[A pregnant woman with de novo atrial fibrillation]. / Atriumfibrilleren bij een zwangere vrouw.

BACKGROUND: De novo atrial fibrillation (AF) is rare in pregnancy. The exact pathophysiology of AF is unclear; it might be caused by several cardiovascular and hemodynamic changes that occur in pregnancy, leading to an increased stretch in myocardial cells of the atrial wall. CASE DESCRIPTION: A 26-year-old primigravida with a thus far uncomplicated pregnancy presents with symptoms of heart palpitations, shortness of breath and chest pain. The CTG was normal but an ECG showed de novo atrial fibrillation. The patient was given two doses of digoxin 0.25mg after which sinus rhythm was achieved. No anatomical substrate was found; hence it was seen as most likely caused by increased hemodynamic demands in pregnancy. The delivery and postpartum period were uncomplicated. CONCLUSION: AF is rarely seen in pregnancy. Treatment favours rate and/or rhythm control with metoprolol and digoxin, respectively. Anticoagulation is not indicated in lone AF during pregnancy. Vaginal birth is preferred.

Cooperative Lewis Acid-1,2,3-Triazolium-Aryloxide Catalysis: Pyrazolone Addition to Nitroolefins as Entry to Diaminoamides.

Pyrazolones represent an important structural motif in active pharmaceutical ingredients. Their asymmetric synthesis is thus widely studied. Still, a generally highly enantio- and diastereoselective 1,4-addition to nitroolefins providing products with adjacent stereocenters is elusive. In this article, a new polyfunctional CuII -1,2,3-triazolium-aryloxide catalyst is presented which enables this reaction type with high stereocontrol. DFT studies revealed that the triazolium stabilizes the transition state by hydrogen bonding between C(5)-H and the nitroolefin and verify a cooperative mode of activation. Moreover, they show that the catalyst adopts a rigid chiral cage/pore structure by intramolecular hydrogen bonding, by which stereocontrol is achieved. Control catalyst systems confirm the crucial role of the triazolium, aryloxide and CuII , requiring a sophisticated structural orchestration for high efficiency. The addition products were used to form pyrazolidinones by chemoselective C=N reduction. These heterocycles are shown to be valuable precursors toward ß,γ'-diaminoamides by chemoselective nitro and N-N bond reductions. Morphological profiling using the Cell painting assay identified biological activities for the pyrazolidinones and suggest modulation of DNA synthesis as a potential mode of action. One product showed biological similarity to Camptothecin, a lead structure for cancer therapy.

A Practical and Robust Zwitterionic Cooperative Lewis Acid/Acetate/Benzimidazolium Catalyst for Direct 1,4-Additions.

A catalyst type is disclosed allowing for exceptional efficiency in direct 1,4-additions. The catalyst is a zwitterionic entity, in which acetate binds to CuII , which is formally negatively charged and serving as counterion for benzimidazolium. All 3 functionalities are involved in the catalytic activation. For maleimides productivity was increased by a factor >300 compared to literature (TONs up to 6700). High stereoselectivity and productivity was attained for a broad range of other Michael acceptors as well. The polyfunctional catalyst is accessible in only 4 steps from N-Ph-benzimidazole with an overall yield of 96 % and robust during catalysis. This allowed to reuse the same catalyst multiple times with nearly constant efficiency. Mechanistic studies, in particular by DFT, give a detailed picture how the catalyst operates. The benzimidazolium unit stabilizes the coordinated enolate nucleophile and prevents that acetate/acetic acid dissociate from the catalyst.

Stereoretentive Regio- and Enantioselective Allylation of Isoxazolinones by a Planar Chiral Palladacycle Catalyst.

The catalytic allylic substitution is one of the most important tools in asymmetric synthesis to form C-C bonds in an enantioselective way. While high efficiency was previously accomplished in terms of enantio- and regiocontrol using different catalyst types, a strong general limitation is a very pronounced preference for the formation of allylic substitution products with (E)-configured C=C double bonds. Herein, we report that with a planar chiral palladacycle catalyst a diastereospecific reaction outcome is achieved using isoxazolinones and allylic imidates as substrates, thus maintaining the C=C double bond geometry of the allylic substrates in the highly enantioenriched products. DFT calculations show that the reactions proceed via an SN 2 mechanism and not via π-allyl Pd complexes. Crucial for the high control is the stabilization of the allylic fragment in the SN 2 transition state by π-interactions with the phenyl substituents of the pentaphenylferrocenyl catalyst core.

Direct Enantioselective Addition of Alkynes to Imines by a Highly Efficient Palladacycle Catalyst.

Enantiopure propargylic amines are highly valuable synthetic building blocks. Much effort has been devoted to develop methods for their preparation. The arguably most important strategy is the 1,2-addition of alkynes to imines. Despite remarkable progress, the known methods using Zn and Cu catalysts suffer from the need for high catalyst loadings, typically ranging from 2-60 mol % for neutral aldimine substrates. Here we report a planar chiral Pd complex acting as very efficient catalyst for direct asymmetric alkyne additions to imines, requiring very low catalyst loadings. Turnover numbers of up to 8700 were accomplished. Our investigation suggests that a Pd-acetylide complex is generated as a catalytically relevant intermediate by the aid of an acac ligand acting as internal catalytic base. It is shown that the catalyst is quite stable under the reaction conditions and that product inhibition is not an issue. A total of 39 examples is shown which all yielded almost enantiopure products.

Enantioenriched γ-Aminoalcohols, ß-Amino Acids, ß-Lactams, and Azetidines Featuring Tetrasubstituted Fluorinated Stereocenters via Palladacycle-Catalyzed Asymmetric Fluorination of Isoxazolinones.

Enantiopure fluorine containing ß-amino acids are of large biological and pharmaceutical interest. Strategies to prepare ß-amino acid derivatives possessing a F-containing tetrasubstituted stereocenter at the α-C atom in a catalytic asymmetric sense are rare, in particular using an enantioselective electrophilic C-F bond formation. In the present study, a highly enantioselective palladacycle-catalyzed fluorination of isoxazolinones was developed. It is demonstrated that isoxazolinones are useful precursors toward enantiopure ß-amino acid derivatives by diastereo- and chemoselective reduction. The formed γ-aminoalcohols served as valuable precursors toward ß-amino acids, ß-amino acid esters, and ß-lactams, all featuring tetrasubstituted fluorinated stereocenters. In addition, by this work, enantioenriched fluorinated azetidines were accessible for the first time.

[Communication about in hospital resuscitation orders]. / Communicatie over reanimatiebeleid in het ziekenhuis.

BACKGROUND: The decision to attempt or refrain from resuscitation is preferably based on prognostic factors for outcome and subsequently communicated with patients. Both patients and physicians consider good communication important, however little is known about patient involvement in and understanding of cardiopulmonary resuscitation (CPR) directives. AIM: To determine the prevalence of Do Not Resuscitate (DNR)-orders, to describe recollection of CPR-directive conversations and factors associated with patient recollection and understanding. METHODS: This was a two-week nationwide multicentre cross-sectional observational study using a study-specific survey. The study population consisted of patients admitted to non-monitored wards in 13 hospitals. Data were collected from the electronic medical record (EMR) concerning CPR-directive, comorbidity and at-home medication. Patients reported their perception and expectations about CPR-counselling through a questionnaire. RESULTS: A total of 1136 patients completed the questionnaire. Patients' CPR-directives were documented in the EMR as follows: 63.7% full code, 27.5% DNR and in 8.8% no directive was documented. DNR was most often documented for patients >80 years (66.4%) and in patients using >10 medications (45.3%). Overall, 55.8% of patients recalled having had a conversation about their CPR-directive and 48.1% patients reported the same CPR-directive as the EMR. Most patients had a good experience with the CPR-directive conversation in general (66.1%), as well as its timing (84%) and location (94%) specifically. CONCLUSIONS: The average DNR-prevalence is 27.5%. Correct understanding of their CPR-directive is lowest in patients aged ≥80 years and multimorbid patients. CPR-directive counselling should focus more on patient involvement and their correct understanding.

Long-term survival and health-related quality of life after in-hospital cardiac arrest.

INTRODUCTION: In-hospital cardiac arrest (IHCA) is an adverse event associated with high mortality. Because of the impact of IHCA more data is needed on incidence, outcomes and associated factors that are present prior to cardiac arrest. The aim was to assess one-year survival, patient-centred outcomes after IHCA and their associated pre-arrest factors. METHODS: A multicentre prospective cohort study in 25 hospitals between January 1st 2017 and May 31st 2018. Patients ≥ 18 years receiving cardiopulmonary resuscitation (CPR) for IHCA were included. Data were collected using Utstein and COSCA-criteria, supplemented by pre-arrest Modified Rankin Scale (MRS, functional status) and morbidity through the Charlson Comorbidity Index (CCI). Main outcomes were survival, health-related quality of life (HRQoL, EuroQoL) and functional status (MRS) after one-year. RESULTS: A total of 713 patients were included, 64.5% was male, median age was 63 years (IQR 52-72) and 72.8% had a non-shockable rhythm, 394 (55.3%) achieved ROSC, 231 (32.4%) survived to hospital discharge and 198 (27.8%) survived one year after cardiac arrest. Higher pre-arrest MRS, age and CCI were associated with mortality. At one year, patients rated HRQoL 72/100 points on the EQ-VAS and 69.7% was functionally independent. CONCLUSION: One-year survival after IHCA in this study is 27.8%, which is relatively high compared to previous studies. Survival is associated with a patient's pre-arrest functional status and morbidity. HRQoL appears acceptable, however functional rehabilitation warrants attention. These findings provide a comprehensive insight in in-hospital cardiac arrest prognosis.

Highly Active Cooperative Lewis Acid-Ammonium Salt Catalyst for the Enantioselective Hydroboration of Ketones.

Enantiopure secondary alcohols are fundamental high-value synthetic building blocks. One of the most attractive ways to get access to this compound class is the catalytic hydroboration. We describe a new concept for this reaction type that allowed for exceptional catalytic turnover numbers (up to 15 400), which were increased by around 1.5-3 orders of magnitude compared to the most active catalysts previously reported. In our concept an aprotic ammonium halide moiety cooperates with an oxophilic Lewis acid within the same catalyst molecule. Control experiments reveal that both catalytic centers are essential for the observed activity. Kinetic, spectroscopic and computational studies show that the hydride transfer is rate limiting and proceeds via a concerted mechanism, in which hydride at Boron is continuously displaced by iodide, reminiscent to an SN 2 reaction. The catalyst, which is accessible in high yields in few steps, was found to be stable during catalysis, readily recyclable and could be reused 10 times still efficiently working.

Enantiodivergent [4+2] Cycloaddition of Dienolates by Polyfunctional Lewis Acid/Zwitterion Catalysis.

Diels-Alder reactions have become established as one of the most effective ways to prepare stereochemically complex six-membered rings. Different catalysis concepts have been reported, including dienophile activation by Lewis acids or H-bond donors and diene activation by bases. Herein we report a new concept, in which an acidic prodiene is acidified by a Lewis acid to facilitate deprotonation by an imidazolium-aryloxide entity within a polyfunctional catalyst. A metal dienolate is thus formed, while an imidazolium-ArOH moiety probably forms hydrogen bonds with the dienophile. The catalyst type, readily prepared in few steps in high overall yield, was applied to 3-hydroxy-2-pyrone and 3-hydroxy-2-pyridone as well as cyclopentenone prodienes. Maleimide, maleic anhydride, and nitroolefin dienophiles were employed. Kinetic, spectroscopic, and control experiments support a cooperative mode of action. High enantioselectivity was observed even with unprecedented TONs of up to 3680.

Stereospecific Asymmetric Synthesis of Tertiary Allylic Alcohol Derivatives by Catalytic [2,3]-Meisenheimer Rearrangements.

Chiral acyclic tertiary allylic alcohols are very important synthetic building blocks, but their enantioselective synthesis is often challenging. A major limitation in catalytic asymmetric 1,2-addition approaches to ketones is the enantioface differentiation by steric distinction of both ketone residues. Herein we report the development of a catalytic asymmetric Meisenheimer rearrangement to overcome this problem, as it proceeds in a stereospecific manner. This allows for high enantioselectivity also for the formation of products in which the residues at the generated tetrasubstituted stereocenter display a similar steric demand. Low catalyst loadings were found to be sufficient and the reaction conditions were mild enough to tolerate even highly reactive functional groups, such as an enolizable aldehyde, a primary tosylate, or an epoxide. Our investigations suggest an intramolecular rearrangement pathway.

Polyfunctional Imidazolium Aryloxide Betaine/Lewis Acid Catalysts as Tools for the Asymmetric Synthesis of Disfavored Diastereomers.

Enzymes are Nature's polyfunctional catalysts tailor-made for specific biochemical synthetic transformations, which often proceed with almost perfect stereocontrol. From a synthetic point of view, artificial catalysts usually offer the advantage of much broader substrate scopes, but stereocontrol is often inferior to that possible with natural enzymes. A particularly difficult synthetic task in asymmetric catalysis is to overwrite a pronounced preference for the formation of an inherently favored diastereomer; this requires a high level of stereocontrol. In this Article, the development of a novel artificial polyfunctional catalyst type is described, in which an imidazolium-aryloxide betaine moiety cooperates with a Lewis acidic metal center (here Cu(II)) within a chiral catalyst framework. This strategy permits for the first time a general, highly enantioselective access to the otherwise rare diastereomer in the direct 1,4-addition of various 1,3-dicarbonyl substrates to ß-substituted nitroolefins. The unique stereocontrol by the polyfunctional catalyst system is also demonstrated with the highly stereoselective formation of a third contiguous stereocenter making use of a diastereoselective nitronate protonation employing α,ß-disubstituted nitroolefin substrates. Asymmetric 1,4-additions of ß-ketoesters to α,ß-disubstituted nitroolefins have never been reported before in literature. Combined mechanistic investigations including detailed spectroscopic and density functional theory (DFT) studies suggest that the aryloxide acts as a base to form a Cu(II)-bound enolate, whereas the nitroolefin is activated by H-bonds to the imidazolium unit and the phenolic OH generated during the proton transfer. Detailed kinetic analyses (RPKA, VTNA) suggest that (a) the catalyst is stable during the catalytic reaction, (b) not inhibited by product and (c) the rate-limiting step is most likely the C-C bond formation in agreement with the DFT calculations of the catalytic cycle. The robust catalyst is readily synthesized and recyclable and could also be applied to a cascade cyclization.

In Situ Generated Gold Nanoparticles on Active Carbon as Reusable Highly Efficient Catalysts for a C sp 3 -C sp 3 Stille Coupling.

Gold nanoparticle catalysts are important in many industrial production processes. Nevertheless, for traditional C sp 2 -C sp 2 cross-coupling reactions they have been rarely used and Pd catalysts usually give a superior performance. Herein we report that in situ formed gold metal nanoparticles are highly active catalysts for the cross coupling of allylstannanes and activated alkylbromides to form C sp 3 -C sp 3 bonds. Turnover numbers up to 29 000 could be achieved in the presence of active carbon as solid support, which allowed for convenient catalyst recovery and reuse. The present study is a rare case where a gold metal catalyst is superior to Pd catalysts in a cross-coupling reaction of an organic halide and an organometallic reagent.

Polyfunctional Bis-Lewis-Acid-/Bis-Triazolium Catalysts for Stereoselective 1,4-Additions of 2-Oxindoles to Maleimides.

Achieving enzyme-like catalytic activity and stereoselectivity without the typically high substrate specificity of enzymes is a challenge in the development of artificial catalysts for asymmetric synthesis. Polyfunctional catalysts are considered to be a promising tool for achieving excellent catalytic efficiency. A polyfunctional catalyst system was developed, which incorporates two Lewis acidic/Brønsted basic cobalt centers in combination with triazolium moieties that are crucial for high reactivity and excellent stereoselectivity in the direct 1,4-addition of oxindoles to maleimides. The catalyst is assembled through click chemistry and is readily recyclable through precipitation by making use of its charges. Kinetic studies support a cooperative mode of action. Diastereodivergency is achievable with either Boc-protected or unprotected maleimide.

Asymmetric Carboxycyanation of Aldehydes by Cooperative AlF/Onium Salt Catalysts: from Cyanoformate to KCN as Cyanide Source.

Asymmetric 1,2-additions of cyanide yield enantioenriched cyanohydrins as versatile chiral building blocks. Next to HCN, volatile organic cyanide sources are usually used. Among them, cyanoformates are more attractive on technical scale than TMSCN for cost reasons, but catalytic productivity is usually lower. Here, the development of a new strategy for cyanations is described, in which this activity disadvantage is overcome. A Lewis acidic Al center cooperates with an aprotic onium moiety within a remarkably robust bifunctional Al-F-salen complex. This allowed for unprecedented turnover numbers of up to 104 . DFT studies suggest an unexpected unique trimolecular pathway in which the ammonium bound cyanide attacks the aldehyde, which itself is activated by the carbonyl group of the cyanoformate binding to the Al center. In addition, a novel practical carboxycyanation method was developed that makes use of KCN as the sole cyanide source. The use of a pyrocarbonate as carboxylating reagent provided the best results.

Intervalence of two planar chiral 2-methylferrocenyl groups over a diaurum bridge.

The electronic structure of recently reported diaurum (AuIAuI and XAuII-AuIIX) complexes, containing two methylferrocenyloxazoline ligands are described. Oxidations occurred at the methylferrocenyl and the monocation complex containing AuIAuI bridge was valence localized while the AuII-AuII complex was valence delocalized, i.e., Fe2.5+/Fe2.5+. These findings were supported by electrochemical, and spectroscopic measurements and further supported by computational analysis (DFT).

Diastereoselective synthesis, structure and reactivity studies of ferrocenyloxazoline gold(i) and gold(ii) complexes.

In the last few decades, gold complexes have demonstrated huge potential for soft Lewis acid catalysis. Despite the intensive research on Au complexes and planar chiral metallacycles, enantiopure ferrocenylgold complexes have - surprisingly - not been reported until the studies presented in this article. Herein, we report the asymmetric synthesis of planar chiral ferrocenyl Au(i) complexes. These dinuclear species form helically chiral ten-membered (NCCCAu)2 rings stabilized by aurophilic interactions. In supramolecular solid state structures, linear, zigzag or helical Au(i) wires with regular AuAu separations were observed. The dissolved dinuclear entities could be oxidized by Au(i) to unique ferrocenyl Au(ii) complexes featuring short Au(ii)-Au(ii) bonds, while the ferrocene core remained intact. However, our initial studies revealed the issue of configurational lability of the ferrocenyl Au(ii) complexes in terms of the element of planar chirality in the presence of the gold source, (Me2S)AuCl. This was successfully addressed by a systematic study implementing permanent σ-donor ortho-protecting groups such as methyl and trimethylsilyl, which impede an epimerization event. Oxidation of the dinuclear Au(i) complexes was also accomplished by oxidative addition reactions with halogenated solvents, preferably CHCl3. Additional reactivity studies revealed that dinuclear Au(ii) dihalide complexes are also formed with reactive alkylhalides such as iodomethane, benzylbromide and benzyliodide. Interestingly, the whole spectral range of colors (violet, blue, green, yellow, and red) is covered by the title complexes depending on the Au oxidation state and the anionic ligands in the Au(ii) complexes. This appears to be quite unusual for ferrocenes, which typically adopt orange to red colors in a non-oxidized state.

Double Regioselective Asymmetric C-Allylation of Isoxazolinones: Iridium-Catalyzed N-Allylation Followed by an Aza-Cope Rearrangement.

Isoxazolinones are biologically and synthetically interesting densely functionalized heterocycles, which for a long time were not accessible in enantioenriched form by asymmetric catalysis. Next to the deficit of enantioselective methods, the functionalization of isoxazolinones is often plagued by regioselectivity issues due to the competition of various nucleophilic centers within the heterocycles. We report the first regio- and enantioselective C-allylations of isoxazolinones. These occur with high regioselectivity in favor of the linear allylation products, although Ir phosphoramidite catalysts were used, which commonly results in branched isomers. Our studies suggest that this outcome is the result of a reaction cascade via an initial regio- and enantioselective N-allylation to provide a branched allyl intermediate, followed by a spontaneous [3,3]-rearrangement resulting in chirality transfer.

Ruthenium-Catalyzed Synthesis of 2H-Azirines from Isoxazolinones.

2H-Azirines are synthetically versatile, highly strained, three-membered heterocycles containing an imino double bond. We report their efficient Ru-catalyzed synthesis using low catalyst loadings under neutral conditions from isoxazolinone substrates, which are readily accessible from ß-ketoesters. The azirines were shown to be efficient precursors for functionalized pyridine, indole, dihydropyrrole, and pyrrolidine heterocycles.