Publications by authors named "Bernd Schmidt"

135 Publications

Scope and Applications of 2,3-Oxidative Aryl Rearrangements for the Synthesis of Isoflavone Natural Products.

J Org Chem 2021 08 27;86(15):10699-10712. Epub 2021 Jul 27.

Universitaet Potsdam, Institut fuer Chemie, Karl-Liebknecht-Straße 24-25, D-14476 Potsdam-Golm, Germany.

The reaction of flavanones with hypervalent iodine reagents was investigated with a view to the synthesis of naturally occurring isoflavones. In contrast to several previous reports in the literature, we did not observe the formation of any benzofurans via a ring contraction pathway, but could isolate only isoflavones, resulting from an oxidative 2,3-aryl rearrangement, and flavones, resulting from an oxidation of the flavanones. Although the 2,3-oxidative rearrangement allows a synthetically useful approach toward some isoflavone natural products due to the convenient accessibility of the required starting materials, the overall synthetic utility and generality of the reaction appear to be more limited than previous literature reports suggest.
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http://dx.doi.org/10.1021/acs.joc.1c01375DOI Listing
August 2021

Synthesis of Arylidene-β-lactams via -Selective Matsuda-Heck Arylation of Methylene-β-lactams.

J Org Chem 2021 07 22;86(13):8786-8796. Epub 2021 Jun 22.

Universitaet Potsdam, Institut für Chemie, Karl-Liebknecht-Straße 24-25, D-14476 Potsdam-Golm, Germany.

-Methylene-β-lactams were synthesized in two steps from commercially available 3-bromo-2-(bromomethyl)propionic acid and reacted with arene diazonium salts in a Heck-type arylation in the presence of catalytic amounts of Pd(OAc) under ligand-free conditions. The products, arylidene-β-lactams, were obtained in high yields as single isomers. The β-hydride elimination step of the Pd-catalyzed coupling reaction proceeds with high -regioselectivity and -stereoselectivity. With aryl iodides, triflates, or bromides, the coupling products were isolated only in low yields, due to extensive decomposition of the starting material at elevated temperatures. This underlines that arene diazonium salts can be superior arylating reagents in Heck-type reactions and yield coupling products in synthetically useful yields and selectivities when conventional conditions fail.
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http://dx.doi.org/10.1021/acs.joc.1c00638DOI Listing
July 2021

Matsuda-Heck arylation of itaconates: a versatile approach to heterocycles from a renewable resource.

Org Biomol Chem 2021 May;19(19):4292-4302

Universitaet Potsdam, Institut fuer Chemie, Organische Synthesechemie, Karl-Liebknecht-Straße 24-25, D-14476 Potsdam-Golm, Germany.

Itaconic acid esters and hemiesters undergo Pd-catalyzed coupling reactions with arene diazonium salts in high to excellent yields. The coupling products of ortho-nitro arene diazonium salts can be converted in one or two steps to benzazepine-2-ones.
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http://dx.doi.org/10.1039/d1ob00392eDOI Listing
May 2021

Supramolecular Alloys from Fluorinated Hybrid Tri Di Imine Cages.

Chemistry 2021 Jun 14;27(33):8457-8460. Epub 2021 May 14.

Institut für Organische Chemie und Makromolekulare Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany.

To create innovative materials, efficient control and engineering of pore sizes and their characteristics, crystallinity and stability is required. Eight hybrid Tri Di imine cages with a tunable degree of fluorination and one fully fluorinated Tri Di imine cage are investigated. Although the fluorinated and the non-fluorinated building blocks used herein differ vastly in reactivity, it was possible to gain control over the outcome of the self-assembly process, by carefully controlling the feed ratio. This represents the first hybrid material based on fluorinated/hydrogenated porous organic cages (POCs). These cages with unlimited miscibility in the solid state were obtained as highly crystalline samples after recrystallization and even showed retention of the crystal lattice, forming alloys. All mixtures and the fully fluorinated Tri Di imine cage were analyzed by MALDI-MS, single-crystal XRD, powder XRD and in regard to thermal stability (TGA).
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http://dx.doi.org/10.1002/chem.202100891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252657PMC
June 2021

The Role of Total Synthesis in Structure Revision and Elucidation of Decanolides (Nonanolides).

Authors:
Bernd Schmidt

Prog Chem Org Nat Prod 2021 ;115:1-57

Institut für Chemie, Universität Potsdam, Karl-Liebknecht-Strasse 24-25, 14476, Potsdam-Golm, Germany.

Ten-membered lactones are commonly observed structures of natural products. They are mostly fungal metabolites, which often act as plant pathogens, but recently ten-membered lactones were identified as pheromones of frogs and termites. Although modern spectroscopic methods are nowadays routinely used to elucidate the structure of natural products, structural assignments of ten-membered lactones often remain incomplete or are surprisingly often erroneous. Most errors concern the absolute configuration. The examples discussed in this chapter demonstrate that enantioselective total synthesis is not only an efficient tool for corroborating or revising a proposed structure, but that the synthesis of different stereoisomers as references for gas chromatographic investigations can be a vital part of the structure elucidation process if only minute amounts of material are available. As a method of outstanding importance for the synthesis of ten-membered lactones olefin metathesis has emerged. Most of the examples discussed herein use one or more olefin metathesis reactions as key steps.
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http://dx.doi.org/10.1007/978-3-030-64853-4_1DOI Listing
April 2021

Mechanochemical Release of Non-Covalently Bound Guests from a Polymer-Decorated Supramolecular Cage.

Angew Chem Int Ed Engl 2021 06 5;60(24):13626-13630. Epub 2021 May 5.

Institut für Organische Chemie und Makromolekulare Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, 40225, Düsseldorf, Germany.

Supramolecular coordination cages show a wide range of useful properties including, but not limited to, complex molecular machine-like operations, confined space catalysis, and rich host-guest chemistries. Here we report the uptake and release of non-covalently encapsulated, pharmaceutically-active cargo from an octahedral Pd cage bearing polymer chains on each vertex. Six poly(ethylene glycol)-decorated bipyridine ligands are used to assemble an octahedral Pd (TPT) cage. The supramolecular container encapsulates progesterone and ibuprofen within its hydrophobic nanocavity and is activated by shear force produced by ultrasonication in aqueous solution entailing complete cargo release upon rupture, as shown by NMR and GPC analyses.
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http://dx.doi.org/10.1002/anie.202102383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251918PMC
June 2021

Endoscopic lung volume reduction with endobronchial valves in very low patients: results from the German Registry - Lungenemphysemregister e.V.

ERJ Open Res 2021 Jan 25;7(1). Epub 2021 Jan 25.

Dept of Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Background: Endoscopic lung volume reduction (ELVR) with valves has been suggested to be the key strategy for patients with severe emphysema and concomitant low diffusing capacity of the lung for carbon monoxide ( ). However, robust evidence is still missing. We therefore aim to compare clinical outcomes in relation to for patients treated with ELVR.

Methods: We assessed at baseline and 3 months follow-up and compared pre- and postprocedural pulmonary function test, quality of life, exercise capacity and adverse events. This is a retrospective subanalysis of prospectively collected data from the German Lung Emphysema Registry.

Results: In total, 121 patients treated with ELVR were analysed. Thirty-four patients with a ≤20% and 87 patients with a >20% showed similar baseline characteristics. After ELVR, there was a decrease of residual volume (both p<0.001 to baseline) in both groups, and both demonstrated better quality of life (p<0.01 to baseline). Forced expiratory volume in 1 s (FEV) improved significantly only in patients with a >20% (p<0.001 to baseline). Exercise capacity remained almost unchanged in both groups (p=0.3). The most frequent complication for both groups was a pneumothorax ( ≤20%: 17.6% >20%: 16.1%; p=0.728). However, there were no significant differences in other adverse events between both groups.

Conclusions: ELVR improves lung function as well as quality of life in patients with >20% and ≤20%. Adverse events did not differ between groups. Therefore, ELVR should be considered as a treatment option, even in patients with a very low .
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http://dx.doi.org/10.1183/23120541.00449-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836438PMC
January 2021

Source attribution of community-acquired cases of Legionnaires' disease-results from the German LeTriWa study; Berlin, 2016-2019.

PLoS One 2020 25;15(11):e0241724. Epub 2020 Nov 25.

Health Department, DHA Tempelhof-Schöneberg, Berlin, Germany.

Introduction: Sources of infection of most cases of community-acquired Legionnaires' disease (CALD) are unknown.

Objective: Identification of sources of infection of CALD.

Setting: Berlin; December 2016-May 2019.

Participants: Adult cases of CALD reported to district health authorities and consenting to the study; age and hospital matched controls.

Main Outcome Measure: Percentage of cases of CALD with attributed source of infection.

Methods: Analysis of secondary patient samples for monoclonal antibody (MAb) type (and sequence type); questionnaire-based interviews, analysis of standard household water samples for Legionella concentration followed by MAb (and sequence) typing of Legionella pneumophila serogroup 1 (Lp1) isolates; among cases taking of additional water samples to identify the infectious source as appropriate; recruitment of control persons for comparison of exposure history and Legionella in standard household water samples. For each case an appraisal matrix was filled in to attribute any of three source types (external (non-residence) source, residential non-drinking water (RnDW) source (not directly from drinking water outlet), residential drinking water (RDW) as source) using three evidence types (microbiological results, cluster evidence, analytical-comparative evidence (using added information from controls)).

Results: Inclusion of 111 study cases and 202 controls. Median age of cases was 67 years (range 25-93 years), 74 (67%) were male. Among 65 patients with urine typable for MAb type we found a MAb 3/1-positive strain in all of them. Compared to controls being a case was not associated with a higher Legionella concentration in standard household water samples, however, the presence of a MAb 3/1-positive strain was significantly associated (odds ratio (OR) = 4.9, 95% confidence interval (CI) 1.7 to 11). Thus, a source was attributed by microbiological evidence if it contained a MAb 3/1-positive strain. A source was attributed by cluster evidence if at least two cases were exposed to the same source. Statistically significant general source types were attributed by calculating the population attributable risk (analytical-comparative evidence). We identified an external source in 16 (14%) cases, and RDW as source in 28 (25%). Wearing inadequately disinfected dentures was the only RnDW source significantly associated with cases (OR = 3.2, 95% CI 1.3 to 7.8) and led to an additional 8% of cases with source attribution, for a total of 48% of cases attributed.

Conclusion: Using the appraisal matrix we attributed almost half of all cases of CALD to an infectious source, predominantly RDW. Risk for LD seems to be conferred primarily by the type of Legionella rather than the amount. Dentures as a new infectious source needs further, in particular, integrated microbiological, molecular and epidemiological confirmation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241724PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688155PMC
December 2020

Total Syntheses of Prenylated Isoflavones from and Their Antibacterial Activity: 5-Deoxy-3'-prenylbiochanin A and Erysubin F.

J Nat Prod 2020 11 10;83(11):3445-3453. Epub 2020 Nov 10.

Institut fuer Chemie, Universitaet Potsdam, Karl-Liebknecht-Strasse 24-25, D-14476 Potsdam-Golm, Germany.

The prenylated isoflavones 5-deoxyprenylbiochanin A (7-hydroxy-4'-methoxy-3'-prenylisoflavone) and erysubin F (7,4'-dihydroxy-8,3'-diprenylisoflavone) were synthesized for the first time, starting from mono- or di--allylated chalcones, and the structure of 5-deoxy-3'-prenylbiochanin A was corroborated by single-crystal X-ray diffraction analysis. Flavanones are key intermediates in the synthesis. Their reaction with hypervalent iodine reagents affords isoflavones via a 2,3-oxidative rearrangement and the corresponding flavone isomers via 2,3-dehydrogenation. This enabled a synthesis of 7,4'-dihydroxy-8,3'-diprenylflavone, a non-natural regioisomer of erysubin F. Erysubin F (), 7,4'-dihydroxy-8,3'-diprenylflavone (), and 5-deoxy-3'-prenylbiochanin A () were tested against three bacterial strains and one fungal pathogen. All three compounds are inactive against subsp. (NCTC 13349), (ATCC 25922), and (ATCC 90028), with MIC values greater than 80.0 μM. The diprenylated natural product erysubin F () and its flavone isomer 7,4'-dihydroxy-8,3'-diprenylflavone () show in vitro activity against methicillin-resistant (MRSA, ATCC 43300) at MIC values of 15.4 and 20.5 μM, respectively. In contrast, the monoprenylated 5-deoxy-3'-prenylbiochanin A () is inactive against this MRSA strain.
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http://dx.doi.org/10.1021/acs.jnatprod.0c00932DOI Listing
November 2020

Segmented flow generator for serial crystallography at the European X-ray free electron laser.

Nat Commun 2020 09 9;11(1):4511. Epub 2020 Sep 9.

Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron, Notkestrasse 85, 22607, Hamburg, Germany.

Serial femtosecond crystallography (SFX) with X-ray free electron lasers (XFELs) allows structure determination of membrane proteins and time-resolved crystallography. Common liquid sample delivery continuously jets the protein crystal suspension into the path of the XFEL, wasting a vast amount of sample due to the pulsed nature of all current XFEL sources. The European XFEL (EuXFEL) delivers femtosecond (fs) X-ray pulses in trains spaced 100 ms apart whereas pulses within trains are currently separated by 889 ns. Therefore, continuous sample delivery via fast jets wastes >99% of sample. Here, we introduce a microfluidic device delivering crystal laden droplets segmented with an immiscible oil reducing sample waste and demonstrate droplet injection at the EuXFEL compatible with high pressure liquid delivery of an SFX experiment. While achieving ~60% reduction in sample waste, we determine the structure of the enzyme 3-deoxy-D-manno-octulosonate-8-phosphate synthase from microcrystals delivered in droplets revealing distinct structural features not previously reported.
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http://dx.doi.org/10.1038/s41467-020-18156-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481229PMC
September 2020

Oxidation of Isodrimeninol with PCC Yields Drimane Derivatives with Activity against Yeast by Inhibition of Lanosterol 14-Alpha Demethylase.

Biomolecules 2020 07 24;10(8). Epub 2020 Jul 24.

Laboratory of Natural Products & Drug Discovery, Department of Basic Science, Universidad de La Frontera, Av. Francisco Salazar 01145, 4780000 Temuco, Chile.

species cause an opportunistic yeast infection called Candidiasis, which is responsible for more than 50,000 deaths every year around the world. Effective treatments against candidiasis caused by non-albicans species such as and are limited due to severe resistance to conventional antifungal drugs. Natural drimane sesquiterpenoids have shown promising antifungal properties against yeast and have emerged as valuable candidates for developing new candidiasis therapies. In this work, we isolated isodrimeninol () from barks of and used it as starting material for the hemi-synthesis of four sesquiterpenoids by oxidation with pyridinium chlorochromate (PCC). The structure of the products (, , and ) was elucidated by 1D and 2D NMR spectroscopy resulting in being a novel compound. Antifungal activity assays against and revealed that exhibited an increased activity (IC of 75 μg/mL) compared to (IC of 125 μg/mL) in all yeast strains. The antifungal activity of and was rationalized in terms of their capability to inhibit lanosterol 14-alpha demethylase using molecular docking, molecular dynamics simulations, and MM/GBSA binding free energy calculations. In silico analysis revealed that and bind to the outermost region of the catalytic site of 14-alpha demethylase and block the entrance of lanosterol () to the catalytic pocket. Binding free energy estimates suggested that forms a more stable complex with the enzyme than , in agreement with the experimental evidence. Based on this new approach it is possible to design new drimane-type sesquiterpenoids for the control of species as inhibitors of 14-alpha demethylase.
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http://dx.doi.org/10.3390/biom10081101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463952PMC
July 2020

A porous fluorinated organic [4+4] imine cage showing CO and H adsorption.

Chem Commun (Camb) 2020 Apr;56(35):4761-4764

Institut für Organische Chemie und Makromolekulare Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, D-40225 Düsseldorf, Germany.

We present the synthesis of a porous, organic [4+4] imine cage containing perfluorinated aromatic panels. Gas adsorption experiments show an uptake of 19.0 wt% CO2 (4.2 mmol g-1, 273 K and at 1 bar) and 1.5 wt% H2 (7.5 mmol g-1, 77 K and at 1 bar) for the specific surface area of 536 m2 g-1 of the crystalline material obtained directly from the reaction mixture, combined with an outstanding thermal stability, making it a very interesting porous material suitable for gas adsorption.
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http://dx.doi.org/10.1039/d0cc01872dDOI Listing
April 2020

Stereoselective Synthesis of Conjugated Polyenes Based on Tethered Olefin Metathesis and Carbonyl Olefination: Application to the Total Synthesis of (+)-Bretonin B.

J Org Chem 2020 04 18;85(7):5122-5130. Epub 2020 Mar 18.

Universität Potsdam, Institut für Chemie, Karl-Liebknecht-Strasse 24-25, D-14476 Potsdam-Golm, Germany.

The combination of a highly stereoselective tethered olefin metathesis reaction and a Julia-Kocienski olefination is presented as a strategy for the synthesis of conjugated polyenes with at least one -configured C═C bond. The strategy is exemplified by the synthesis of the marine natural product (+)-bretonin B.
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http://dx.doi.org/10.1021/acs.joc.0c00446DOI Listing
April 2020

Circulating Tumor Cells as a Biomarker to Assist Molecular Diagnosis for Early Stage Non-Small Cell Lung Cancer.

Cancer Manag Res 2020 5;12:841-854. Epub 2020 Feb 5.

Cancer Institute, The Fourth Hospital of Hebei Medical University/The Tumor Hospital of Hebei Province, Shijiazhuang, Hebei 050011, People's Republic of China.

Background And Objective: Compared with tissue biopsy, liquid biopsy is the most preferable non-invasive promising method in personalized medicine, although it has many limitations in isolating circulating tumor cells (CTC). Lung cancer associated mortality is drastically increased due to a shortfall of early-stage detection, which remains a challenge. Herein, we aimed to detect lung cancer at an early-stage using CellCollector device.

Methods: 39,627 volunteers underwent low-dose computed tomography; 2508 cases with pulmonary nodules and 7080 with no pulmonary nodules were chosen. After follow-up, 24 patients were diagnosed with early-stage non-small cell lung cancer (NSCLC), and subjected to CTC detection using CellCollector, along with 72 healthy volunteers. Immunofluorescence staining for EpCAM/CKs and CD45 were performed for CTC validation.

Results: Fifteen out of twenty-four (stage I, n = 18; stage II, n = 6) early-stage lung cancer patients were found to be CTC-positive, whereas no CTC was found in the control group. Genetic mutation of TP53, ERBB2, PDGFRA, CFS1R and FGFR1 in the CTC revealed 71.6% of the mutation sites similar to the tumor tissues of 13 patients. Molecular characterization revealed higher expression of protein PD-LI in CTC (40%) as compared to tumor tissue (26.7%). Moreover, CTC clusters were detected in 40% of patients.

Conclusion: CTC detection using the CellCollector in early-stage NSCLC had a relative high capture rate. Moreover, CTC analysis is a prospective setting for molecular diagnostic in cases when tumor tissue biopsy is not desirable.
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http://dx.doi.org/10.2147/CMAR.S240773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008188PMC
February 2020

Matsuda-Heck Arylation of Glycals for the Stereoselective Synthesis of Aryl -Glycosides.

J Org Chem 2019 11 29;84(22):14816-14829. Epub 2019 Oct 29.

Universitaet Potsdam, Institut fuer Chemie , Karl-Liebknecht-Straße 24-25 , D-14476 Potsdam-Golm , Germany.

The methoxymethyl-protected glycal l-amicetal, synthesized de novo from l-ethyl lactate through tandem ring-closing metathesis-isomerization sequence, undergoes a highly -diastereoselective Heck-type coupling reaction with various arene diazonium salts to furnish 2,3-unsaturated aryl -glycosides in moderate to excellent yields. The products can be further functionalized, e.g., by hydrogenation, epoxidation, or dihydroxylation to furnish 2,3,6-tridesoxy, 2,3-anhydro-6-desoxy, or 6-desoxy aryl -glycosides, respectively. The method was applied to the synthesis of an α-configured 6-desoxy-gliflozin derivative.
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http://dx.doi.org/10.1021/acs.joc.9b02410DOI Listing
November 2019

Law in the Cubic Lattice.

J Stat Phys 2019 24;176(6):1480-1499. Epub 2019 Jul 24.

2Faculty of Mathematics, University of Vienna, Oskar-Morgenstern-Platz 1, 1090 Vienna, Austria.

We investigate the Edge-Isoperimetric Problem (EIP) for sets with elements of the cubic lattice by emphasizing its relation with the emergence of the Wulff shape in the crystallization problem. Minimizers of the edge perimeter are shown to deviate from a corresponding cubic Wulff configuration with respect to their symmetric difference by at most elements. The exponent 3 / 4 is optimal. This extends to the cubic lattice analogous results that have already been established for the triangular, the hexagonal, and the square lattice in two space dimensions.
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http://dx.doi.org/10.1007/s10955-019-02350-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733839PMC
July 2019

Fluorinated azobenzenes as supramolecular halogen-bonding building blocks.

Beilstein J Org Chem 2019 23;15:2013-2019. Epub 2019 Aug 23.

Institut für Organische Chemie und Makromolekulare Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, D-40225 Düsseldorf, Germany.

-Fluoroazobenzenes are a remarkable example of bistable photoswitches, addressable by visible light. Symmetrical, highly fluorinated azobenzenes bearing an iodine substituent in -position were shown to be suitable supramolecular building blocks both in solution and in the solid state in combination with neutral halogen bonding acceptors, such as lutidines. Therefore, we investigate the photochemistry of a series of azobenzene photoswitches. Upon introduction of iodoethynyl groups, the halogen bonding donor properties are significantly strengthened in solution. However, the bathochromic shift of the π→π* band leads to a partial overlap with the n→π* band, making it slightly more difficult to address. The introduction of iodine substituents is furthermore accompanied with a diminishing thermal half-life. A series of three azobenzenes with different halogen bonding donor properties are discussed in relation to their changing photophysical properties, rationalized by DFT calculations.
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http://dx.doi.org/10.3762/bjoc.15.197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720338PMC
August 2019

Chirality-Controlled Self-Assembly of Amphiphilic Dibenzo[6]helicenes into Langmuir-Blodgett Thin Films.

Chemistry 2019 Sep 1;25(49):11494-11502. Epub 2019 Jul 1.

Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 166 10, Prague 6, Czech Republic.

Racemic and highly enantioenriched 3-methoxycarbonyl, 3-carboxy, and 3-hydroxymethyl derivatives of dibenzo[6]helicene were prepared. The Langmuir layers of these helicenes were formed at the air-water interface and transferred onto solid substrates to afford Langmuir-Blodgett films, which were then studied by ambient atomic force microscopy and (chir)optical spectroscopy. Significant differences were found in the behaviour of the Langmuir layers as well as in the morphology, UV/Vis, electronic circular dichroism (ECD), and fluorescence spectra of the Langmuir-Blodgett thin films depending on the molecular chirality and nature of the polar group. The experimental results were supported by molecular dynamics simulations.
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http://dx.doi.org/10.1002/chem.201901695DOI Listing
September 2019

[2+2] Halogen-bonded boxes employing azobenzenes.

Chem Commun (Camb) 2019 Jul;55(60):8768-8771

Institut für Organische Chemie und Makromolekulare Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, D-40225 Düsseldorf, Germany.

Herein, we report the synthesis and crystal structures of three [2+2] supramolecular boxes assembled by halogen bonding. The discrete, two-dimensional boxes with a length of 25-30 Å are based on rigid u-shaped halogen acceptors paired with highly fluorinated, azobenzenes bearing halogen bond donors.
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http://dx.doi.org/10.1039/c9cc03061aDOI Listing
July 2019

Iterative Arylation of Itaconimides with Diazonium Salts through Electrophilic Palladium Catalysis: Divergent β-H-Elimination Pathways in Repetitive Matsuda-Heck Reactions.

J Org Chem 2019 May 23;84(9):5732-5746. Epub 2019 Apr 23.

Institut fuer Chemie , Universitaet Potsdam , Karl-Liebknecht-Straße 24-25 , D-14476 Potsdam-Golm , Germany.

N-Arylitaconimides, accessible from maleic anhydride, anilines, and paraformaldehyde, react with arene diazonium salts in Pd-catalyzed Matsuda-Heck arylation to the pharmacologically relevant E-configured 3-arylmethylidene pyrrolidine-2,5-diones (also known as arylmethylidene succinimides) through exo-selective β-H-elimination. The coupling proceeds at ambient temperature with the simple and easy-to-handle precatalyst Pd-II-acetate under ligand- and base-free conditions. Notable features are high isolated yields, regio- and stereoselectivities, and short reaction times. In a comparative investigation, aryl iodides, bromides, and triflates were shown to be inferior coupling reagents in this reaction. The 3-arylmethylidene pyrrolidine-2,5-diones undergo second Matsuda-Heck coupling, which proceeds via endo-selective β-H-elimination to give diarylmethyl-substituted maleimides as coupling products. These products can also be accessed in one flask by sequential addition of different arene diazonium salts to the starting itaconimide. The potential of 3-arylmethylidene succinimides as photoswitches was tested. Upon irradiation of the E-isomer at 300 nm, partial isomerization to the Z-isomer (E/Z = 65:35 in the photostationary state) was observed. The isomerization was found to be nearly completely reversible by irradiating the mixture at 400 nm.
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http://dx.doi.org/10.1021/acs.joc.9b00627DOI Listing
May 2019

Optically switchable organic light-emitting transistors.

Nat Nanotechnol 2019 04 18;14(4):347-353. Epub 2019 Feb 18.

Université de Strasbourg, CNRS, ISIS, Strasbourg, France.

Organic light-emitting transistors are pivotal components for emerging opto- and nanoelectronics applications, such as logic circuitries and smart displays. Within this technology sector, the integration of multiple functionalities in a single electronic device remains the key challenge. Here we show optically switchable organic light-emitting transistors fabricated through a judicious combination of light-emitting semiconductors and photochromic molecules. Irradiation of the solution-processed films at selected wavelengths enables the efficient and reversible tuning of charge transport and electroluminescence simultaneously, with a high degree of modulation (on/off ratios up to 500) in the three primary colours. Different emitting patterns can be written and erased through a non-invasive and mask-free process, on a length scale of a few micrometres in a single device, thereby rendering this technology potentially promising for optically gated highly integrated full-colour displays and active optical memory.
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http://dx.doi.org/10.1038/s41565-019-0370-9DOI Listing
April 2019

Editorial for "Longitudinal cell-free DNA analysis in patients with small cell lung cancer reveals dynamic insights into treatment efficacy and disease relapse".

Transl Lung Cancer Res 2018 Dec;7(Suppl 4):S367-S369

Klinik für Innere Medizin, Schwerpunkt Pneumologie und Schlafmedizin, DRK Kliniken Berlin | Mitte, Berlin, Germany.

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http://dx.doi.org/10.21037/tlcr.2018.09.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328699PMC
December 2018

Ring-closing-metathesis-based synthesis of annellated coumarins from 8-allylcoumarins.

Beilstein J Org Chem 2018 5;14:2991-2998. Epub 2018 Dec 5.

Universität Potsdam, Institut fuer Chemie, Karl-Liebknecht-Straße 24-25, D-14476 Potsdam-Golm, Germany.

8-Allylcoumarins are conveniently accessible through a microwave-promoted tandem Claisen rearrangement/Wittig olefination/cyclization sequence. They serve as a versatile platform for the annellation of five- to seven-membered rings using ring-closing olefin metathesis (RCM). Furano-, pyrano-, oxepino- and azepinocoumarins were synthesized from the same set of precursors using Ru-catalyzed double bond isomerizations and RCM in a defined order. One class of products, pyrano[2,3-]chromene-2,8-diones, were inaccessible through direct RCM of an acrylate, but became available from the analogous allyl ether via an assisted tandem catalytic RCM/allylic oxidation sequence.
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http://dx.doi.org/10.3762/bjoc.14.278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296409PMC
December 2018

Microcrystal Electron Diffraction (MicroED) for Small-Molecule Structure Determination.

Angew Chem Int Ed Engl 2019 Jan 12;58(3):666-668. Epub 2018 Dec 12.

Institut für Organische Chemie und Makromolekulare Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, 40225, Düsseldorf, Germany.

The development of new methods to analyze and determine molecular structures parallels the ability to accelerate synthetic research. For many decades, single-crystal analysis by X-ray diffraction (SXRD) has been the definitive tool for structural analysis at the atomic level; the drawback, however, is that a suitable single crystal of the analyte needs to be grown. The recent innovation of the crystalline sponge (CS) method allows the microanalysis of compounds simply soaked in a readily prepared CS crystal, thus circumventing the need to screen crystallization conditions while also using only a trace amount of the sample. In this context, electron diffraction for the structure determination of small molecules is discussed as potentially the next big development in this field.
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http://dx.doi.org/10.1002/anie.201813215DOI Listing
January 2019

Local ablative treatment for synchronous single organ oligometastatic lung cancer-A propensity score analysis of 180 patients.

Lung Cancer 2018 11 25;125:164-173. Epub 2018 Sep 25.

Klinik für Pneumologie - Evangelische Lungenklinik Berlin Buch, Berlin, Germany.

Introduction: Local ablative treatment (LAT) improves outcome in lung cancer with oligometastatic disease (OMD) and potentially leads to long term survival. The aim of this retrospective study was to evaluate and quantify the additional benefit of LAT in synchronous OMD and to further identify prognostic factors for survival.

Patients And Methods: A propensity score-matched pairs analysis was performed on a set of patient and disease variables in 180 patients, treated for synchronous single organ OMD including non small-cell and neuroendocrine lung cancer with ≤4 metastases between 2000 and 2016 in 3 lung cancer centers in Berlin, Germany. Patients either received LAT for all sites of disease (intervention group) by means of surgery or stereotactic radiotherapy, or standard chemotherapy, if necessary combined with a local treatment with palliative intent (control group).

Results: Median follow-up time was 32.2 and 18.8 months for the intervention and control group, respectively. Substantial benefits in median progression-free survival (PFS, 25.1 vs. 8.2 months; HR, 0.30; 95% CI, 0.21-0.43; p < 0.001) and overall survival (OS, 60.4 vs. 22.5 months; HR, 0.42; 95% CI, 0.28-0.62; p < 0.001) were associated with LAT. Histology of adenocarcinoma and T1a primaries also predicted a favorable prognosis concerning PFS and OS. More favorable nodal stage (N0-2 vs. 3) and solitary metastases were associated with an extended PFS, whereas initial ECOG-PS (0-1 vs. 2) predicted OS.

Conclusions: LAT was the strongest predictor for PFS and OS in OMD with ≤4 metastases. Survival in the control group identifies OMD as a subset of lung cancer with a generally more favorable prognosis.
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http://dx.doi.org/10.1016/j.lungcan.2018.09.021DOI Listing
November 2018

Helicenes as Chirality-Inducing Groups in Transition-Metal Catalysis: The First Helically Chiral Olefin Metathesis Catalyst.

Chemistry 2018 Aug 6;24(43):10994-10998. Epub 2018 Jul 6.

Institut für Chemie, Universität Potsdam, Karl-Liebknecht-Str. 24-25, 14476, Potsdam, Germany.

Helical chirality is a novel enantioselectivity-inducing property in transition-metal-catalyzed transformations. The principle is illustrated herein for the example of asymmetric olefin metathesis. This work reports the synthesis of the first helically chiral Ru-NHC alkylidene complex from an aminohelicene-derived imidazolium salt, which was ligated to the first generation Hoveyda-Grubbs catalyst. Kinetic data were acquired for benchmark test reactions and compared to an achiral catalyst. The helically chiral Ru-catalyst was evaluated in asymmetric ring-closing metathesis (RCM) and ring-opening metathesis-cross-metathesis (ROM/CM) reactions, which proceeded with promising levels of enantioselectivity. Extensive NMR-spectroscopic investigations and a DFT geometry optimization were performed. These results led to a topographic steric map and calculation of percent-buried-volume values for each quadrant around the metal center.
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http://dx.doi.org/10.1002/chem.201802786DOI Listing
August 2018

Three new dihydro-β-agarofuran sesquiterpenes from the seeds of Maytenus boaria.

Acta Crystallogr C Struct Chem 2018 05 11;74(Pt 5):564-570. Epub 2018 Apr 11.

Gerencia de Investigación y Aplicaciones, Centro Atómico Constituyentes, Comisión Nacional de Energía Atómica, Buenos Aires, Argentina.

As part of a project studying the secondary metabolites extracted from the Chilean flora, we report herein three new β-agarofuran sesquiterpenes, namely (1S,4S,5S,6R,7R,8R,9R,10S)-6-acetoxy-4,9-dihydroxy-2,2,5a,9-tetramethyloctahydro-2H-3,9a-methanobenzo[b]oxepine-5,10-diyl bis(furan-3-carboxylate), CHO, (II), (1S,4S,5S,6R,7R,9S,10S)-6-acetoxy-9-hydroxy-2,2,5a,9-tetramethyloctahydro-2H-3,9a-methanobenzo[b]oxepine-5,10-diyl bis(furan-3-carboxylate), CHO, (III), and (1S,4S,5S,6R,7R,9S,10S)-6-acetoxy-10-(benzoyloxy)-9-hydroxy-2,2,5a,9-tetramethyloctahydro-2H-3,9a-methanobenzo[b]oxepin-5-yl furan-3-carboxylate, CHO, (IV), obtained from the seeds of Maytenus boaria and closely associated with a recently published relative [Paz et al. (2017). Acta Cryst. C73, 451-457]. In the (isomorphic) structures of (II) and (III), the central decalin system is esterified with an acetate group at site 1 and furoate groups at sites 6 and 9, and differ at site 8, with an OH group in (II) and no substituent in (III). This position is also unsubstituted in (IV), with site 6 being occupied by a benzoate group. The chirality of the skeletons is described as 1S,4S,5S,6R,7R,8R,9R,10S in (II) and 1S,4S,5S,6R,7R,9S,10S in (III) and (IV), matching the chirality suggested by NMR studies. This difference in the chirality sequence among the title structures (in spite of the fact that the three skeletons are absolutely isostructural) is due to the differences in the environment of site 8, i.e. OH in (II) and H in (III) and (IV). This diversity in substitution, in turn, is responsible for the differences in the hydrogen-bonding schemes, which is discussed.
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http://dx.doi.org/10.1107/S2053229618005429DOI Listing
May 2018

Asymmetric Synthesis of Nonracemic 2-Amino[6]helicenes and Their Self-Assembly into Langmuir Films.

J Org Chem 2018 05 30;83(10):5523-5538. Epub 2018 Apr 30.

Institute of Organic Chemistry and Biochemistry , Czech Academy of Sciences , Flemingovo n. 2 , 166 10 Prague 6 , Czech Republic.

Alternative ways of preparing nonracemic 2-amino[6]helicene derivatives were explored. The enantioselective [2 + 2 + 2] cycloisomerization of a nonchiral triyne under Ni(cod)/( R)-QUINAP catalysis delivered the enantioenriched (+)-( P)-2-aminodibenzo[6]helicene derivative in 67% ee. An ultimate "point-to-helical" chirality transfer was observed in the cyclization of enantiopure triynes mediated by Ni(CO)(PPh) affording (-)-( M)- or (+)-( P)-7,8-bis( p-tolyl)hexahelicen-2-amine in >99% ee as well as its benzoderivative in >99% ee. The latter mode of stereocontrol was inefficient for a 2-aminobenzo[6]helicene congener with an embedded five-membered ring. The rac-, (-)-( M)-, and (+)-( P)-7,8-bis( p-tolyl)hexahelicen-2-amines formed Langmuir monolayers at the air-water interface featuring practically identical surface pressure vs mean molecular area isotherms. The corresponding Langmuir-Blodgett films on quartz or silicon substrates were characterized by UV-vis/ECD spectroscopy and AFM microscopy, respectively.
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http://dx.doi.org/10.1021/acs.joc.8b00538DOI Listing
May 2018

Prenylcoumarins in One or Two Steps by a Microwave-Promoted Tandem Claisen Rearrangement/Wittig Olefination/Cyclization Sequence.

J Org Chem 2018 05 16;83(9):5210-5224. Epub 2018 Apr 16.

Universitaet Potsdam, Institut fuer Chemie , Karl-Liebknecht-Straße 24-25 , D-14476 Potsdam-Golm , Germany.

The one-pot synthesis of 8-prenylcoumarins from 1,1-dimethylallylated salicylaldehydes and the stabilized ylide [(ethoxycarbonyl)methylene]triphenylphosphorane under microwave conditions was found to have a limited scope. The sequence suffers from a difficult and sometimes low-yielding synthesis of the precursors and from a competing deprenylation upon microwave irradiation. This side reaction occurs in particular with electron rich arenes with two or more alkoxy groups at adjacent positions, a prominent substitution pattern in naturally occurring 8-prenylcoumarins. Both limitations of this one-step sequence were overcome by a two-step synthesis consisting of a microwave-promoted tandem allyl ether Claisen rearrangement/Wittig olefination and a subsequent olefin cross metathesis with 2-methyl-2-butene. The cross metathesis step proceeds with a high selectivity and yields exclusively the desired prenyl, rather than the alternative crotyl substituent. Several naturally occurring 8-prenylcoumarins that were previously inaccessible have been synthesized in good overall yields along this route.
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http://dx.doi.org/10.1021/acs.joc.8b00667DOI Listing
May 2018

Drimane Sesquiterpenoids Noncompetitively Inhibit Human α4β2 Nicotinic Acetylcholine Receptors with Higher Potency Compared to Human α3β4 and α7 Subtypes.

J Nat Prod 2018 04 10;81(4):811-817. Epub 2018 Apr 10.

Facultad de Medicina , Universidad de Morón and CONICET , Morón 1708 , Argentina.

The drimane sesquiterpenoids drimenin, cinnamolide, dendocarbin A, and polygodial were purified from the Canelo tree ( Drimys winteri) and chemically characterized by spectroscopic methods. The pharmacological activity of these natural compounds were determined on hα4β2, hα3β4, and hα7 nicotinic acetylcholine receptors (AChRs) by Ca influx measurements. The results established that drimane sesquiterpenoids inhibit AChRs with the following selectivity: hα4β2 > hα3β4 > hα7. In the case of hα4β2 AChRs, the following potency rank order was determined (IC's in μM): drimenin (0.97 ± 0.35) > cinnamolide (1.57 ± 0.36) > polygodial (62.5 ± 19.9) ≫ dendocarbin A (no activity). To determine putative structural features underlying the differences in inhibitory potency at hα4β2 AChRs, additional structure-activity relationship and molecular docking experiments were performed. The Ca influx and structural results supported a noncompetitive mechanism of inhibition, where drimenin interacted with luminal and nonluminal (TMD-β2 intrasubunit) sites. The structure-activity relationship results, i.e., the lower the ligand polarity, the higher the inhibitory potency, supported the nonluminal interaction. Ligand binding to both sites might inhibit the hα4β2 AChR by a cooperative mechanism, as shown experimentally ( n > 1). Drimenin could be used as a molecular scaffold for the development of more potent inhibitors with higher selectivity for the hα4β2 AChR.
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http://dx.doi.org/10.1021/acs.jnatprod.7b00893DOI Listing
April 2018
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