reduction of all alkyne classes, including challenging enynes and complex polyfunctionalized molecules. Comparison with a cationic monohydride complex bearing a noncoordinating BArF- ion elucidates the beneficial role of the Cl- ion in controlling the stereoselectivity, and comparison between 1-amine-EtOH and 1-NaOtBu-EtOH underscores the fact that this base variable, albeit in catalytic amounts, leads to different mechanisms and consequently different stereoselectivity.