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The site-selective C-H oxygenation of alkyl chains as well as deactivated positions remains a great challenge for chemists. Here, we report the synthesis and application of four new supramolecular tweezer-based oxidation catalysts. They consist of the well-explored M(pdp/mcp) oxidation moiety and a molecular tweezer capable of binding ammonium salts. All catalysts display preferential oxidation of the strongly deactivated C3/C4 positions, however to different degrees. Furthermore, the best performing catalyst Fe(pdp)Twe was explored with an expanded substrate scope. It was demonstrated that the deactivated positions C3/C4 are also preferentially oxidized in these cases.

Deep cavitands, concave molecular containers, represent an important supramolecular host class that has been explored for a variety of applications ranging from sensing, switching, purification and adsorption to catalysis. A major limitation in the field has been the cavitand volume that is restricted by the size of the structural platform utilized (diameter approx. 7 Å). We here report the synthesis of a novel, unprecedentedly large structural platform, named acridane[4]arene (diameter approx. 14 Å), suitable for the construction of cavitands with volumes of up to 814 Å3. These megalo-cavitands serve as size-selective hosts for fullerenes with mM to sub-μM binding affinity for C60 and C70. Furthermore, the selective binding of fullerene C70 in the presence of C60 was demonstrated., Angewandte Chemie. International Edition, 61 (42), ISSN:1433-7851, ISSN:1521-3773, ISSN:0570-0833

A molecular tweezer based on a glycoluril-derived framework bearing four phosphate groups was synthesized and shown to be capable of binding organic amines in aqueous solution. This work reports the Ka values for 30 complexes of this molecular tweezer and amine guests, determined by means of 1 H NMR titrations. Both the hydrophobic cavity and the phosphate groups contribute to the binding. Bulkier molecules and molecules bearing negatively charged groups like carboxylates in amino acids bind less tightly due to a steric clash and coulombic repulsion. The narrow cavity and the strong ionic interactions of the phosphate groups with ammonium guests favor binding of aliphatic diamines. These binding properties clearly distinguish this system from structurally related molecular clips and tweezers.

The synthesis of terpene natural products remains a challenging task due to the enormous structural diversity in this class of compounds. Synthetic catalysts are unable to reproduce the tail-to-head terpene cyclization of cyclase enzymes, which create this diversity from just a few simple linear terpene substrates. Recently, supramolecular structures have emerged as promising enzyme mimetics. In the present study, the hexameric resorcinarene capsule was utilized as an artificial cyclase to catalyze the cyclization of sesquiterpenes. With the cyclization reaction as the key step, the first total synthesis of the sesquiterpene natural product delta-selinene was achieved. This represents the first total synthesis of a sesquiterpene natural product that is based on the cyclization of a linear terpene precursor inside a supramolecular catalyst. To elucidate the reaction mechanism, detailed kinetic studies and kinetic isotope measurements were performed. Surprisingly, the obtained kinetic data indicated that a rate-limiting encapsulation step is operational in the cyclization of sesquiterpenes.

The sizes of available self-assembled hydrogen-bond-based supramolecular capsules and cages are rather limited. The largest systems have volumes of approximately 1400-2300 A3 . Herein, we report a large, hexameric cage based on intermolecular amide-amide dimerization. The unusual structure with openings, reminiscent of covalently linked cages, is held together by 24 hydrogen bonds. With a diameter of 2.3 nm and a cavity volume of ∼2800 A3 , the assembly is larger than any previously known capsule/cage structure relying exclusively on hydrogen bonds. The self-assembly process in chlorinated, organic solvents was found to be strongly concentration dependent, with the monomeric form prevailing at low concentrations. Additionally, the formation of host-guest complexes with fullerenes (C60 and C70 ) was observed.

Aims and objectives To test the method of self- and external assessment as a feedback system to decrease illegibility and incorrectness of handwritten prescriptions and to reduce additional workload for nursing staff. Background Illegibility and incorrectness of handwritten prescriptions occur very often and are the most crucial factors affecting patient safety. Design Self- versus external assessment using a 15 items checklist. Methods Nurses randomly selected five fever charts of their wards. Each fever chart was self- as well as externally assessed. Nurses and doctors took part in the self-assessment, and the external assessment was performed by external experts. According to a monitor suspension system, assessment results were considered "green," "yellow" or "red." After the first assessment and issuing feedback of the results "red" scored wards by the external assessment, additional trainings were performed. Thereafter, a second assessment was performed to rate eligibility and completeness of prescriptions. The research and reporting methodology followed squire 2.0. Results In total, 580 fever charts were self- as well as externally assessed (290 in each of the two assessment periods). Out of the 58 participating wards, 31 were surgical and 27 were non-surgical wards. Averaging over all checklist items, surgical and non-surgical wards improved only slightly over time. Linear regression models for ward means showed that there were significant improvements over time for non-surgical wards. Conclusions This method directly involves those who commit errors and stimulate learning from errors. The approach of self- and external assessment was a useful instrument to detect inadequate prescriptions and to monitor improvements. Relevance to clinical practice Significant improvements were achieved regarding correctness and legibility of handwritten prescription and helped to decrease additional workload for nursing staff and thereby enhanced patient safety.

SummaryIntroduction The inclusion of a heat treatment step has improved the classic Nijmegen-Bethesda assay for detection of factor VIII (FVIII) inhibitors in the presence of residual FVIII activity (FVIII:C). However, information regarding heat-modified Nijmegen-Bethesda assays for the detection of FIX inhibitors is still limited. Methods Three methods to measure FIX inhibitors in the presence or absence of residual FIX activity (FIX:C) using three different activated partial thromboplastin time (aPTT) reagents were investigated. These included the standard Nijmegen-Bethesda assay (method 1), a heat-modified assay (method 2) and a novel heat/cold-modified assay (method 3). Results In the absence of FIX:C, all methods measured similar levels of FIX inhibitor, while FIX inhibitor titres varied widely in the presence of residual FIX:C. Using method 1, inhibitors were not accurately measured in the presence of residual circulating FIX:C. Using method 2, detection was improved, especially at higher inhibitor titres. Using method 3, some additional sensitivity was obtained. The choice of aPTT reagent did not affect the detection of inhibitors. Conclusion Heat pretreatment is recommended for detecting FIX inhibitors in samples with residual FIX:C. The heat/cold modification improved the sensitivity of the Nijmegen-Bethesda assay, resulting in higher tolerance for residual FIX:C.

The noncovalent combination of a supramolecular host with iminium organocatalysis is described. Due to cation-π interactions the reactive iminium species is held inside the host and reacts in this confined environment. The products formed differ up to 92 % ee from the control experiments without added host. A model rationalizing the observed difference is presented.

Control over the local chemical environment of a molecule can be achieved by encapsulation in supramolecular host systems. In supramolecular catalysis, this control is used to gain advantages over classical homogeneous catalysis in bulk solution. Two of the main advantages concern influencing reactions in terms of substrate and product selectivity. Due to size and/or shape recognition, substrate selective conversion can be realized. Additionally, noncovalent interactions with the host environment facilitate alternative reaction pathways and can yield unusual products. This Concept article discusses and highlights literature examples utilizing self-assembled molecular capsules to achieve catalytic transformations displaying a high degree of substrate and/or product selectivity. Furthermore, the advantage of supramolecular hosts in multicatalyst tandem reactions is covered.

This survey of resorcinarene‐capsule‐catalyzed reactions demonstrates that HCl functions as a crucial cocatalyst by increasing the capsule's inherent Bronsted acidity to enable or accelerate cationic reactions. The presence of HCl appears to be without consequences for other reactions.

Background Extended‐duration betrixaban showed a significant reduction in venous thromboembolism in the APEX trial (Acute Medically Ill VTE Prevention With Extended Duration Betrixaban Study). Given the variable clinical impact of different efficacy and safety events, one approach to assess net clinical outcomes is to include only those events that are either fatal or cause irreversible harm. Methods and Results This was a post hoc analysis of the APEX trial—a multicenter, double‐blind, randomized controlled trial comparing extended‐duration betrixaban versus standard‐of‐care enoxaparin. A composite of all fatal or irreversible safety (fatal bleeding or intracranial hemorrhage) and efficacy events (cardiopulmonary death, myocardial infarction, pulmonary embolism, and ischemic stroke) was evaluated in a time‐to‐first event analysis. In patients with positive D‐dimer results, betrixaban reduced fatal or irreversible events at 35 to 42 days (4.80% versus 3.54%; hazard ratio, 0.73; absolute risk reduction, 1.26%; number needed to treat, 79 [ P =0.033]) and at study end at 77 days (6.27% versus 4.36%; hazard ratio, 0.70; absolute risk reduction, 1.91%; number needed to treat, 52 [ P =0.005]) versus enoxaparin. In all patients, betrixaban reduced fatal or irreversible events at 35 to 42 days (4.08% versus 2.90%; hazard ratio, 0.71; absolute risk reduction, 1.18%; number needed to treat, 86 [ P =0.006]) and 77 days (5.17% versus 3.64%; hazard ratio, 0.70; absolute risk reduction, 1.53%; number needed to treat, 65 [ P =0.002]). Conclusions Among hospitalized medically ill patients, extended‐duration betrixaban demonstrated an ≈30% reduction in fatal or irreversible ischemic or bleeding events compared with standard‐duration enoxaparin. A total of 65 patients would require treatment with betrixaban to prevent 1 fatal or irreversible event versus enoxaparin. Clinical Trial Registration URL : http://www.ClinicalTrials.gov . Unique identifier: NCT 01583218.

Neurotrophic natural products hold potential as privileged structures for the development of therapeutic agents against neurodegeneration. However, only a few studies have been conducted to investigate a common pharmacophoric motif and structure-activity relationships (SARs). Here, an investigation of structurally more simple analogues of neurotrophic sesquiterpenes of the illicium family is presented. A concise synthetic route enables preparation of the carbon framework of (±)-Merrilactone A and (±)-Anislactone A/B on a gram scale. This has allowed access to a series of structural analogues by modification of the core structure, including variation of oxidation levels and alteration of functional groups. In total, 15 derivatives of the natural products have been synthesized and tested for their neurite outgrowth activities. Our studies indicate that the promising biological activity can be retained by structurally simpler natural product analogues, which are accessible by a straightforward synthetic route.

The Brønsted acidic resorcin[4]arene hexamer can be applied as an effective catalyst in the dehydrative cyclization and subsequent rearrangement of unsaturated tertiary alcohols. This is the first report on catalyzing such a reaction with a Brønsted acid. Scope and limitations of this cyclopentene-forming reaction sequence are presented. Furthermore, substrate-selective conversion as well as competitive inhibition are described and provide evidence that the reactions proceed within the cavity of the self-assembled structure. Additionally, a cyclobutanone-forming intramolecular hydride transfer of an encapsulated cyclopropyl acetate is reported.

The binding behavior of a cavitand introduced by de Mendoza is explored with new guest species. Dimerization to hydrogen-bonded capsules occurs in the presence of appropriate guests, including alkanes, alkylated arenes, stilbenes, benzanilides, and carbodiimides. Peripheral tetraethylene glycol groups are attached to the cavitand to improve solubility. Encapsulation of hydrophobic compounds can be observed in aqueous media. Copyright © 2014 John Wiley & Sons, Ltd.

Control over the local chemical environment of a molecule can be achieved by encapsulation in supramolecular host systems. In supramolecular catalysis, this control is used to gain advantages over classical homogeneous catalysis in bulk solution. Two of the main advantages concern influencing reactions in terms of substrate and product selectivity. Due to size and/or shape recognition, substrate selective conversion can be realized. Additionally, noncovalent interactions with the host environment facilitate alternative reaction pathways and can yield unusual products. This Concept article discusses and highlights literature examples utilizing self-assembled molecular capsules to achieve catalytic transformations displaying a high degree of substrate and/or product selectivity. Furthermore, the advantage of supramolecular hosts in multicatalyst tandem reactions is covered.

Self-assembled supramolecular structures represent easily accessible systems for the study of enzyme-like catalysis. The hydrophobic cavities of the assemblies provide a distinct chemical environment that can lead to unusual chemo- and stereoselectivities. This review summarizes the application of such host structures in the catalysis of reactions involving cationic transition states and includes detailed discussion of mechanisms and substrate–host interactions. The literature up to April 2015 is covered. 1 Introduction 2 Molecular Capsules: Structures and Background 3 Catalyzed Reactions 4 Summary and Outlook

Platencin is a novel antibiotic which is active against multiresistant pathogens. We describe efficient syntheses of three platencin analogues of varying activities which allow further conclusions about the pharmacophoric part of the molecule. The unnatural antibiotic iso-platencin, which is about as active as natural platencin, but much more selective, was identified as a new lead structure.