While a broad variety of iron-catalyzed cross-couplings involve the use of main-group organometallics R-M as nucleophiles, the role of the M
n
+
cation in the coupling process is generally ...disregarded. However, several beneficial effects of M
n
+
cations by themselves or involved in ionic salts used as additives have been observed in such procedures. At the molecular level, interaction of those M
n
+
cations with on-cycle organoiron intermediates can proceed in several ways. Intermolecular interactions can be observed, and also the implication of M
n
+
in the iron's first or second coordination sphere,
e.g.
by ambiphilic coordination of a M-X salt to an R-Fe bond. The use of M
n
+
cations in the reaction medium is also a powerful strategy enabling control of the distribution of iron oxidation states within the coupling process.
The beneficial role of main-group cations M
n
+
brought by nucleophilic partners in Fe-mediated cross-couplings is highlighted. Examples of synergistic effects of Fe/M
n
+
pairs on the elementary steps of the catalytic processes are discussed.
The mechanism of the reactions of aryl/heteroaryl halides with aryl Grignard reagents catalyzed by FeIII(acac)3 (acac=acetylacetonate) has been investigated. It is shown that in the presence of ...excess PhMgBr, FeIII(acac)3 affords two reduced complexes: PhFeII(acac)(thf)n (n=1 or 2) (characterized by 1H NMR and cyclic voltammetry) and PhFeI(acac)(thf)− (characterized by cyclic voltammetry, 1H NMR, EPR and DFT). Whereas PhFeII(acac)(thf)n does not react with any of the investigated aryl or heteroaryl halides, the FeI complex PhFeI(acac)(thf)− reacts with ArX (Ar=Ph, 4‐tolyl; X=I, Br) through an inner‐sphere monoelectronic reduction (promoted by halogen bonding) to afford the corresponding arene ArH together with the Grignard homocoupling product PhPh. In contrast, PhFeI(acac)(thf)− reacts with a heteroaryl chloride (2‐chloropyridine) to afford the cross‐coupling product (2‐phenylpyridine) through an oxidative addition/reductive elimination sequence. The mechanism of the reaction of PhFeI(acac)(thf)− with the aryl and heteroaryl halides has been explored on the basis of DFT calculations.
Iron(I) does the job: The reduction of FeIII(acac)3 by PhMgBr gives PhFeI(acac)(thf)−, which reacts with ArX (Ar=Ph, 4‐tol; X=I, Br) through an inner‐sphere monoelectronic reduction promoted by halogen bonding to afford ArH and PhPh (see scheme; acac=acetylacetonate). In contrast, PhFeI(acac)(thf)− reacts with 2‐chloropyridine to give the cross‐coupling product (2‐phenylpyridine) through a classical oxidative addition/reductive elimination sequence.
To the editor—We read with interest the comments by Dr Musher about our manuscript entitled “High Frequency of Specific Polysaccharide Antibody Deficiency in Adults With Unexplained, Recurrent and/or ...Severe Infections With Encapsulated Bacteria” 1.Dr Musher notes that no etiologic diagnosis for the pneumonia was established in 23 of the 37 specific polysaccharide antibody deficiency (SPAD) patients. Indeed, patients were included when they had a history of recurrent and/or severe bacterial infections, and most were outcome patients with recurrent upper and/or lower respiratory tract infections (RTIs): bacterial identification is not easily available in such patients but must be encouraged. Dr Musher also noted that we did not confirm that Haemophilus infections were due to encapsulated organisms: once again, this is easily explained by the fact that this identification is not available in routine practice. However, the 3 patients had recurrent lower (n = 3) RTIs, upper RTIs (n = 1), and/or bronchiectasis (n = 2): documented Haemophilus infections in this context were just an additional information, and not the only reason for suspecting an antibody deficiency.Considering the extremely low frequency of meningococcal infections in healthy adults in absence of any outbreaks and in absence of any personal history of asplenia, human immunodeficiency virus (HIV) infection, active/passive smoking…, there is a broad consensus on the need to look for immune deficiencies such complement pathway deficiencies, but antibody deficiencies can also be found 2, 3.Dr Musher also adds that around 10% of healthy subjects can display low responses to pneumococcal capsular polysaccharides (PCP), implying that a poor response is not synonymous of immunodeficiency. We used the guidelines proposed by the American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma and Immunology (ACAAI) for the use and the interpretation of anti-PCP response: these guidelines are widely accepted, despite the arbitrarily choices of the cutoff levels for anti-PCP antibodies 4–6. The most important is that we used these criteria in patients with relevant unexplained bacterial infections (and not healthy subjects). More robust arguments are needed to contest these expert recommendations.Dr Musher considers that we should have measured anti-PCP antibody concentration after pneumococcal conjugate vaccine (PCV) before suggesting immunoglobulin replacement therapy. Conjugate vaccines were given as the only treatment after SPAD diagnosis in a large part of patients with recurrent infections (10/23), when infections were not too frequent. However, a part of pneumococcal polysaccharide vaccine (PPV) non-responders (SPAD patients) are also PCV non responders suggesting that the defect of PCP recognition and/or specific antibody production is not bypassed by PCP conjugation with protein (6 and several personal unpublished observations in adult patients). We must also recall that the number of serotypes in available conjugate vaccines was limited to 13 and that some emerging non-PCV13 serotypes are responsible for most invasive infections in the general population 7: further studies are warranted to know if PCV containing 20 conjugated PCP or more, would change this practice.Dr Musher adds that “levels of antibody to pneumococcal capsular polysaccharide are relatively low in commercial preparations of IVIG”. We must reaffirm that all SPAD patients must not be treated with Ig replacement therapy. But we fully agree with some experts who consider immunoglobulin G (IgG) replacement therapy in SPAD patients who have severe or very frequent recurrent infections and/or bronchiectasis, inability to tolerate antibiotic prophylaxis (severe side effects or complications), or failure to respond to prophylactic antibiotics 8. Our study also supports this recommendation, since all patients were dramatically improved by Ig therapy: this confirms, if necessary, that the diagnosis criteria of this antibody deficiency seem appropriate in these patients, and that Ig preparations seem to contain enough anti-pneumococcal antibodies.
An iron‐catalyzed Sonogashira coupling of non‐activated secondary alkyl iodides with terminal alkynes is described. The reaction proceeds under mild conditions in N‐MethylPyrrolidone without ...auxiliary ligand or co‐catalyst. This procedure allowed the obtention of 28 coupling products. Moreover, slow addition of LiHMDS base allows to achieve up to 89% yields. This method enables the conversion of non‐activated alkyl iodides in a Fe‐catalyzed Sonogashira‐type cross‐coupling, which was so far not achievable with iron catalysts. Preliminary mechanistic studies suggest the implication of a key single electron transfer in the catalytic process.
Breast cancer is a major health problem worldwide. In ~15% of breast cancers, the epidermal growth factor receptor HER2, a transmembrane protein, is overexpressed. This HER2 overexpression is ...associated with an aggressive form of the disease and a poor clinical prognosis. The extracellular domain (ECD) of HER2 is released into the blood by a proteolytic mechanism known as “ECD shedding”. This proteolytic shedding leaves a constitutively active truncated receptor in the membrane that is 10–100-fold more oncogenic than the full-length receptor and promotes the growth and survival of cancer cells. Shedding of the HER2 ECD is increased during metastasis: whereas 15% of primary breast cancer patients have elevated levels of serum HER2 ECD (sHER2 ECD), the levels reach 45% in patients with metastatic disease. Thus, sHER2 ECD has been proposed as a promising biomarker for cancer recurrence and for monitoring the disease status of patients overexpressing HER2. Nevertheless, in 2016, the American Society of Clinical Oncology advises clinicians not to use soluble HER2 levels to guide their choice of adjuvant therapy for patients with HER2-positive breast cancer, because the evidence was considered not strong enough. Currently, biomarkers such as carcinoembryonic antigen and cancer antigen 15-3 are widely used to monitor metastatic breast cancer disease even if the level of evidence of clinical impact of this monitoring is poor. In this article, we review the evidence that sHER2 ECD might be used in some situations as a biomarker for breast cancer. Although this serum biomarker will not replace the direct measurement of tumor HER2 status for diagnosis of early-stage tumors; it might be especially useful in metastatic disease for prognosis, as an indicator of cancer progression and of therapy response, particularly to anti-HER2 therapies. Owing to these data, sHER2 ECD should be considered as a promising biomarker to detect cancer recurrence and metastasis.
This review deals with some key synthetic developments based on the use of iron or cobalt complexes to promote radical reactivity which have been devised over the last decades. We have more ...particularly focused on reactions for which the impact of this chemistry has yielded greener alternatives to existing processes and also on new transformations, notably hydrogen atom transfer (HAT) triggered processes, which can be promoted through the use of metallic complexes. Preliminary synthetic developments based on the use of photoactive iron and cobalt complexes are also covered.
Iron and cobalt complexes are at the origin of high valuable synthetic pathways involving radical intemediates.
We demonstrate in this work that two drastically distinct mechanisms can be involved in aryl-(hetero)aryl Fe-mediated cross-couplings between Grignard reagents and organic halides, depending on the ...nature of the latter. (Hetero)aryl electrophiles, which easily undergo one-electron reduction, can be involved in a Fe$^{II}$/Fe$^{III}$ coupling sequence featuring an in situ generated organoiron(II) species, akin to their aliphatic analogues. On the other hand, less easily reduced substrates can be activated by transient Fe$^0$ species formed by the reduction of the precatalyst. In this case, the coupling mechanism relies on two-electron elementary steps involving the Fe$^0$/Fe$^{II}$ redox couple and proceeds by an oxidative addition/reductive elimination sequence. Hammett analysis shows that both those elementary steps are faster for electrophiles substituted by electron-withdrawing groups. The two mechanisms discussed herein can be involved concomitantly for electrophiles displaying an average oxidative power. Attesting to the feasibility of the aforementioned bielectronic mechanism, high-spin organoiron(II) intermediates formed by two-electron oxidative addition onto (hetero)aryl halides in catalytically relevant conditions were also characterized for the first time. Those results are sustained by paramagnetic $^1$H NMR, kinetics monitoring, and density functional theory (DFT) calculations.
Copper(I) species associated with 1,10-phenanthroline are generated from copper(0) precursors by chemical oxidation by the aryl halides (via electron transfer) or from copper(II) precursors by ...chemical reduction by N- or O-nucleophiles in the presence of a base. The mechanism of cross-coupling reactions between ArX (X = I, Br, Cl) and N- or O-nucleophiles catalyzed by copper(I) ligated to 1,3-diketonate ligands (generated from 2-acetylcyclohexanone or 2,2,6,6-tetramethyl-3,5-heptanedione) is proposed on the basis of cyclic voltammetry, 1H NMR, ESI-MS, and DFT calculations. The key anionic complexes (1,3-diketonate)CuI-ZR− (ZR = NHCy, OH, OPh) undergo oxidative additions to PhI via intermediate complexes formed by halogen bonding between PhI and the negatively charged N or O atom (Z) of (1,3-diketonate)CuI-ZR−. The reductive eliminations from the CuIII complexes (1,3-diketonate)CuIII(Ph)-ZR generated in the oxidative additions are always faster than the rds oxidative additions.
Abstract
Preeclampsia (PE) results in placental dysfunction and is one of the primary causes of maternal and fetal mortality and morbidity. During pregnancy, estrogen is produced primarily in the ...placenta by conversion of androgen precursors originating from maternal and fetal adrenal glands. These processes lead to increased plasma estrogen concentrations compared with levels in nonpregnant women. Aberrant production of estrogens could play a key role in PE symptoms because they are exclusively produced by the placenta and they promote angiogenesis and vasodilation. Previous assessments of estrogen synthesis during PE yielded conflicting results, possibly because of the lack of specificity of the assays. However, with the introduction of reliable analytical protocols using liquid chromatography/mass spectrometry or gas chromatography/mass spectrometry, more recent studies suggest a marked decrease in estradiol levels in PE. The aim of this review is to summarize current knowledge of estrogen synthesis, regulation in the placenta, and biological effects during pregnancy and PE. Moreover, this review highlights the links among the occurrence of PE, estrogen biosynthesis, angiogenic factors, and cardiovascular risk factors. A close link between estrogen dysregulation and PE occurrence might validate estrogen levels as a biomarker but could also reveal a potential approach for prevention or cure of PE.
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