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While the integration of supramolecular principles in catalysis attracts increasing attention, a direct comparative assessment of the resulting systems catalysts to work out distinct characteristics is often difficult. Herein is reported how the broad responsiveness of ether cyclizations to diverse inputs promises to fill this gap. Cyclizations in the confined, π-basic and Brønsted acidic interior of supramolecular capsules, for instance, are found to excel with speed (exceeding general Brønsted acid and hydrogen-bonding catalysts by far) and selective violations of the Baldwin rules (as extreme as the so far unique pnictogen-bonding catalysts). The complementary cyclization on π-acidic aromatic surfaces remains unique with regard to autocatalysis, which is shown to be chemo- and diastereoselective with regard to product-like co-catalysts but, so far, not enantioselective., Chemistry - A European Journal, 27 (47), ISSN:0947-6539, ISSN:1521-3765

Background Limited information exists regarding the factor IX (FIX) coagulant activity (FIX:C) measured by different assays following FIX‐Padua gene therapy. Objective Assess for the first time FIX:C in five commonly used coagulation assays in plasma samples from hemophilia B subjects receiving FIX‐Padua gene transfer. Methods FIX:C was compared between central (n = 1) and local laboratories (n = 5) in the study, and across four commonly used FIX:C one‐stage assays and one FIX:C chromogenic assay. For comparison, samples of pooled congenital FIX‐deficient plasma spiked with purified recombinant human FIX (rHFIX)‐Padua protein or rHFIX (nonacog alfa) to obtain FIX:C concentrations from ~20% to ~40% were tested. Results FIX:C results at local laboratories strongly correlated with central laboratory results. However, absolute values at the central laboratory were consistently lower than those at local laboratories. Across five different FIX:C assays, a consistent pattern of FIX:C was observed for subjects receiving fidanacogene elaparvovec‐expressed gene transfer. Use of Actin FSL activated partial thromboplastin time (APTT) reagent in the central laboratory resulted in lower FIX:C values compared with other APTT reagents tested. The chromogenic assay determined lower FIX:C than any of the one‐stage assays. The rHFIX‐Padua protein–spiked samples showed similar results. In contrast, FIX:C results for rHFIX‐nonacog alfa measured within 25% of expected for all one‐stage assays and below 25% in the chromogenic assay. Conclusions Assay‐based differences in FIX:C were observed for fidanacogene elaparvovec transgene product and rHFIX‐Padua protein, suggesting the variable FIX:C determined with different assay reagents is inherent to the FIX‐Padua protein and is not specific to gene therapy–derived FIX‐Padua.

A modular synthetic platform for the construction of flexible glycoluril-derived molecular tweezers was developed. The binding properties of four exemplary supramolecular hosts obtained via this approach towards 16 organic amines were investigated by means of 1H NMR titration. In this work, we compare the Ka values obtained this way with those of three structurally related molecular tweezers and provide a computational approach towards an explanation of the observed behavior of those novel hosts. The results showcase that certain structural modifications lead to very potent and selective binders of natural polyamines, with observed binding of spermine below 10 nM., Organic & Biomolecular Chemistry, 19 (16), ISSN:1477-0520, ISSN:1477-0539

We designed and synthesized two resorcin[4]arene scaffolds with four phosphate binding groups. The ligands effectively bind in at least a tridentate fashion at low surface coverage. The superior binding affinity is demonstrated using solution NMR spectroscopy and exceeds that of single phosphonates., Chemical Communications, 57 (38), ISSN:1359-7345, ISSN:1364-548X

The coronavirus disease outbreak was a moment of unprecedented global change in which the regular pattern of life of hundreds of millions of people around the world was disrupted. To prevent the spread of this virus, governments halted many economic activities so that people would sequester at home. The decline in the consumption of petroleum and other fossil fuels has led to a reduction in greenhouse gas emissions which resulted in things that most living people had never before witnessed. Another consequence of coronavirus disease is a slight deceleration of global warming. The First-quarter 2020 global daily CO2 emissions from surface transport, power, and industry fell by 36%, 7.4%, and 19%, respectively, relative to the annual mean daily emissions in 2019. If they grow accustomed to these adjustments, oil consumption is likely to decline and investment in oil extraction will no longer be profitable. This radical interruption of the global economic system has made a serious move toward a greener economy.

Self-assembled molecular capsules, host structures that form spontaneously when their building blocks are mixed, have been known since the 1990s. They share some basic similarities with enzyme pockets, as they feature defined hydrophobic binding pockets that are able to bind molecules of appropriate size and shape. The potential to utilize such host structures for catalysis has been explored since their discovery; however, applications that solve current challenges in synthetic organic chemistry have remained limited. In this short article, we discuss the challenges associated with the use of molecular capsules as catalysts, and highlight some recent applications of supramolecular capsules to overcome challenges in synthetic organic chemistry., Chimia, 74 (7-8), ISSN:0009-4293

Terpenes constitute one of the most structurally varied classes of natural products. A wide range of these structures are produced in nature by type I terpene cyclase enzymes from one single substrate. However, such reactivity has proven difficult to reproduce in solution with man-made systems. Herein we report the shortest synthesis of the tricyclic sesquiterpene presilphiperfolan-1β-ol to date, utilizing the supramolecular resorcinarene capsule as catalyst for the key step. This synthetic approach also allows access to unnatural derivatives of the natural product, which would not be accessible through the biosynthetic machinery. Additionally, this study provides useful insight into the biosynthesis of the presilphiperfolanol natural products, including the first experimental evidence consistent with the proposed biosynthetic connection between caryophyllene and the presilphiperfolanols.

Three novel thiol bearing resorcin[4]arene and pyrogallol[4]arene derivatives were synthesized. Their properties were studied with regards to self-assembly, disulfide chemistry, and Brønsted acid catalysis. This work demonstrates that (1) one aromatic thiol on the resorcin[4]arene framework is tolerated in the self-assembly process to a hexameric hydrogen bond-based capsule, (2) thio-derivatized resorcin[4]arene analogs can be covalently linked through disulfides, and (3) the increased acidity of aromatic thio-substituent is not sufficient to replace HCl as cocatalyst for capsule catalyzed terpene cyclizations.

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.

Carbohydrates are of central importance in biology. The selective chemical synthesis of carbohydrates, however, still poses a challenge; particularly, the selective formation of thethermodynamically labile b-glycosidic bond is difficult and depends on the substrate’s substitution pattern. We here demonstrate that a molecular capsule catalyzes the highlychallenging selective formation of b-glycosides independent of the substrate’s substitution pattern and configuration. We demonstrate the versatility of the catalyst by synthesizing small to medium sized 1,2-cis, 2-deoxy, and 1,2-trans b-glycosides in very high selectivity and good yield. The confined space inside the molecular capsule naturally limits the scope concerning the size of reactants. Interestingly, the proposed mechanism involves the synchronized activation of the glycosyl donor and acceptor inside the supramolecular capsule via a relay involving seven hydrogen bonds. Such an activation is known for enzymes, however, to our knowledge, is unprecedented for man-made catalysts.

We designed and synthesized two resorcin[4]arene scaffolds with four phosphoric acid binding groups. The ligands effectively bind in at least a tridentate fashion. The superior binding affinity is demonstrated using solution NMR spectroscopy and exceeds that of phosphonic acids.

A new class of macrocycles denoted as "xanthene[ n ]arenes" was synthesized. In contrast to most other macrocycles, they feature a conformationally restricted bowl shape due to the attached alkyl groups at the linking methylene units. This facilitates the synthesis of cavitands and the self-assembly to molecular capsules via noncovalent interactions. The derivatization potential of the novel macrocycles was demonstrated on the xanthene[3]arene scaffold. Besides a deep cavitand and an oxygen-embedded zigzag hydrocarbon belt[12]arene, a modified macrocycle was synthesized that self-assembles into a hydrogen-bonded tetrameric capsule, demonstrating the potential of xanthene[ n ]arenes as a new set of macrocyclic building blocks.

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.

Besides the importance of dissolved organic matter (DOM) in soil biogeochemical processes, there is still a debate on how agricultural intensification affects the leaching of terrestrial DOM into adjacent aquatic ecosystems. In order to close this linkage, we conducted a short-term (45 day) lysimeter experiment with silt loam and sandy loam undisturbed/intact soil cores. Mineral (calcium ammonium nitrate) or organic (pig slurry) fertilizer was applied on the soil surface with a concentration equivalent to 130 kg N ha&minus, 1. On average, amounts of leached DOC over 45 days ranged between 20.4 mg (silt loam, mineral fertilizer) and 34.4 mg (sandy loam, organic fertilizer). Both, mineral and organic fertilization of a silt loam reduced concentration of dissolved organic carbon (DOC) in the leachate and shifted its composition towards a microbial-like signature (BIX) with a higher aromaticity (Fi) and a lower molecular size (E2:E3). However, in sandy loam only mineral fertilization affected organic matter leaching. There, lowered DOC concentrations with a smaller molecular size (E2:E3) could be detected. The overall effect of fertilization on DOC leaching and DOM composition was interrelated with soil texture and limited to first 12 days. Our results highlight the need for management measures, which prevent or reduce fast flow paths leading soil water directly into aquatic systems, such as surface flow, fast subsurface flow, or drainage water.

The site-selective C-H oxidation of unactivated positions in aliphatic ammonium chains poses a tremendous synthetic challenge, for which a solution has not yet been found. Here, we report the preferential oxidation of the strongly deactivated C3/C4 positions of aliphatic ammonium substrates by employing a novel supramolecular catalyst. This chimeric catalyst was synthesized by linking the well-explored catalytic moiety Fe(pdp) to an alkyl ammonium binding molecular tweezer. The results highlight the vast potential of overriding the intrinsic reactivity in chemical reactions by guiding catalysis using supramolecular host structures that enable a precise orientation of the substrates.

Besides the importance of dissolved organic matter (DOM) in soil biogeochemical processes, there is still a debate on how agricultural intensification affects the composition and concentration of dissolved organic matter leached from soils into adjacent aquatic ecosystems. In order to investigate the immediate response of DOM leaching to fertilization, we conducted a short-term (45 day) lysimeter experiment with undisturbed silt loam and loamy sand soil cores. Mineral (calcium ammonium nitrate) or organic (pig slurry) fertilizer was applied on the soil surface with a concentration equivalent to 130 kg N ha−1. After fertilization, soil leachate was collected in 6-days intervals. Dissolved organic carbon concentrations (DOC) were measured with gas chromatography, while shifts in DOM composition were analysed using absorbance and excitation- emission fluorescence indices from peak-picking as well as from PARAFAC analysis. During the first 12 days, fertilization of a silt loam reduced DOC concentrations in the leachate and shifted its composition towards more microbial- like compounds. Additionally, the discrepancy in DOM composition between fertilizer and control treatments of a silt loam increased with time. However, in loamy sand only mineral fertilization affected organic matter leaching and decreased DOC concentrations in the leachate during the first 12 days. Furthermore, mineral fertilization of the loamy sand led to DOM compounds with low molecular size in the first 12 days. Our results show that fertilization tends to increase microbial transformed DOM, while it reduces leached DOC concentrations. Furthermore, the magnitude of fertilization on DOC concentrations and DOM composition was highly depending on the soil texture they originate from. However, in our set-up, the experimental soil units were restricted to a soil depth of 16 cm (Ap horizon). At ecosystem level, a sufficiently long soil passage might mitigate the impact of fertilization on soil DOM.

The elucidation of the requirements for efficient catalysis within supramolecular host systems is an important prerequisite for developing novel supramolecular catalysts. The resorcinarene hexamer has recently been shown to be the first supramolecular catalyst to promote the tail-to-head terpene cyclization in a biomimetic fashion. We herein present the synthesis of a number of resorcinarene-based macrocycles composed of different ratios of resorcinol and pyrogallol units capable of self-assembly and compare the corresponding assemblies regarding their catalytic activity in the cyclization of monoterpenes. The assemblies were investigated in detail with respect to a number of properties including the encapsulation of substrate and ion pairs, the structural incorporation of water, and the response to externally added acid (HCl). The results obtained strongly indicate that water incorporated into the hydrogen-bond network of the self-assembled structure plays an integral role for catalysis, effectively acting as a proton shuttle to activate the encapsulated substrate. These findings are also supported by molecular dynamics simulations, providing further insight into the protonation pathway and the relative energies of the intermediates involved.

A missing, inherently chiral member of the calix[4]arene family denoted "catechol[4]arene" was synthesized. Its properties were studied and compared to the ones of its close relatives resorcin[4]arene and pyrogallol[4]arene. This novel supramolecular host exhibits binding capabilities that are superior to its sister molecules in polar media. The enantiomerically pure forms of the macrocycle display modest recognition of chiral ammonium salts.

The scope of the trimerisation reaction of 3-substituted benzyl alcohols was explored. Several C 3 -symmetric cyclotribenzylene derivatives were obtained in preparative useful yields in one step and applied to the short synthesis (one or two steps) of two CTB derivatives, so far only accessible in six or seven linear steps.

Journal of catalysis 356, 147 - 156 (2017). doi:10.1016/j.jcat.2017.10.009, ZrO$_2$ supported Ni with an average particle diameter of 1–2 nm were synthesized by binding Ni$^{2+}$ in rccc-5,11,17,23-tetrahydroxy-2,8,14,20-tetra(n-decyl)resorcin[4]arene (pyrogallol[4]arene) nanocapsules as Ni precursor. The Ni/ZrO$_2$ catalyst with a 1.1 nm particle diameter showed outstanding stability in dry reforming of methane (DRM), which maintained nearly 90% of the initial activity after 60 h time on stream. The high stability is attributed to nearly all Ni atoms being located at the interface and perimeter to ZrO$_2$. This led to a higher accessibility to the oxygen from activated CO$_2$ at the Ni-ZrO$_2$ interface, facilitating conversion of surface carbon to CO. Ni/ZrO$_2$ catalysts with larger Ni particle diameter have a fraction of non-perimeter Ni that deactivates rapidly. The decrease of the H2 formation rate was faster with time on stream than the decrease of the H$_2$O formation rate. At longer time on stream the ratio of H$_2$O to H$_2$ yield reached 0.40 ± 0.08 for all Ni/ZrO$_2$ catalysts, independently if a catalyst was stable from the reaction start or deactivated to a stable level. The ratio between H$_2$O and H$_2$ yield reflects the abundance of oxygen availability on the Ni surface, the oxygen availability index (OAI). For an OAI value of 0.40, the deactivation of Ni catalyst was negligible, while below that deactivation was pronounced. The reorganization of surface carbon to graphitic overlayers and carbon fibers is hypothesized to start from surface domains that are not adjacent to the metal-support perimeter., Published by Elsevier, Amsterdam [u.a.]

Under conditions of climate change, the severity and probability of storm events and droughts are expected to increase, this may affect the partitioning into surface and subsurface runoff. However, there is still a debate on how such extreme weather conditions affect the leaching of soil organic carbon. The aim of this study was to ascertain the impact of rainfall intensity (63 vs 79 mm h−1) and antecedent soil moisture (Matric potential: −10 hPa vs −450 hPa) on flow partitioning in the transportation (fluxes and timing) of dissolved (DOC) and particulate organic carbon (POC). Rainfall simulation experiments using undisturbed soil monoliths (1 m × 0.5 m × 0.3 m) allowed to monitor the transport of water, sediments, DOC, and POC via surface and shallow subsurface runoff. In addition, the composition of the leached organic matter was analysed using photometric and fluorometric methods. Most of the organic carbon was transported as POC via surface runoff. In the surface runoff, the influence of antecedent soil moisture on POC loss was larger than rainfall intensity, while rainfall intensity had a greater influence on DOC losses. Under initially unsaturated conditions, surface sealing reduced the infiltration rate, thus fuelling the total surface runoff, which, in turn, enhanced the transported total sediment and POC load of the surface runoff. While POC dominated surface runoff, DOC played a crucial role in the subsurface runoff with higher DOC concentrations under unsaturated conditions. In contrast to other treatments, DOC exported from unsaturated soils rained with high intensity had a unique composition with the highest proportion of humic-like peaks (A, M, C), protein-like peaks (T) and components (C4), suggesting a concentrating effect on DOC at those soils. Altogether, this research acquires new insights into how flow partitioning under extreme weather conditions affects organic carbon losses and which transport mechanism might pose a risk for aquatic systems.

Background: Stroke is a morbid and potentially mortal complication among patients hospitalized with acute medical illness. The potential of extended-duration thromboprophylaxis with the factor Xa inhibitor betrixaban to reduce the risk of stroke compared with standard-dose enoxaparin in this population was assessed in this retrospective APEX trial substudy (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban). Methods: Hospitalized acutely medically ill subjects (n=7513) were randomized in a double-dummy double-blind fashion to either extended-duration oral betrixaban (80 mg once daily for 35–42 days) or standard-dose subcutaneous enoxaparin (40 mg once daily for 10±4 days) for venous thromboprophylaxis. Stroke events were adjudicated by an independent, blinded event adjudication committee. Results: The mean age of study participants was 76 years; 45% were male; 13% had had a stroke; and 45% had congestive heart failure. There were fewer all-cause strokes (0.54% versus 0.97%; relative risk [RR]=0.56; 95% confidence interval, 0.32–0.96; P =0.032; adjusted RR=0.43%; number needed to treat=233) and ischemic strokes (0.48% versus 0.91%; RR=0.53; 95% confidence interval, 0.30–0.94; P =0.026; adjusted RR=0.43%; number needed to treat=233) among patients treated with betrixaban versus enoxaparin through 77 days of follow-up. Among high-risk subjects, those with congestive heart failure or ischemic stroke as their index event, betrixaban reduced the risk of all-cause stroke (0.72% versus 1.48%; RR=0.49; 95% confidence interval, 0.26–0.90; P =0.019; adjusted RR=0.76%; number needed to treat=132) and ischemic stroke (0.63% versus 1.38%; RR=0.45; 95% confidence interval, 0.24–0.87; P =0.014; adjusted RR=0.75%; number needed to treat=134) compared with enoxaparin. Conclusions: Among hospitalized medically ill patients, extended-duration betrixaban significantly reduced all-cause stroke and ischemic stroke through 77 days of follow-up Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01583218.

Herein we report the shortest synthesis of the tricyclic sesquiterpene presilphiperfolan-1β-ol to date, utilizing the supramolecular resorcinarene capsule as catalyst for the key step. This synthetic approach also allows access to unnatural derivatives of the natural product, which would not be accessible through the biosynthetic machinery. Additionally, this study provides useful insight into the biosynthesis of the presilphiperfolanol natural products, including the first direct experimental evidence for the proposed biosynthetic connection between caryophyllene and the presilphiperfolanols.

Large-scale production of natural products, such as terpenes, presents a significant scientific and technological challenge. One promising approach to tackle this problem is chemical synthesis inside nanocapsules, although enzyme-like control of such chemistry has not yet been achieved. In order to better understand the complex chemistry inside nanocapsules, we design a multiscale nanoreactor simulation approach. The nanoreactor simulation protocol consists of hybrid quantum mechanics-molecular mechanics-based high temperature Langevin molecular dynamics simulations. Using this approach we model the tail-to-head formation of monoterpenes inside a resorcin[4]arene-based capsule (capsule I ). We provide a rationale for the experimentally observed kinetics of monoterpene product formation and product distribution using capsule I , and we explain why additional stable monoterpenes, like camphene, are not observed. On the basis of the in-capsule I simulations, and mechanistic insights, we propose that feeding the capsule with pinene can yield camphene, and this proposal is verified experimentally. This suggests that the capsule may direct the dynamic reaction cascades by virtue of π-cation interactions.

Terpenes are a class of natural products characterized by remarkable structural diversity. Much of this diversity arises biosynthetically from a handful of linear precursors through the so-called tail-to-head terpene cyclization reaction. This reaction is one of the most complex observed in nature, and historically attempts to replicate it with non-enzymatic means have met with little success. In recent years, however, the development of manmade binding pockets that allow such reactions to take place has been reported. This Highlight provides an overview of this nascent field, and outlines the challenges that need to be overcome moving forward. ISSN:0265-0568 ISSN:0265-0568 ISSN:1460-4752

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.

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

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.

Conspectus In this Account, we outline our investigation into the supramolecular resorcinarene capsule as a catalyst. Molecular capsules not only are of interest due to the similarities of their binding pockets with those of natural enzymes but also feature potential advantages for catalysis. Due to the restricted internal volume of the binding pockets, substrate selectivities are commonly observed. Substrates that are encapsulated more efficiently will be converted selectively in the presence of less suitable substrates. This size selectivity cannot be obtained in a regular solution experiment. In addition, because of the distinct chemical environment inside the capsule, different product selectivities may be observed. Furthermore, the encapsulation of reactive catalysts inside confined environments may improve catalyst compatibility for multicatalyst tandem reactions. Although the potential advantages of performing catalysis inside closed microenvironments are generally recognized, the number of known catalytically active supramolecular host systems is still very limited. There are several reasons, the most important of which is that it is very difficult to predict the catalytic potential of known supramolecular host systems. In several cases, even the encapsulation behavior of host systems is not completely understood or explored. Therefore, it is evident that further research is required to explore the potential of catalysis inside supramolecular capsules. Our initial research mainly focused on understanding the puzzling encapsulation behavior of the self-assembled resorcinarene capsule I and the closely related pyrogallolarene capsule II. After the elucidation of the decisive differences between these two systems, we explored the catalytic potential of capsule I. A variety of different reactions were successfully performed inside its cavity. The most important examples highlighted in this Account are iminium catalysis, the tail-to-head terpene cyclization, and the carbonyl–olefin metathesis. In the case of proline-mediated iminium catalysis, we were able to demonstrate that the enantioselectivity for the product formation was increased when the reaction was performed inside the cavity of capsule I. This is remarkable since the capsule is formed from achiral building blocks and, therefore, does not add chiral information to the reaction mixture. The tail-to-head terpene cyclization is the most complex reaction performed so far inside capsule I. The cyclic monoterpenes eucalyptol and α-terpinene were formed in useful yields. Interestingly, these products have not yet been synthetically accessible in solution directly from acyclic terpene precursors. Furthermore, we demonstrated that the cocatalytic system of capsule I and HCl is suitable for carbonyl-olefin metathesis. HCl was shown to be an inefficient catalyst for this reaction in solution experiments. This demonstrates that the different chemical environment inside the supramolecular container can lead to altered product selectivity. In general, we hope to demonstrate in this Account that research on catalysis inside supramolecular capsules, although still in its infancy, is starting to produce the first synthetically relevant results.

Carbonyl-olefin metathesis represents a powerful yet underdeveloped method for the formation of carbon-carbon bonds. So far, no Bronsted acid based method for the catalytic carbonyl-olefin metathesis has been described. Herein, a cocatalytic system based on a simple Bronsted acid (HCl) and a self-assembled supramolecular host is presented. The developed system compares well with the current benchmark catalyst for carbonyl-olefin metathesis in terms of substrate scope and yield of isolated product. Control experiments provide strong evidence that the reaction proceeds inside the cavity of the supramolecular host. A mechanistic probe indicates that a stepwise reaction mechanism is likely.

In nature, complex terpene natural products are formed by the so-called tail-to-head terpene (THT) cyclization. The cationic reaction cascade is promoted efficiently in complex enzyme pockets, in which cationic intermediates and transition states are stabilized. In solution, the reaction is hard to control and man-made catalysts able to perform selective THT cyclizations are lacking. We herein report the first example of a successful THT cyclization inside a supramolecular structure. The basic mode of operation in cyclase enzymes was mimicked successfully and a catalytic non-stop THT was achieved with geranyl acetate as the substrate. The results presented have implications for the postulated reaction mechanism in cyclase enzymes. Evidence indicates that the direct isomerization of a geranyl cation to the cisoid isomer, which so far was considered unlikely, is feasible.

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.

Previous studies have shown that some lipoglycopeptide and lipopeptide antimicrobial agents may cause falsely elevated values for some phospholipid-dependent coagulation tests. The effect of oritavancin, a lipoglycopeptide antibiotic, on coagulation test results was explored using pooled human plasma samples spiked with drug and in a clinical study after an infusion of a single 1,200-mg intravenous dose of oritavancin in normal healthy volunteers. Pooled plasma with oritavancin added ex vivo showed concentration-dependent prolongation of prothrombin time/international normalized ratio (PT/INR), activated partial thromboplastin time (aPTT), and dilute Russell viper venom time (DRVVT) test results. In contrast, oritavancin had no effect on the activated protein C resistance assay, chromogenic anti-factor Xa assay (anti-FXa), thrombin time, and an immunoassay for the laboratory diagnosis of heparin-induced thrombocytopenia. In participants that received a single dose of oritavancin, elevations in PT/INR result, aPTT, DRVVT, activated clotting time, and silica clotting time occurred, with the maximum times to resolution of test interference determined to be 12, 120, 72, 24, and 18 h, respectively. The anti-FXa assay was unaffected, whereas transient elevations in D dimer levels were observed in 30% of participants, with a maximum time to resolution of 72 h. Although oritavancin has no impact on the coagulation system in vivo , a single dose of oritavancin can produce falsely elevated values of some coagulation tests used to monitor hemostasis. The interference of oritavancin on affected tests is transient, and the test results revert to normal ranges within specified times after dosing.

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 tail-to-head terpene cyclization is arguably one of the most complex reactions found in nature. The hydrogen-bond-based resorcinarene capsule represents the first man-made enzyme-like catalyst that is capable of catalyzing this reaction. Based on noncovalent interactions between the capsule and the substrate, the product selectivity can be tuned by using different leaving groups. A detailed mechanistic investigation was performed to elucidate the reaction mechanism. For the cyclization of geranyl acetate, it was found that the cleavage of the leaving group is the rate-determining step. Furthermore, the studies revealed that trace amounts of acid are required as cocatalyst. A series of control experiments demonstrate that a synergistic interplay between the supramolecular capsule and the acid traces is required for catalytic activity.

This chapter provides technological information on sweeteners, oils, fats and emulsifiers, important ingredients in wafers, waffles and their fillings and enrobings.

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.

Seed dressing, i.e., the treatment of crop seeds with insecticides and/or fungicides, aiming to protect seeds from pests and diseases, is widely used in conventional agriculture. During the growing season, those crop fields often receive additional broadband herbicide applications. However, despite this broad utilization, very little is known on potential side effects or interactions between these different pesticide classes on soil organisms. In a greenhouse pot experiment, we studied single and interactive effects of seed dressing of winter wheat (Triticum aestivum L. var. Capo) with neonicotinoid insecticides and/or strobilurin and triazolinthione fungicides and an additional one-time application of a glyphosate-based herbicide on the activity of earthworms, soil microorganisms, litter decomposition, and crop growth. To further address food-web interactions, earthworms were introduced to half of the experimental units as an additional experimental factor. Seed dressings significantly reduced the surface activity of earthworms with no difference whether insecticides or fungicides were used. Moreover, seed dressing effects on earthworm activity were intensified by herbicides (significant herbicide × seed dressing interaction). Neither seed dressings nor herbicide application affected litter decomposition, soil basal respiration, microbial biomass, or specific respiration. Seed dressing did also not affect wheat growth. We conclude that interactive effects on soil biota and processes of different pesticide classes should receive more attention in ecotoxicological research.

This chapter provides technological information on water and flours, the two main ingredients in preparing batters for wafers and waffles. Particularly for wafers, these ingredients are dominant, both in quantity and influence on the baking performance and the end-product quality. For water, the hardness and the temperature are most influential parameters. Wheat flour as a natural ingredient with quality fluctuations as well as other flours and starches are main focuses of technological activity for the objective of obtaining trouble-free manufacturing. A detailed discussion is on analytical parameters for wheat flour and their significance in wafer and waffle manufacturing. The gluten development test introduces a method to study wafer flours and the options used to correct flour-related issues. The application of nonwheat flours and starches offers additional ways to improve wafers and waffles in respect to quality and marketing potential. An extensive discussion of flours and starches for gluten-free products underlines the growing importance of that segment.