Publications by authors named "Peter Mayer"

270 Publications

Steric Effects on the Thermal Processes of Hemithioindigo Based Molecular Motor Rotation.

Chemistry 2021 May 4. Epub 2021 May 4.

Friedrich-Alexander-Universitat Erlangen-Nurnberg, Chemistry and Pharmacy, Nikolaus-Fiebiger-Str. 10, 91058, Erlangen, GERMANY.

Tuning the thermal behavior of light driven molecular motors is fundamentally important for their future rational design. In many molecular motors thermal ratcheting steps are comprised of helicity inversions, energetically stabilizing the initial photoproducts. In this work we investigated a series of five hemithioindigo (HTI) based molecular motors to reveal the influence of steric hindrance in close proximity to the rotation axle on this process. Applying a high yielding synthetic procedure, we synthesized constitutional isomeric derivatives to distinguish between substitution effects at the aromatic and aliphatic position on the rotor fragment. The kinetics of thermal helix inversions were elucidated using low temperature 1H NMR spectroscopy and an in situ irradiation technique. In combination with a detailed theoretical description, a comparative analysis of substituent effects on the thermal helix inversions of the rotation cycle is now possible. Such deeper understanding of the rotational cycle of HTI molecular motors is essential for speed regulation and future applications of visible light triggered nanomachines.
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http://dx.doi.org/10.1002/chem.202100950DOI Listing
May 2021

Foslevodopa/Foscarbidopa: A New Subcutaneous Treatment for Parkinson's Disease.

Ann Neurol 2021 Mar 26. Epub 2021 Mar 26.

Discovery Centralized Medicinal Chemistry, AbbVie Inc., North Chicago, IL.

Objective: The aim was to demonstrate that continuous s.c. infusion of a soluble levodopa (LD)/carbidopa (CD) phosphate prodrug combination effectively delivers stable LD exposure via a minimally invasive and convenient mode and has the potential to treat Parkinson's disease (PD) patients who are not well controlled on oral medication.

Methods: Foslevodopa and foscarbidopa were prepared and the equilibrium solubility and chemical stability examined in aqueous media with different values of pH. Solutions of foslevodopa/foscarbidopa (ratios ranging from 4:1 to 20:1) were prepared by dissolving pH-adjusted lyophilized materials in water and infused s.c. in healthy volunteers for ≤72 hours. Frequent blood samples were collected to measure LD and CD exposure, and safety was monitored throughout the study.

Results: Foslevodopa/foscarbidopa (ABBV-951) demonstrates high water solubility and excellent chemical stability near physiological pH, enabling continuous s.c. infusion therapy. After s.c. infusion, a stable LD pharmacokinetic (PK) profile was maintained for ≤72 hours, and the infusion was well tolerated.

Interpretation: Preparation of foslevodopa and foscarbidopa enables preclinical and clinical PK, safety, and tolerability studies in support of their advancement for the treatment of PD. In phase 1 clinical trials, foslevodopa/foscarbidopa demonstrates consistent and stable LD plasma exposure, supporting further studies of this treatment as a potentially transformational option for those suffering from PD. ANN NEUROL 2021.
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http://dx.doi.org/10.1002/ana.26073DOI Listing
March 2021

Construction and Properties of Donor-Acceptor Stenhouse Adducts on Gold Surfaces.

Langmuir 2021 Mar 1;37(10):3057-3066. Epub 2021 Mar 1.

MTA TTK Lendület Functional Organic Materials Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Magyar tudósok körútja 2, 1117 Budapest, Hungary.

The construction of a donor-acceptor Stenhouse adduct molecular layer on a gold surface is presented. To avoid the incompatibility of the thiol surface-binding group with the donor-acceptor polyene structure of the switch, an interfacial reaction approach was followed. Poly(dopamine)-supported gold nanoparticles on quartz slides were chosen as substrates, which was expected to facilitate both the interfacial reaction and the switching process by providing favorable steric conditions due to the curved particle surface. The reaction between the surface-bound donor half and the CF-isoxazolone-based acceptor half was proved to be successful by X-ray photoelectron spectroscopy (XPS). However, UV-vis measurements suggested that a closed, cyclopentenone-containing structure of the switch formed on the surface irreversibly. Analysis of the wetting behavior of the surface revealed spontaneous water spreading that could be associated with conformational changes of the closed isomer.
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http://dx.doi.org/10.1021/acs.langmuir.0c03275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8031373PMC
March 2021

Investigation of Structural Changes of Cu(I) and Ag(I) Complexes Utilizing a Flexible, Yet Sterically Demanding Multidentate Phosphine Oxide Ligand.

Inorg Chem 2021 Feb 3;60(4):2437-2445. Epub 2021 Feb 3.

Department of Chemistry, Ludwig Maximilian University of Munich, Butenandtstraße 5-13, DE 81377 Munich, Germany.

The syntheses of a sterically demanding, multidentate bis(quinaldinyl)phenylphosphine oxide ligand and some Cu(I) and Ag(I) complexes thereof are described. By introducing a methylene group between the quinoline unit and phosphorus, the phosphine oxide ligand gains additional flexibility. This specific ligand design induces not only a versatile coordination chemistry but also a rarely observed and investigated behavior in solution. The flexibility of the birdlike ligand offers the unexpected opportunity of open-wing and closed-wing coordination to the metal. In fact, the determined crystal structures of these complexes show both orientations. Investigations of the ligand in solution show a strong dependency of the chemical shift of the CH protons on the solvent used. Variable-temperature, multinuclear NMR spectroscopy was carried out, and an interesting dynamic behavior of the complexes is observed. Due to the introduced flexibility, the quinaldinyl substituents change their arrangements from open-wing to closed-wing upon cooling, while still staying coordinated to the metal. This change in conformation is completely reversible when warming up the sample. Based on 2D NMR spectra measured at -80 °C, an assignment of the signals corresponding to the different arrangements was possible. Additionally, the copper(I) complex shows reversible redox activity in solution. The combination of structural flexibility of a multidentate ligand and the positive redox properties of the resulting complexes comprises key factors for a possible application of such compounds in transition-metal catalysis. a reorganization of the ligand, occurring transition states could be stabilized, and selectivity might be enhanced.
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http://dx.doi.org/10.1021/acs.inorgchem.0c03334DOI Listing
February 2021

Crystal structure of a calcium(II)-pyrroloquinoline quinone (PQQ) complex outside a protein environment.

Acta Crystallogr C Struct Chem 2020 12 5;76(Pt 12):1051-1056. Epub 2020 Nov 5.

Department of Chemistry, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, Munich, Bavaria 81377, Germany.

Pyrroloquinoline quinone (PQQ) is an important cofactor of calcium- and lanthanide-dependent alcohol dehydrogenases, and has been known for over 30 years. Crystal structures of Ca-MDH enzymes (MDH is methanol dehydrogenase) have been known for some time; however, crystal structures of PQQ with biorelevant metal ions have been lacking in the literature for decades. We report here the first crystal structure analysis of a Ca-PQQ complex outside the protein environment, namely, poly[[undecaaquabis(μ-4,5-dioxo-4,5-dihydro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylato)tricalcium(II)] dihydrate], {[Ca(CHNO)(HO)]·2HO}. The complex crystallized as CaPQQ·13HO with Ca in three different positions and PQQ, including an extensive hydrogen-bond network. Similarities and differences to the recently reported structure with biorelevant europium (EuPQQ) are discussed.
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http://dx.doi.org/10.1107/S2053229620014278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716187PMC
December 2020

Synthesis and Characterization of a Novel Triangular RhAu Cluster Compound Inspired by the Isolobality Concept.

ChemistryOpen 2020 10 5;9(10):991-995. Epub 2020 Oct 5.

Institut für Anorganische Chemie, Universität Regensburg, Universitätsstrasse 31, 93040, Regensburg, Germany.

The synthesis of [Rh(η-Cp)(μ-H)(μ-PPh)]BF () by protonation reaction of the metal basic complex [Rh(η-Cp)(μ-PPh)] () with tetrafluoroboric acid in diethyl ether is described. Complex salt was obtained in high yield and fully characterized by spectroscopic means and X-ray crystal diffraction. Applying the isolobal analogy between H and the fragment Au(PPh) as a synthetic strategy on the reaction of compound with equimolar amounts of [Au(CH)(PPh)] in refluxing acetone resulted in the formation of the expected triangular cluster compound [Rh{μ-Au(PPh)}(η-Cp)(μ-PPh)]BF () in good yield. Metal cluster salt was fully characterized by spectroscopic data and its molecular structure in the crystal was determined by X-ray diffraction. The structural comparison of the protonated dirhodium core in the cationic complex of with the RhAu framework in is in good accordance with the isolobal relation between H and Au because they share the respective same position in these closely related molecular structures.
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http://dx.doi.org/10.1002/open.202000217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536363PMC
October 2020

OrthoFRET in Diamantane FRET in Orthogonal Stiff Dyads; Diamond Restriction for Frozen Vibrations.

J Org Chem 2020 Sep 10;85(17):11154-11169. Epub 2020 Aug 10.

Department of Chemistry, LMU University of Munich, Butenandtstr. 13, Munich D-81377, Germany.

Energy transfer proceeds in orthogonal dyads in contrast to Förster's theory and cannot be prohibited even by rigid interconnecting cage compounds such as cubane or diamantane.
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http://dx.doi.org/10.1021/acs.joc.0c01184DOI Listing
September 2020

Zn(II) and Cd(II) thiosemicarbazones for stimulation/inhibition of kojic acid biosynthesis from Aspergillus flavus and the fungal defense behavior against the metal complexes' excesses.

J Biol Inorg Chem 2020 08 13;25(5):797-809. Epub 2020 Jul 13.

Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, Haus, 81377, Munich, Germany.

The complexes {[ZnLCl] C1, [ZnLCl].0.5HO C2, [CdLCl] C3, and [CdLCl] C4} were prepared from tridentate thiosemicarbazones {HL = 4-(3-nitrophenyl)-1-((pyridin-2-yl)methylene) thiosemicarbazide and HL = 4-(2,4-dimethoxyphenyl)-1-((pyridin-2-yl)methylene)thiosemicarbazide} and identified by elemental CHNS, spectroscopic {IR and UV-Vis.}, thermal and DMF solution electrical conductivity data. On another hand, kojic acid (KA) which represents important secondary metabolite with numerous hot spot applications was successfully biosynthesized from Aspergillus flavus and structurally analyzed by single crystal analysis. The Zn(II) complexes C1&C2 (0.3 mM) enhanced the KA biosynthesis by 70.87% and 42.26%, while 76.09% of C1 and 72.78% of C2 were absorbed by the fungal cells. The Cd(II) complexes C3&C4 at 0.3 mM inhibited KA production by 87.95% and 97.03% with Cd(II) consumption reaching to 40.09% & 37.3%, while 0.4 mM of C3&C4 resulted in 100% inhibition of kojic acid biosynthesis. Light microscopic analysis showed the fungal structural abnormalities and the cell antioxidant behavior was detected. These complexes could be highly applicable as new stimulators and inhibitors of kojic acid production.
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http://dx.doi.org/10.1007/s00775-020-01802-2DOI Listing
August 2020

The Earlier the Better: Structural Analysis and Separation of Lanthanides with Pyrroloquinoline Quinone.

Chemistry 2020 Aug 7;26(44):10133-10139. Epub 2020 Jul 7.

Department of Chemistry, Ludwig-Maximilians-University Munich, Butenandtstraße 5-13, 81377, München, Germany.

Lanthanides (Ln) are critical raw materials, however, their mining and purification have a considerable negative environmental impact and sustainable recycling and separation strategies for these elements are needed. In this study, the precipitation and solubility behavior of Ln complexes with pyrroloquinoline quinone (PQQ), the cofactor of recently discovered lanthanide (Ln) dependent methanol dehydrogenase (MDH) enzymes, is presented. In this context, the molecular structure of a biorelevant europium PQQ complex was for the first time elucidated outside a protein environment. The complex crystallizes as an inversion symmetric dimer, Eu PQQ , with binding of Eu in the biologically relevant pocket of PQQ. LnPQQ and Ln1Ln2PQQ complexes were characterized by using inductively coupled plasma mass spectrometry (ICP-MS), infrared (IR) spectroscopy, Eu-Mössbauer spectroscopy, X-ray total scattering, and extended X-ray absorption fine structure (EXAFS). It is shown that a natural enzymatic cofactor is capable to achieve separation by precipitation of the notoriously similar, and thus difficult to separate, lanthanides to some extent.
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http://dx.doi.org/10.1002/chem.202002653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496819PMC
August 2020

Oxidized Hemithioindigo Photoswitches-Influence of Oxidation State on (Photo)physical and Photochemical Properties.

Chemistry 2020 Aug 23;26(47):10712-10718. Epub 2020 Jul 23.

Department of Chemistry and Center for Integrated Protein Science CIPSM, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377, München.

The photophysical and photochemical properties of sulfoxide and sulfone derivatives of hemithioindigo photoswitches are scrutinized and compared to the unoxidized parent chromophores. Oxidation results in significantly blue-shifted absorptions and mostly reduction of photochromism while thermal stabilities of individual isomers remain largely unaltered. Effective photoswitching takes place at shorter wavelengths compared to parent hemithioindigos and high isomeric yields can be obtained reversibly in the respective photostationary states. Reversible solid-state photoswitching is observed for a twisted sulfone derivative accompanied by visible color changes. These results establish oxidized hemithioindigo photoswitches as promising and versatile tools for robust light-control of molecular behavior for a wide range of applications.
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http://dx.doi.org/10.1002/chem.202002176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496871PMC
August 2020

Structure-Property Relationships in Unsymmetric Bis(antiaromatics): Who Wins the Battle between Pentalene and Benzocyclobutadiene?†.

J Org Chem 2020 04 30;85(8):5158-5172. Epub 2020 Mar 30.

MTA-TTK "Lendület" Functional Organic Materials Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, 1117 Budapest, Hungary.

According to the currently accepted structure-property relationships, aceno-pentalenes with an angular shape (fused to the 1,2-bond of the acene) exhibit higher antiaromaticity than those with a linear shape (fused to the 2,3-bond of the acene). To explore and expand the current view, we designed and synthesized molecules where two isomeric, yet, different, 8π antiaromatic subunits, a benzocyclobutadiene (BCB) and a pentalene, are combined into, respectively, an angular and a linear topology via an unsaturated six-membered ring. The antiaromatic character of the molecules is supported experimentally by H NMR, UV-vis, and cyclic voltammetry measurements and X-ray crystallography. The experimental results are further confirmed by theoretical studies including the calculation of several aromaticity indices (NICS, ACID, HOMA, FLU, MCI). In the case of the angular molecule, double bond-localization within the connecting six-membered ring resulted in reduced antiaromaticity of both the BCB and pentalene subunits, while the linear structure provided a competitive situation for the two unequal [4]π subunits. We found that in the latter case the BCB unit alleviated its unfavorable antiaromaticity more efficiently, leaving the pentalene with strong antiaromaticity. Thus, a reversed structure-antiaromaticity relationship when compared to aceno-pentalenes was achieved.
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http://dx.doi.org/10.1021/acs.joc.9b03119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311060PMC
April 2020

Thiete Dioxides as Templates Towards Twisted Scaffolds and Macrocyclic Structures.

Chemistry 2020 May 28;26(27):6029-6035. Epub 2020 Apr 28.

Department of Chemistry, Ludwig-Maximilians University, Butenandtstraße 5-13, 81377, Munich, Germany.

Thiete dioxide units have been employed as a template for further functionalization through C-H activation strategies. Using simple thiete dioxide building blocks, a new library of axially chiral molecules has been synthesized that owe their stability to electrostatic interactions in the solid state. Similar starting materials were further engaged in the formation of cyclic trimeric structures, opening the pathway to unprecedented macrocyclic ring systems.
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http://dx.doi.org/10.1002/chem.201905751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318563PMC
May 2020

Electrophilic Reactivities of Vinyl -Quinone Methides.

Org Lett 2020 Mar 2;22(6):2182-2186. Epub 2020 Mar 2.

Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstraße 5-13, 81377 München, Germany.

The electrophilic reactivity of a series of 8-arylated vinyl -quinone methides (VQMs) was determined by analyzing the kinetics of their reactions with carbanions in DMSO at 20 °C according to the linear free energy relationship log = s( + ). The electrophilicity parameters for VQMs were used to successfully predict Michael-additions with structurally diverse C-, N-, S-, and H-nucleophiles.
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http://dx.doi.org/10.1021/acs.orglett.0c00338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7091536PMC
March 2020

Active and Unidirectional Acceleration of Biaryl Rotation by a Molecular Motor.

Angew Chem Int Ed Engl 2020 03 20;59(14):5730-5737. Epub 2020 Feb 20.

Ludwig-Maximilians-Universität München, Department of Chemistry and Center for Integrated Protein Science CIPSM, Butenandtstr. 5-13, 81377, München, Germany.

Light-driven molecular motors possess immense potential as central driving units for future nanotechnology. Integration into larger molecular setups and transduction of their mechanical motions represents the current frontier of research. Herein we report on an integrated molecular machine setup allowing the transmission of potential energy from a motor unit onto a remote receiving entity. The setup consists of a motor unit connected covalently to a distant and sterically encumbered biaryl receiver. By action of the motor unit, single-bond rotation of the receiver is strongly accelerated and forced to proceed unidirectionally. The transmitted potential energy is directly measured as the extent to which energy degeneration is lifted in the thermal atropisomerization of this biaryl. Energy degeneracy is reduced by more than 1.5 kcal mol , and rate accelerations of several orders of magnitude in terms of the rate constants are achieved.
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http://dx.doi.org/10.1002/anie.201913798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154650PMC
March 2020

Enantioselective Synthesis of a Tricyclic, sp -Rich Diazatetradecanedione: an Amino Acid-Based Natural Product-Like Scaffold.

Chemistry 2020 Apr 19;26(21):4677-4681. Epub 2020 Feb 19.

Department of Chemistry, Institute of Chemistry and Biochemistry, Darmstadt University of Technology, Alarich-Weiss-Strasse 4, 64287, Darmstadt, Germany.

6-, 7-, and 8-membered rings are assembled from a linear precursor by successive cyclisation reactions to construct a tricyclic diazatricyclo[6.5.1.0 ]-tetradecanedione scaffold. Advanced building blocks based on d-aspartic acid and l-pyroglutamic acid were combined by a sp -sp Negishi coupling. A carbamate-guided syn-diastereoselective epoxidation followed by an intramolecular epoxide opening allowed the construction of the piperidine ring. An efficient one-pot hydroxyl-group protection twofold deprotection reaction prepared the ground for the cyclisation to the bicycle. A final deprotection of the orthogonal protecting groups and lactamisation led to the novel, sp -rich tricycle. The final compound is a substrate mimic of peptidyl-prolyl cis-trans isomerases featuring a locked trans-amide bond. Cheminformatic analysis of 179 virtual derivatives indicates favourable physicochemical properties and drug-like characteristics. As proof of concept we, show a low micromolar activity in a fluorescence polarisation assay towards the FK506-binding protein 12.
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http://dx.doi.org/10.1002/chem.201905144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187416PMC
April 2020

Characterization of two new degradation products of atorvastatin calcium formed upon treatment with strong acids.

Beilstein J Org Chem 2019 2;15:2085-2091. Epub 2019 Sep 2.

Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians University Munich, Butenandtstr. 5-13, 81377 Munich, Germany.

Atorvastatin calcium (Lipitor, Sortis) is a well-established cholesterol synthesis enzyme (CSE) inhibitor commonly used in the therapy of hypercholesterolemia. This drug is known to be sensitive to acid treatment, but only little data has been published on the structures of the degradation products. Here we report the identification of two novel degradation products of atorvastatin, which are formed only under drastic acidic conditions. While treatment with conc. sulfuric acid led to a loss of the carboxanilide residue (accompanied by an expectable lactonization/dehydration process in the side chain), treatment with conc. aqueous hydrochloric acid gave a complex, bridged molecule under C-C-bond formation of the lactone moiety with the pyrrole, migration of the isopropyl group and loss of the carboxanilide residue. The novel degradation products were characterized by NMR spectroscopy, HRMS data and X-ray crystal structure analysis.
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http://dx.doi.org/10.3762/bjoc.15.206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753681PMC
September 2019

Green light powered molecular state motor enabling eight-shaped unidirectional rotation.

Nat Commun 2019 10 1;10(1):4449. Epub 2019 Oct 1.

Department of Chemistry and Center for Integrated Protein Science CIPSM, Ludwig Maximilians-Universität München, Butenandtstrasse 5-13, 81377, München, Germany.

Molecular motors convert external energy into directional motions at the nano-scales. To date unidirectional circular rotations and linear motions have been realized but more complex directional trajectories remain unexplored on the molecular level. In this work we present a molecular motor powered by green light allowing to produce an eight-shaped geometry change during its unidirectional rotation around the central molecular axis. Motor motion proceeds in four different steps, which alternate between light powered double bond isomerizations and thermal hula-twist isomerizations. The result is a fixed sequence of populating four different isomers in a fully unidirectional trajectory possessing one crossing point. This motor system opens up unexplored avenues for the construction and mechanisms of molecular machines and will therefore not only significantly expand the toolbox of responsive molecular devices but also enable very different applications in the field of miniaturized technology than currently possible.
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http://dx.doi.org/10.1038/s41467-019-12463-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773862PMC
October 2019

Synthetic Entry to Polyfunctionalized Molecules through the [3+2]-Cycloaddition of Thiocarbonyl Ylides.

J Am Chem Soc 2019 08 16;141(34):13352-13357. Epub 2019 Aug 16.

Institute of Organic Chemistry and Center for Molecular Biosciences, Leopold-Franzens-University Innsbruck , Innrain 80-82 , 6020 Innsbruck , Austria.

Here we present a comprehensive study on the [3+2]-cycloaddition of thiocarbonyl ylides with a wide variety of alkenes and alkynes. The obtained dihydro- and tetrahydrothiophene products serve as exceptionally versatile intermediates providing access to thiophenes, dienes, dendralenes, and -quarternary carbon centers. The use of high-pressure conditions enables thermally unstable, sterically encumbered or moderately reactive substrates to undergo the cycloaddition under mild conditions, thereby increasing the yield by up to 58%. In addition, we showcase its utility by the formal syntheses of the pharmaceuticals NGB 4420 and tenilapine.
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http://dx.doi.org/10.1021/jacs.9b07729DOI Listing
August 2019

Aromatic β-sheet foldamers based on tertiary squaramides.

Chem Commun (Camb) 2019 Aug;55(70):10392-10395

Department of Pharmacy and Center for Integrated Protein Science, Ludwig-Maximilians-Universität, Butenandtstraße 5-13, D-81377 München, Germany.

The preference of N,N-aryl, alkyl tertiary amides for cis conformations has been exploited through the use of tertiary squaramides as hairpin turn units that promote the folding of aromatic β-sheets. Head-to-head aromatic arrangements were shown to prevail in sufficiently long bent aromatic sequences.
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http://dx.doi.org/10.1039/c9cc04849aDOI Listing
August 2019

Influencing Epigenetic Information with a Hydrolytically Stable Carbocyclic 5-Aza-2'-deoxycytidine.

Angew Chem Int Ed Engl 2019 09 25;58(37):12984-12987. Epub 2019 Jul 25.

Department of Chemistry, Ludwig-Maximilians-Universität, Butenandtstrasse 5-13, Munich, Germany.

5-Aza-2'-deoxycytidine (AzadC) is an antimetabolite in clinical use, which reduces the level of the epigenetic modification 5-methyl-2'-deoxycytidine (mdC). AzadC is incorporated into the genome of proliferating cells, where it inhibits DNA methyltransferases (DNMTs), leading to a reduction of mdC. The loss of mdC, which is a transcriptional silencer in the promoter region found upstream of genes, leads to the reactivation of the corresponding gene, including tumor-suppressor genes, which elicits a beneficial effect. The problem associated with AzadC is that the compound is hydrolytically unstable. It decomposes during treatment to a variety of poorly characterized hydrolysis products. After its incorporation into the genome, this hydrolytic instability generates abasic sites. It is consequently difficult to dissect whether the activity of the compound is caused by DNMT inhibition or more generally by DNA lesion formation. We now discovered that a disarmed version of AzadC, in which the ribose oxygen was replaced by a CH group, is surprisingly stable under a variety of pH values while keeping activity against the DNMTs.
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http://dx.doi.org/10.1002/anie.201904794DOI Listing
September 2019

Ring-Expansion Approaches for the Total Synthesis of Salimabromide.

Tetrahedron 2019 Jun 9;75(24):3195-3215. Epub 2019 Mar 9.

Institute of Organic Chemistry and Center for Molecular Biosciences, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.

We describe the evolution of a synthetic strategy for the construction of the marine polyketide salimabromide. Combining a bicyclo[3.1.0]hexan-2-one ring-expansion to build up a functionalized naphthalene and an unprecedented rearrangement/cyclization cascade, enabled synthesis of a dearomatized tricyclic subunit of the target compound. Alternatively, an intramolecular ketiminium [2+2]-cycloaddition and subsequent Baeyer-Villiger ring-expansion gave access to the sterically encumbered architecture of salimabromide. Sequential oxidation of the carbon framework finally enabled the total synthesis of this unusual natural product.
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http://dx.doi.org/10.1016/j.tet.2019.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544523PMC
June 2019

Towards Smart Adaptive Care Toilets.

Stud Health Technol Inform 2019 ;260:9-16

HCI Group, Institute of Visual Computing and Human-Centered Technology, TU Wien (Vienna University of Technology), Vienna, Austria.

Standard toilets in Western countries often do not meet the needs of elderly and disabled people with physical limitations. While the existing concept of barrier-free toilets and the emerging "changing places" concept offer more space and support, the fixed height of the toilet seat still imposes a major problem during all phases of toilet use and can limit the users' autonomy by requiring personal assistance. Thus, in the EU project iToilet an innovative ICT-based modular height adjustable toilet system was designed to support the autonomy, dignity and safety of older people living at home by digital technology enhancements adapting the toilet to their needs and preferences. The main requirements were: double foldable handrails, height and tilt adjustment, emergency detection and call, and ease of use. The ICT component in this approach serves a double purpose of enhancing usability of the base assistive technology while at the same time providing safety for independent use. A field test of a prototype system in real environments of a day care center and a rehabilitation clinic has been successfully finished. The application of the iToilet concept also in semi-public settings is currently studied in the Toilet4me project.
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September 2019

Towards Smart Adaptive Care Toilets.

Stud Health Technol Inform 2019 ;260:9-16

HCI Group, Institute of Visual Computing and Human-Centered Technology, TU Wien (Vienna University of Technology), Vienna, Austria.

Standard toilets in Western countries often do not meet the needs of elderly and disabled people with physical limitations. While the existing concept of barrier-free toilets and the emerging "changing places" concept offer more space and support, the fixed height of the toilet seat still imposes a major problem during all phases of toilet use and can limit the users' autonomy by requiring personal assistance. Thus, in the EU project iToilet an innovative ICT-based modular height adjustable toilet system was designed to support the autonomy, dignity and safety of older people living at home by digital technology enhancements adapting the toilet to their needs and preferences. The main requirements were: double foldable handrails, height and tilt adjustment, emergency detection and call, and ease of use. The ICT component in this approach serves a double purpose of enhancing usability of the base assistive technology while at the same time providing safety for independent use. A field test of a prototype system in real environments of a day care center and a rehabilitation clinic has been successfully finished. The application of the iToilet concept also in semi-public settings is currently studied in the Toilet4me project.
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September 2019

The crystal structures of benzyl-ammonium phenyl-acetate and its hydrate.

Acta Crystallogr E Crystallogr Commun 2019 Feb 11;75(Pt 2):194-201. Epub 2019 Jan 11.

Ludwig-Maximilians-Universität, Department Chemie, Butenandtstrasse, 5-13, 81377 München, Germany.

The title compounds benzyl-ammonium phenyl-acetate, CHN·CHO (), and its monohydrate, CHN·CHO·HO (), can be obtained by evaporating methano-lic solutions containing equimolar amounts of benzyl-amine and phenyl-acetic acid in the absence and presence of water, respectively. N-H⋯O hydrogen bonds in the crystal structure of lead to the formation of hydro-philic channels running along the axis direction. The hydrogen-bonding system is best described by fused (10) ring patterns, often observed in ammonium carboxyl-ate salts. In , the presence of the crystal water leads to the formation of a two-dimensional hydrogen-bonding network. The benzyl moieties in and form hydro-phobic layers in the crystal structures with the aromatic rings adopting edge-to-face arrangements.
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http://dx.doi.org/10.1107/S2056989019000288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362638PMC
February 2019

Photon-Only Molecular Motor with Reverse Temperature-Dependent Efficiency.

J Am Chem Soc 2018 12 21;140(48):16442-16445. Epub 2018 Nov 21.

Department für Chemie and Munich Center for Integrated Protein Science CIPSM , Ludwig-Maximilians-Universität München , D-81377 Munich , Germany.

Light-driven molecular motors are archetypal molecular machines and enable fast and efficient unidirectional motions under photoirradiation. Their common working mechanism contains thermal ratcheting steps leading to slowed-down and even halted directional movement at lower temperatures. In this work, an alternative type of molecular motor is presented, which operates without thermal ratcheting in the ground state. Instead, three consecutive and different photoreactions lead to a directional stepwise rotation of one molecular fragment with respect to the other. This motion is increased in speed and directionality at lower temperatures and at the same time allows a considerably larger fraction of the supplied photon energy to be used for performing work.
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http://dx.doi.org/10.1021/jacs.8b10660DOI Listing
December 2018

Nucleophilicity and Electrophilicity Parameters for Predicting Absolute Rate Constants of Highly Asynchronous 1,3-Dipolar Cycloadditions of Aryldiazomethanes.

J Am Chem Soc 2018 Dec 16;140(48):16758-16772. Epub 2018 Nov 16.

Department Chemie , Ludwig-Maximilians-Universität München , Butenandtstr. 5-13 , 81377 München , Germany.

Kinetics of the reactions of aryldiazomethanes (ArCHN) with benzhydrylium ions (ArCH) have been measured photometrically in dichloromethane. The resulting second-order rate constants correlate linearly with the electrophilicities E of the benzhydrylium ions which allowed us to use the correlation lg k = s( N + E) (eq 1) for determining the nucleophile-specific parameters N and s of the diazo compounds. UV-vis spectroscopy was analogously employed to measure the rates of the 1,3-dipolar cycloadditions of these aryldiazomethanes with acceptor-substituted ethylenes of known electrophilicities E. The measured rate constants for the reactions of the diazoalkanes with highly electrophilic Michael acceptors ( E > -11, for example 2-benzylidene Meldrum's acid or 1,1-bis(phenylsulfonyl)ethylene) agreed with those calculated by eq 1 from the one-bond nucleophilicities N and s of the diazo compounds and the one-bond electrophilicities of the dipolarophiles, indicating that the incremental approach of eq 1 may also be applied to predict the rates of highly asynchronous cycloadditions. Weaker electrophiles, e.g., methyl acrylate, react faster than calculated from E, N, and s, and the ratio of experimental to calculated rate constants was suggested to be a measure for the energy of concert Δ G = RT ln( k/ k). Quantum chemical calculations indicated that all products isolated from the reactions of the aryldiazomethanes with acceptor substituted ethylenes (Δ-pyrazolines, cyclopropanes, and substituted ethylenes) arise from intermediate Δ-pyrazolines, which are formed through concerted 1,3-dipolar cycloadditions with transition states, in which the C-N bond formation lags behind the C-C bond formation. The Gibbs activation energies for these cycloadditions calculated at the PCM(UA0,CHCl)/(U)B3LYP-D3/6-31+G(d,p) level of theory agree within 5 kJ mol with the experimental numbers showing the suitability of the applied polarizable continuum model (PCM) for considering solvation.
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http://dx.doi.org/10.1021/jacs.8b09995DOI Listing
December 2018

A hemithioindigo molecular motor for metal surface attachment.

Org Biomol Chem 2019 02;17(7):1979-1983

Ludwig-Maximilians-Universität München, Department für Chemie and Munich Center for Integrated Protein Science CIPSM, D-81377 Munich, Germany.

Functionalization of surfaces with responsive molecular entities is currently an important research field allowing the organization of molecular functions in space in a defined way and thus accessing emergent properties not observed in solution. Herein we report on the synthesis of a hemithioindigo molecular motor bearing thioether feet for surface attachment on its thioindigo fragment. We also give a full theoretical description of its ground state energy profile together with an experimental evaluation of the visible light driven unidirectional rotation in solution. Comparison with the corresponding unsubstituted original motor shows that after feet-attachment the hemithioindigo molecular motor is fully operative with a similar maximum attainable speed and degree of unidirectionality.
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http://dx.doi.org/10.1039/c8ob02424cDOI Listing
February 2019

CIC fusion-positive sarcoma of the spermatic cord.

Virchows Arch 2019 Feb 11;474(2):253-257. Epub 2018 Oct 11.

Institute of Pathology, University Medical Center Göttingen, Robert-Koch-Str.40, 37075, Göttingen, Germany.

In addition to germ cell tumors and tumors of the sex cord stroma, the WHO classification of testis and paratesticular tumors also contains malignant soft tissue tumors. Among them, liposarcomas of the spermatic cord are the most common entities. Other mesenchymal tumors with smooth muscle, skeletal muscle, fibroblastic/myofibroblastic, or nerve sheath differentiation are rare. Ewing sarcoma is composed of uniform small round cells and typically characterized by translocations of the EWSR1 gene. In rare cases, Ewing sarcoma-like tumors lack an EWSR1 gene fusion. Some of these tumors harbor a specific CIC translocation. However, Ewing-like sarcoma has up to now never been described in the testis or spermatic cord. The present case describes the first EWSR1-negative, undifferentiated round cell sarcoma with CIC translocation of the spermatic cord. Potential differential diagnoses are discussed.
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http://dx.doi.org/10.1007/s00428-018-2471-5DOI Listing
February 2019

Direct evidence for hula twist and single-bond rotation photoproducts.

Nat Commun 2018 06 28;9(1):2510. Epub 2018 Jun 28.

Department of Chemistry, Ludwig-Maximilians-Universität München and Munich Center for Integrated Protein Science CIPSM, Butenandtstrasse 5-13, 81377, München, Germany.

Photoisomerization reactions are quintessential processes driving molecular machines and motors, govern smart materials, catalytic processes, and photopharmacology, and lie at the heart of vision, phototaxis, or vitamin production. Despite this plethora of applications fundamental photoisomerization mechanisms are not well understood at present. The famous hula-twist motion-a coupled single and double-bond rotation-was proposed to explain proficient photoswitching in restricted environments but fast thermal follow-up reactions hamper identification of primary photo products. Herein we describe an asymmetric chromophore possessing four geometrically distinct diastereomeric states that do not interconvert thermally and can be crystallized separately. Employing this molecular setup direct and unequivocal evidence for the hula-twist photoreaction and for photoinduced single-bond rotation is obtained. The influences of the surrounding medium and temperature are quantified and used to favor unusual photoreactions. Based on our findings molecular engineers will be able to implement photo control of complex molecular motions more consciously.
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http://dx.doi.org/10.1038/s41467-018-04928-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023863PMC
June 2018