Research Lab - Michael Schnürch
Direct functionalization of C(sp3)-H bonds:
The direct functionalization of C-H bonds is a hot and rapidly growing field in organic synthesis. Exploiting the C-H bond as “functional group” opens the door for more efficient and sustainable processes. Within this field, the activation of C(sp3)-H bonds is a particular challenge. In the past years we have developed several reactions under ruthenium, rhodium, copper, and iron catalysis realizing arylation, indolation, and alkylation reactions. Recently, our focus has shifted to the field of coupling two different C(sp3)-H bonds with each other, an even greater challenge.
Solid substitutes for gaseous reagents:
The aim of this project is to incorporate small alkyl chains into more complex organic molecules using easy to handle reagents. The type of reagents preferred in organic synthesis is solid, non-toxic, non-corrosive, and stable for a prolonged period of time without special precautions. Unfortunately, the reagents currently in use for the introduction of short alkyl chains do not fulfill these criteria in many cases, since they are often gaseous, toxic, or corrosive or even a combination of the aforementioned undesirable properties. So, what to do, in case you want to use such reagents, but change their properties to make handling easier?
The hypothesis is that new reagents can be developed, which are solid and easy to handle themselves, but deliver in-situ the actual alkylation reagent, overall without experiencing the aforementioned unfavorable properties. For that purpose, we will look into several reagent classes, which can decompose under certain reaction conditions into reactive intermediates, which in turn can act as alkylating agents. Additionally, it has to be secured that the conditions required for liberating the alkylation reagent in-situ, are compatible with the other substrates, catalysts, and overall reaction conditions. The method development will start with selected test substrates and transformations, before the general scope of a certain method will be explored.
Organic small molecules for energy storage:
This research was initiated in the frame of a FFG “Leitprojekt” named Tes4seT – Thermal Energy Storage for Sustainable Energy Technology. In this project we were part of a large consortium of 18 partners and 5 development lines. The overall goal was to develop advanced thermal storage materials, thermal storage devices, numerical simulation tools and control systems to integrate these into energy systems in industry, for mobility applications and in buildings, in order to strengthen these sectors and bring the Austrian industry in a leading European position regarding advanced thermal energy storage. In our project part we cooperated with the Austrian Institute of Technology (AIT), the Austrian company SOLID and the German company Südzucker AG. Our aim was to use derivatives of sugar alcohols to store energy via a phase transfer from the solid to the liquid phase and release it afterwards by inducing crystallization. It turned out that such sugar alcohols are not stable for the desired application, however at the end of the project we identified two new compound classes which have the desired properties.
Ligands for GABAA Receptors:
This project is carried out in collaboration with Assoc. Prof. Margot Ernst from the Medical University of Vienna In the Ernst group biological testing is carried out and my group is charged with the chemical synthesis and lead optimization. The aim of the present project is the development and characterization of compound libraries that target a binding site of a GABAA receptors (gamma-amino butyric acid type A receptors) with a distinct subunit composition. GABAA receptors are the site of action of many clinically important drugs, such as benzodiazepines or barbiturates and the targets for sleep medications, anxiolytics, or various narcotics. In this collaborative effort we generate and investigate new compounds that interact with this site, try to understand the interactions that govern the ligated states and lead to allosteric modulation, and ultimately produce compounds exhibiting higher potency and selectivity for these binding sites for a possible future therapeutic application. Isotopic labelling for developing probe molecules is one of the next research plans on the agenda.
Direct functionalization of C(sp3)-H bonds:
The direct functionalization of C-H bonds is a hot and rapidly growing field in organic synthesis. Exploiting the C-H bond as “functional group” opens the door for more efficient and sustainable processes. Within this field, the activation of C(sp3)-H bonds is a particular challenge. In the past years we have developed several reactions under ruthenium, rhodium, copper, and iron catalysis realizing arylation, indolation, and alkylation reactions. Recently, our focus has shifted to the field of coupling two different C(sp3)-H bonds with each other, an even greater challenge.
Research Lab – Michael Schnürch
Bielec, Björn (Postdoc)
Björn received his PhD in medicinal chemistry in 2022 from University of Vienna under the Supervision of Prof. Dr. Dr. Bernhard Keppler and assoc.-Prof. Dr. Christian Kowol. During his PhD thesis he worked on the development and investigation of prodrug systems for chemotherapeutics. After working in the chemical industry for the last two years, he received research funding by the FWF and will perform his postdoctoral research under the guidance of Prof. Dr. Michael Schnürch. His research focuses on the design of transition metal trigger moieties to develop novel kinds of prodrug systems for tyrosine kinase inhibitors.
Keywords:
- cancer research
- coordination chemistry
- tyrosine kinase inhibitors
- molecular modelling
- biochemical analysis
Pourkaveh Dehkordi, Raheleh (Postdoc)
Keywords:
- C-H activation
- regioselective catalysis
- cross-coupling reaction
Biedermann, Nina (PhD Student)
Nina obtained her Bachelor degree in chemistry at TU Wien in 2019 and then moved on to her Master studies. After spending a semester abroad at Uppsala Universitet (SE), she started her Master thesis in March 2020 under the supervision of Dr. Christian Stanetty and Prof. Dr. Michael Schnürch. In the course of her thesis, Nina is working on the synthesis of non-natural sugar alcohols as promising substances in the field of phase change materials.
ORCID:0000-0001-7709-1156
Keywords:
- phase change materials
- sugar chemistry
- non-natural sugar alcohols
- organoindium chemistry
Narayanan, Nanditha Kattukudiyil (PhD Student)
Keywords:
- C-H activation
- regioselective catalysis
- cross-coupling reaction
Papaplioura, Eleni (PhD Student)
Eleni completed her B.Sc. in Chemistry in the University of Ioannina, Greece. During her studies, she participated in an Erasmus+ internship at the Technological University of Vienna (TUW). She received her M.Sc. „Advanced Synthesis & Catalysis “(SynCat), (Elite program of the Network of Excellence Bavaria) from the Department of Chemistry and Pharmacy, University of Regensburg, Germany, focusing on the: “Total synthesis of gamma-butyrolactone bioactive compounds”, During her master studies, she undertook an internship at the Eshelman School of Pharmacy at the University of North Carolina, USA, working on the ‘’Synthesis of substituted caprolactams’’. She participated into the Graduate School Program Molecular Drug Targets at TU Wien under the supervision of Prof. Marko Mihovilovic and she has been working on the ‘’Target identification of Leoligin’’. Currently, she is working on her doctoral studies focusing on the ”Sustainable and safe C-H activation for large-scale production” within the ”Chair” PhD project.
Keywords:
- C-H activation
- catalysis
- direct alkylation
- kinetic isotope effects
Templ, Johanna (PhD Student)
Keywords:
- (transition-)metal catalysis
- C-H activation
- quaternary ammonium salts
Standfest, Christoph (Master Student)
After he obtained his Bachelor’s Degree in chemistry and chemical engineering at Johannes Kepler University Linz in 2020, he moved to Vienna to do his Masters in chemistry at TU Wien. Currently, he is working on his Master Thesis under the supervision of Dr. Stanetty and Prof. Schnürch on synthesis and evaluation of non-natural sugar alcohols as potential phase change materials.
ORCID: 0009-0000-6784-8696
Keywords:
- carbohydrate chemistry
- total synthesis
- phase change materials
- metathesis
FWF Project P33064N – Substituting Gaseous Reagents for Solid Alternatives (SUGARS)
The aim of this project is to incorporate small alkyl chains into more complex organic molecules using easy to handle reagents.
The type of reagents preferred in organic synthesis is solid, non-toxic, non-corrosive, and stable for a prolonged period of time without special precautions. Unfortunately, the reagents currently in use for the introduction of short alkyl chains do not fulfill these criteria in many cases, since they are often gaseous, toxic, or corrosive or even a combination of the aforementioned undesirable properties. So, what to do, in case you want to use such reagents, but change their properties to make handling easier?
The hypothesis is that new reagents can be developed, which are solid and easy to handle themselves, but deliver in-situ the actual alkylation reagent, overall without experiencing the aforementioned unfavorable properties.
For that purpose, we will look into several reagent classes, which can decompose under certain reaction conditions into reactive intermediates, which in turn can act as alkylating agents. Additionally, it has to be secured that the conditions required for liberating the alkylation reagent in-situ, are compatible with the other substrates, catalysts, and overall reaction conditions. The method development will start with selected test substrates and transformations, before the general scope of a certain method will be explored.
Realizing this project will expand the scope of transformations which can be carried out under “normal” laboratory conditions without the need for special equipment (e.g. high-pressure reactors often required when working with gaseous reagents). Additionally, transformations with gaseous reagents are often actively avoided in university settings, where the reaction scale is typically in the mg region, and dosing gases in such small amounts is extremely difficult. Hence, this project will potentially open a new chemical space to be exploited in the future by chemists at all different types of institutions.
Finally, the utility of the developed methods shall be demonstrated by the late-stage modification of known drug molecules.
Marie Curie International Training Network – “C-H Activation for Industrial Renewal” – CHAIR
Relying on the functionalisation of previously considered latent, yet omnipresent C-H bonds, C-H activation offers a real breakthrough in organic chemistry and allows reconsidering beaten tracks in synthesis, retrosynthesis and late stage diversification for rapid hit-to-lead strategies.
It is consequently one of the most rapidly expanding fields of synthetic chemistry.
Yet, its implementation in the non-academic sector is still scarce, as numerous obstacles still need to be overcome to render C-H activations truly appealing for a large-scale production of drugs, materials or key building blocks. In addition, current academia-industry interactions are still limited and young researchers able to implement these new competences are rare.
Accordingly, the target and ambition of the CHAIR project is dual: to educate a new generation of young chemists in this modern and promising field of chemistry while concomitantly designing new solutions to further improve the attractiveness of C-H activation for industrial purposes.CHAIR fosters research training of early stage researchers (ESRs, i.e. PhD students) on CH-activation. Our project focuses on establishing strong bridges between academia and industry to develop new C-H activation methodologies and generalise their implementation in industry, from both R&D and production perspectives.
To do so, we are training 15 ESRs within the network’s laboratories, to carry-out 15 research projects.
GABAA Receptor Ligands
This project is carried out in collaboration with Assoc. Prof. Margot Ernst from the Medical University of Vienna In the Ernst group biological testing is carried out and my group is charged with the chemical synthesis and lead optimization. The aim of the present project is the development and characterization of compound libraries that target a binding site of a GABAA receptors (gamma-amino butyric acid type A receptors) with a distinct subunit composition. GABAA receptors are the site of action of many clinically important drugs, such as benzodiazepines or barbiturates and the targets for sleep medications, anxiolytics, or various narcotics. In this collaborative effort we generate and investigate new compounds that interact with this site, try to understand the interactions that govern the ligated states and lead to allosteric modulation, and ultimately produce compounds exhibiting higher potency and selectivity for these binding sites for a possible future therapeutic application. Isotopic labelling for developing probe molecules is one of the next research plans on the agenda.
Publications in Scientific Journals
The synthesis of higher-carbon sugar alcohols via indium-mediated acyloxyallylation as potential phase change materials
Markus Draskovits, Nina Biedermann, Marko D. Mihovilovic, Michael Schnürch* & Christian Stanetty*
Monatsh Chem 2023
In recent years, sugar alcohols have gained significant attention as organic phase change materials (PCMs) for thermal energy storage due to their comparably high thermal storage densities up to 350 J/g. In a computational study, outstandingly high values of up to ~ 450–500 J/g have been postulated for specific higher-carbon sugar alcohols. These optimized structures feature an even number of carbon atoms in the backbone and a stereochemical configuration in which all hydroxyl groups are in an 1,3-anti-relationship, as found in the natural hexitol D-mannitol. However, these manno-configured higher-carbon sugar alcohols have not been experimentally investigated as PCMs yet and described synthetic routes are elaborate multiple steps syntheses. Therefore, we aimed to synthesize sugar alcohols of the manno-series with a concise synthetic protocol based on the indium-mediated acyloxyallylation (IMA) of aldoses. En route the C2-epimers were easily accessible, namely gluco-configured sugar alcohols, bearing one set of hydroxyl groups in a suboptimal 1,3-syn-realtionship. The synthesized compounds were found to possess thermal properties consistent with the predicted values, and the “perfect” higher-carbon sugar alcohol with eight carbon atoms was found to have indeed an outstanding high latent heat of fusion of ~ 380 J/g with a melting point of 260 °C.
Sterically Demanding Flexible Phosphoric Acids for Constructing Efficient and Multi-Purpose Asymmetric Organocatalysts
Fabian Scharinger, Ádám Márk Pálvölgyi, Melanie Weisz, Matthias Weil, Christian Stanetty, Michael Schnürch, Katharina Bica-Schröder*
Angew. Chem. Int. Ed. (2022) 61, e202202189
Herein, we present a novel approach for various asymmetric transformations of cyclic enones. The combination of readily accessible chiral diamines and sterically demanding flexible phosphoric acids resulted in a simple and highly tunable catalyst framework. The careful optimization of the catalyst components led to the identification of a particularly powerful and multi-purpose organocatalyst, which was successfully applied for asymmetric epoxidations, aziridinations, aza-Michael-initiated cyclizations, as well as for a novel Robinson-like Michael-initiated ring closure/aldol cyclization. High catalytic activities and excellent stereocontrol was observed for all four reaction types, indicating the excellent versatility of our catalytic system. Furthermore, a simple change in the diamine’s configuration provided easy access to both product antipodes in all cases.
Investigation of Leoligin Derivatives as NF-κΒ Inhibitory Agents
Thomas Linder, Eleni Papaplioura, Diyana Ogurlu, Sophie Geyrhofer, Scarlet Hummelbrunner, Daniel Schachner, Atanas G. Atanasov, Marko D. Mihovilovic, Verena M. Dirsch,* and Michael Schnürch*
Biomedicines, 2022, 10, 62.
The transcription factor NF-κB is an essential mediator of inflammation; thus, the identification of compounds that interfere with the NF-κB signaling pathway is an important topic. The natural products leoligin and 5-methoxyleoligin have served as a starting point for the development of NF-κB inhibitors. Using our modular total synthesis method of leoligin, modifications at two positions were undertaken and the effects of these modifications on the biological activity were investigated. The first modification concerned the ester functionality, where it was found that variations in this position have a significant influence, with bulky esters lacking Michael-acceptor properties being favored. Additionally, the substituents on the aryl group in position 2 of the tetrahydrofuran scaffold can vary to some extent, where it was found that a 3,4-dimethoxy and a 4-fluoro substitution pattern show comparable inhibitory efficiency.
The synthesis of higher-carbon sugar alcohols via indium-mediated acyloxyallylation as potential phase change materials
Markus Draskovits, Nina Biedermann, Marko D. Mihovilovic, Michael Schnürch* & Christian Stanetty*
Monatsh Chem 2023
In recent years, sugar alcohols have gained significant attention as organic phase change materials (PCMs) for thermal energy storage due to their comparably high thermal storage densities up to 350 J/g. In a computational study, outstandingly high values of up to ~ 450–500 J/g have been postulated for specific higher-carbon sugar alcohols. These optimized structures feature an even number of carbon atoms in the backbone and a stereochemical configuration in which all hydroxyl groups are in an 1,3-anti-relationship, as found in the natural hexitol D-mannitol. However, these manno-configured higher-carbon sugar alcohols have not been experimentally investigated as PCMs yet and described synthetic routes are elaborate multiple steps syntheses. Therefore, we aimed to synthesize sugar alcohols of the manno-series with a concise synthetic protocol based on the indium-mediated acyloxyallylation (IMA) of aldoses. En route the C2-epimers were easily accessible, namely gluco-configured sugar alcohols, bearing one set of hydroxyl groups in a suboptimal 1,3-syn-realtionship. The synthesized compounds were found to possess thermal properties consistent with the predicted values, and the “perfect” higher-carbon sugar alcohol with eight carbon atoms was found to have indeed an outstanding high latent heat of fusion of ~ 380 J/g with a melting point of 260 °C.
Publications in Scientific Journals
The synthesis of higher-carbon sugar alcohols via indium-mediated acyloxyallylation as potential phase change materials
Markus Draskovits, Nina Biedermann, Marko D. Mihovilovic, Michael Schnürch* & Christian Stanetty*
Monatsh Chem 2023
In recent years, sugar alcohols have gained significant attention as organic phase change materials (PCMs) for thermal energy storage due to their comparably high thermal storage densities up to 350 J/g. In a computational study, outstandingly high values of up to ~ 450–500 J/g have been postulated for specific higher-carbon sugar alcohols. These optimized structures feature an even number of carbon atoms in the backbone and a stereochemical configuration in which all hydroxyl groups are in an 1,3-anti-relationship, as found in the natural hexitol D-mannitol. However, these manno-configured higher-carbon sugar alcohols have not been experimentally investigated as PCMs yet and described synthetic routes are elaborate multiple steps syntheses. Therefore, we aimed to synthesize sugar alcohols of the manno-series with a concise synthetic protocol based on the indium-mediated acyloxyallylation (IMA) of aldoses. En route the C2-epimers were easily accessible, namely gluco-configured sugar alcohols, bearing one set of hydroxyl groups in a suboptimal 1,3-syn-realtionship. The synthesized compounds were found to possess thermal properties consistent with the predicted values, and the “perfect” higher-carbon sugar alcohol with eight carbon atoms was found to have indeed an outstanding high latent heat of fusion of ~ 380 J/g with a melting point of 260 °C.
Sterically Demanding Flexible Phosphoric Acids for Constructing Efficient and Multi-Purpose Asymmetric Organocatalysts
Fabian Scharinger, Ádám Márk Pálvölgyi, Melanie Weisz, Matthias Weil, Christian Stanetty, Michael Schnürch, Katharina Bica-Schröder*
Angew. Chem. Int. Ed. (2022) 61, e202202189
Herein, we present a novel approach for various asymmetric transformations of cyclic enones. The combination of readily accessible chiral diamines and sterically demanding flexible phosphoric acids resulted in a simple and highly tunable catalyst framework. The careful optimization of the catalyst components led to the identification of a particularly powerful and multi-purpose organocatalyst, which was successfully applied for asymmetric epoxidations, aziridinations, aza-Michael-initiated cyclizations, as well as for a novel Robinson-like Michael-initiated ring closure/aldol cyclization. High catalytic activities and excellent stereocontrol was observed for all four reaction types, indicating the excellent versatility of our catalytic system. Furthermore, a simple change in the diamine’s configuration provided easy access to both product antipodes in all cases.
Investigation of Leoligin Derivatives as NF-κΒ Inhibitory Agents
Thomas Linder, Eleni Papaplioura, Diyana Ogurlu, Sophie Geyrhofer, Scarlet Hummelbrunner, Daniel Schachner, Atanas G. Atanasov, Marko D. Mihovilovic, Verena M. Dirsch,* and Michael Schnürch*
Biomedicines, 2022, 10, 62.
The transcription factor NF-κB is an essential mediator of inflammation; thus, the identification of compounds that interfere with the NF-κB signaling pathway is an important topic. The natural products leoligin and 5-methoxyleoligin have served as a starting point for the development of NF-κB inhibitors. Using our modular total synthesis method of leoligin, modifications at two positions were undertaken and the effects of these modifications on the biological activity were investigated. The first modification concerned the ester functionality, where it was found that variations in this position have a significant influence, with bulky esters lacking Michael-acceptor properties being favored. Additionally, the substituents on the aryl group in position 2 of the tetrahydrofuran scaffold can vary to some extent, where it was found that a 3,4-dimethoxy and a 4-fluoro substitution pattern show comparable inhibitory efficiency.
The synthesis of higher-carbon sugar alcohols via indium-mediated acyloxyallylation as potential phase change materials
Markus Draskovits, Nina Biedermann, Marko D. Mihovilovic, Michael Schnürch* & Christian Stanetty*
Monatsh Chem 2023
In recent years, sugar alcohols have gained significant attention as organic phase change materials (PCMs) for thermal energy storage due to their comparably high thermal storage densities up to 350 J/g. In a computational study, outstandingly high values of up to ~ 450–500 J/g have been postulated for specific higher-carbon sugar alcohols. These optimized structures feature an even number of carbon atoms in the backbone and a stereochemical configuration in which all hydroxyl groups are in an 1,3-anti-relationship, as found in the natural hexitol D-mannitol. However, these manno-configured higher-carbon sugar alcohols have not been experimentally investigated as PCMs yet and described synthetic routes are elaborate multiple steps syntheses. Therefore, we aimed to synthesize sugar alcohols of the manno-series with a concise synthetic protocol based on the indium-mediated acyloxyallylation (IMA) of aldoses. En route the C2-epimers were easily accessible, namely gluco-configured sugar alcohols, bearing one set of hydroxyl groups in a suboptimal 1,3-syn-realtionship. The synthesized compounds were found to possess thermal properties consistent with the predicted values, and the “perfect” higher-carbon sugar alcohol with eight carbon atoms was found to have indeed an outstanding high latent heat of fusion of ~ 380 J/g with a melting point of 260 °C.
Publications in Scientific Journals
Structural features defining nf-κb inhibition by lignan-inspired benzofurans and benzothiophenes
T. Dao-Huy, S. Latkolik, J. Bräuer, A. Pfeil, H. Stuppner, M. Schnürch, V. Dirsch, M.D. Mihovilovic*
Biomolecules, 10 (2020), 1131; 1 – 20.
A silver‑coated copper wire as inexpensive drug eluting stent model: determination of the relative releasing properties of leoligin and derivatives
L. Czollner, E. Papaplioura, T. Linder, R. Liu, Y. Li, A Atanasov, V. Dirsch, M. Schnürch, M.D. Mihovilovic*
Monatshefte für Chemie, – (2020).
Cardiovascular diseases are overall the leading cause of mortality and morbidity worldwide. Therefore, treating and preventing coronary heart disease are of high scientific interest. Among several percutaneous coronary intervention procedures, coronary artery stenting displayed potent activity against restenosis, often observed using other invasive therapies. Nowadays, drug eluting stents’ superiority over bare metal stents is increasingly recognizable, since drug eluting stents are able to overcome problems encountered with bare metal stent technology. Within this study, we developed a novel method for performing drug-releasing experiments utilizing an affordable stent model made from a readily available silver-coated copper wire, which was further coated with poly(n-butyl methacrylate). Leoligin, previously reported to inhibit intimal hyperplasia and the regrowth of endothelial cells, was exploited along with several structural analogs in drug-releasing experiments. It was found that compounds exhibiting similar biological activity can have significantly different releasing properties, a crucial parameter to know for the selection of compounds for in vivo studies.
GABAa receptor ligands often interact with binding sites in the transmembrane domain and in the extracellular domain-can the promiscuity code be cracked?
M.T. Iorio, F. Vogel, F. Koniuszewski, P. Scholze, S. Rehman, X. Simeone, M. Schnürch, M.D. Mihovilovic, M. Ernst*
International Journal of Molecular Sciences, 21 (2020), 334.
Many allosteric binding sites that modulate gamma aminobutyric acid (GABA) effects have been described in heteropentameric GABA type A (GABAA) receptors, among them sites for benzodiazepines, pyrazoloquinolinones and etomidate. Diazepam not only binds at the high affinity extracellular “canonical” site, but also at sites in the transmembrane domain. Many ligands of the benzodiazepine binding site interact also with homologous sites in the extracellular domain, among them the pyrazoloquinolinones that exert modulation at extracellular α+/β− sites. Additional interaction of this chemotype with the sites for etomidate has also been described. We have recently described a new indole-based scaffold with pharmacophore features highly similar to pyrazoloquinolinones as a novel class of GABAA receptor modulators. Contrary to what the pharmacophore overlap suggests, the ligand presented here behaves very differently from the identically substituted pyrazoloquinolinone. Structural evidence demonstrates that small changes in pharmacophore features can induce radical changes in ligand binding properties. Analysis of published data reveals that many chemotypes display a strong tendency to interact promiscuously with binding sites in the transmembrane domain and others in the extracellular domain of the same receptor. Further structural investigations of this phenomenon should enable a more targeted path to less promiscuous ligands, potentially reducing side effect liabilities.
Characterization of a Structural Leoligin Analog as Farnesoid X Receptor Agonist and Modulator of Cholesterol Transport
A. Ladurner, T. Linder, L. Wang, V. Hiebl, D. Schuster, M. Schnürch, M.D. Mihovilovic, A Atanasov, V. Dirsch
Planta Medica, 86 (2020), 1097 – 1107.
The ligand-activated farnesoid X receptor is an emerging therapeutic target for the development of drugs against metabolic syndrome-related diseases. In this context, selective bile acid receptor modulators represent a novel concept for drug development. Selective bile acid receptor modulators act in a target gene- or tissue-specific way and are therefore considered less likely to elicit unwanted side effects. Based on leoligin, a lignan-type secondary plant metabolite from the alpine plant Leontopodium nivale ssp. alpinum, 168 synthesized structural analogs were screened in a farnesoid X receptor in silico pharmacophore-model. Fifty-six virtual hits were generated. These hits were tested in a cell-based farnesoid X receptor transactivation assay and yielded 7 farnesoid X receptor-activating compounds. The most active one being LT-141A, with an EC50 of 6 µM and an Emax of 4.1-fold. This analog did not activate the G protein-coupled bile acid receptor, TGR5, and the metabolic nuclear receptors retinoid X receptor α, liver X receptors α/β, and peroxisome proliferator-activated receptors β/γ. Investigation of different farnesoid X receptor target genes characterized LT-141A as selective bile acid receptor modulators. Functional studies revealed that LT-141A increased cholesterol efflux from THP-1-derived macrophages via enhanced ATP-binding cassette transporter 1 expression. Moreover, cholesterol uptake in differentiated Caco-2 cells was significantly decreased upon LT-141A treatment. In conclusion, the leoligin analog LT-141A selectively activates the nuclear receptor farnesoid X receptor and has an influence on cholesterol transport in 2 model systems.
Toward the Recovery of Platinum Group Metals from a Spent Automotive Catalyst with Supported Ionic Liquid Phases
O. Lanaridi, A Sahoo, A. Limbeck, S. Naghdi, D. Eder, E. Eitenberger, Z. Csendes, M. Schnürch, K. Schröder*
ACS Sustainable Chem. Eng. 2021, 9, 1, 375–386.
We present a novel approach for the separation and recovery of Pt and Pd leached from a spent automotive catalyst relying on conventional and polymerized supported ionic liquid phases (SILPs and polySILPs, respectively). A variety of parameters with possible effects on the separation behavior, namely, acidity and concentration of the platinum group metal (PGM) containing solution, as well as different SILP and polySILP loadings, were evaluated for the separation of PGMs in the presence of high concentrations of Al, Fe, Zn, and Ce. The polySILP material demonstrated the ability to separate the PGMs from major accompanying interferences in a single separation step, while problems arising from ionic liquid leaching in the case of SILPs could be avoided. Moreover, the use of supported ionic liquid phases allowed the drastic reduction of the amount of required ionic liquid compared to conventional liquid–liquid separation, while avoiding problems arising from emulsion formation. Subsequent stripping experiments lead to further purification of the PGMs and finally desorption from the solid material into a pure solution. Eventually, the concept of chemisorbed polySILPs provides a new and convenient approach for the recycling of platinum group metals.
Design and Synthesis of a Compound Library Exploiting 5-Methoxyleoligin as Potential Cholesterol Efflux Promoter
T. Linder, S. Geyrhofer, E. Papaplioura, L. Wang, A Atanasov, H. Stuppner, V. Dirsch, M. Schnürch, M.D. Mihovilovic*
Molecules, 25 (2020), 662; 1 – 13.
5-Methoxyleoligin and leoligin are natural occurring lignans derived from Edelweiss (Leontopodium nivale ssp. alpinum), displaying potent pro-angiogenic and pro-arteriogenic activity. Cholesterol efflux from macrophages is associated with reverse cholesterol transport which inhibits the development of cardiovascular disease. Within this study, we developed a modular and stereoselective total synthesis of 5-methoxyleoligin which can be readily used to prepare a novel compound library of related analogs. The target 5-methoxyleoligin was synthesized exploiting a recently disclosed modular route, which allows also rapid synthesis of analogous compounds. All obtained products were tested towards macrophage cholesterol efflux enhancement and the performance was compared to the parent compound leoligin. It was found that variation on the aryl moiety in 2-position of the furan ring allows optimization of the activity profile, whereas the ester-functionality does not tolerate significant alterations.
Carbamate-based P,O-ligands for asymmetric allylic alkylations
Á. Pálvölgyi, M. Schnürch, K. Schröder*
Tetrahedron, 76 (2020), 51; 1 – 8.
Herein we report the design and successful catalytic application of modified Trost-ligands in asymmetric allylic alkylation (AAA) reactions. A small set of carbamate-monophosphine P,O-ligands has been prepared in a straightforward two-step synthetic procedure. After optimization of the reaction conditions, high catalytic activities and excellent enantioselectivity up to >99% have been attained.
Counterion-Enhanced Pd/Enamine Catalysis: Direct Asymmetric α‑Allylation of Aldehydes with Allylic Alcohols by Chiral Amines and Achiral or Racemic Phosphoric Acids
Á. Pálvölgyi, J. Smith, M. Schnürch, K. Schröder*
Journal of Organic Chemistry, 86 (2020), 850 – 860.
We report a straightforward and efficient Pd/enamine catalytic procedure for the direct asymmetric α-allylation of branched aldehydes. The use of simple chiral amines and easily prepared achiral or racemic phosphoric acids, together with a suitable Pd-source resulted in a highly active and enantioselective catalyst system for the allylation of various α-branched aldehydes with different allylic alcohols. The reported procedure could provide an easy access to both product antipodes. Furthermore, two possible orthogonal derivatizations of the enantioenriched aldehydes were performed without any decrease in enantioselectivity.
Counterion Enhanced Organocatalysis: A Novel Approach for the Asymmetric Transfer Hydrogenation of Enones
F. Scharinger, Á. Pálvölgyi, V. Zeindlhofer, M. Schnürch, C. Schröder, K. Schröder*
ChemCatChem, 12 (2020), 14; 3776 – 3782.
We present a novel strategy for organocatalytic transfer hydrogenations relying on an ion‐paired catalyst of natural l‐amino acids as main source of chirality in combination with racemic, atropisomeric phosphoric acids as counteranion. The combination of a chiral cation with a structurally flexible anion resulted in a novel chiral framework for asymmetric transfer hydrogenations with enhanced selectivity through synergistic effects. The optimized catalytic system, in combination with a Hantzsch ester as hydrogen source for biomimetic transfer hydrogenation, enabled high enantioselectivity and excellent yields for a series of α,β‐unsaturated cyclohexenones under mild conditions. Moreover, owing to the use of readily available and chiral pool‐derived building blocks, it could be prepared in a straightforward and significantly cheaper way compared to the current state of the art.
Photocatalytic deaminative benzylation and alkylation of tetrahydroisoquinolines with N-alkylpyrydinium salts
D. Schönbauer, C. Sambiagio, T. Noël, M. Schnürch*
Beilstein Journal of Organic Chemistry, 16 (2020), 809 – 817.
A ruthenium-catalyzed photoredox coupling of substituted N-aryltetrahydroisoquinolines (THIQs) and different bench-stable pyridinium salts was successfully developed to give fast access to 1-benzyl-THIQs. Furthermore, secondary alkyl and allyl groups were also successfully introduced via the same method. Additionally, the typically applied N-phenyl group in the THIQ substrate could be replaced by the cleavable p-methoxyphenyl (PMP) group and successful N-deprotection was demonstrated.
Allosteric GABAA Receptor Modulators-A Review on the Most Recent Heterocyclic Chemotypes and Their Synthetic Accessibility
B. Vega Alanis, M.T. Iorio, L. Silva, K. Bampali, M. Ernst*, M. Schnürch*, M.D. Mihovilovic
Molecules, 25(4) (2020), 999; 1 – 47.
GABAA receptor modulators are structurally almost as diverse as their target protein. A plethora of heterocyclic scaffolds has been described as modulating this extremely important receptor family. Some made it into clinical trials and, even on the market, some were dismissed. This review focuses on the synthetic accessibility and potential for library synthesis of GABAA receptor modulators containing at least one heterocyclic scaffold, which were disclosed within the last 10 years.
6-[(tert-Butyldimethylsilyl)oxy]-3-ethenyl-7-methoxy-4-[(trimethylsilyl)ethynyl]naphtho[2,3-c]furan-1(3H)-one
M. Weil, T. Kremsmayr, M.D. Mihovilovic
IUCrData (2020). 5, x200224
π interactions between the methine group of the furan ring and the central ring of the tricyclic core of an adjacent molecule lead to inversion-related dimers.Contributions to Books
Book Series: Topics in Heterocyclic Chemistry
Topics in Heterocyclic Chemistry – Vol. XXXI: Metalation of Azines and Diazines
M. Schnürch, M.D. Mihovilovic
Series editor: B. Maes; Springer-Verlag Berlin Heidelberg 2013, Berlin – Heidelberg, 2013, ISBN: 978-3-642-35021-4, 272 pages.
This chapter reviews the metalation of pyridazine, cinnoline, and phthalazine derivatives as well as the usage of the hereby formed organometallic compounds in subsequent reactions. The main topics under discussion are lithiation, magnesation, and zincation, the focus being on deprotonative metalation by properly chosen strong bases, e.g. lithiumdiisopropylamide or lithium 2,2,6,6-tetramethylpiperidide. A short discussion upon boronyl and stannyl derivatives of the three diazines under investigation is enclosed at the end of the chapter.
Book Title: Pd-Catalyzed Cross-Coupling Strategies in Thiazole Chemistry
Pd-catalyzed cross-coupling strategies in thiazole chemistry – synthesis of arylated thiazoles and bithiazole building blocks
M. Schnürch
Südwestdeutscher Verlag für Hochschulschriften, Saarbrücken, 2009, ISBN: 978-3-8381-1246-6; 264 pages.
Within this contribution the synthesis of anilino-substituted bithiazoles as potentially bioactive compounds is reported. The key chemical transformations in the applied synthetic strategy were Pd-catalyzed cross coupling reactions which were used for the formation of various bithiazoles. Different cross coupling methodologies were investigated. Starting from 2-thiazolamine the desired metal organyls were prepared in two steps. Besides the well documented Stille and Negishi reaction on thiazole derivatives, a new method could be established. After successful preparation of the first thiazoleboronic acid ester, Suzuki-Miyaura reactions were performed. Upon reaction with various bromo-thiazoles the desired bithiazole derivatives were obtained, whereby the Stille reaction gave the best results compared to the other two methods. Subsequently the chloro atom was used for a nucleophilic exchange reaction with aniline derivatives to give the target compounds.
Publications in Scientific Journals
Rhodium-catalyzed direct alkylation of benzylic amines using alkyl bromides
M. Anschuber, R. Pollice, M. Schnürch*
Monatshefte für Chemie, 150 (2019), 127 – 138.
Within this contribution, the development and substrate scope evaluation of a direct alkylation protocol of the C(sp3 )–H bond of benzylic amines using alkyl bromides is reported. This pyridine-directed method is initiated by elimination of the alkyl bromide to a terminal olefn, which is then the true alkylating agent.
Variations on a scaffold – Novel GABAA receptor modulators
M.T. Iorio*, S. Rehman*, K. Bampali*, B. Stöger*, M. Schnürch*, M. Ernst*, M.D. Mihovilovic*
European Journal of Medicinal Chemistry, 180 (2019), 340 – 349.
Allosteric ligands of GABAA receptors exist in many different chemotypes owing to their great usefulness as therapeutics, with benzodiazepines being among the best known examples. Many allosteric binding sites have been described, among them a site at the extracellular interface between the alpha principal face and the beta complementary face (α+/β-). Pyrazoloquinolinones have been shown to bind at α+/β-binding sites of GABAA receptors, exerting chiefly positive allosteric modulation at this location. In order to further explore molecular determinants of this type of allosteric modulation, we synthesized a library of ligands based on the PQ pharmacophore employing a ring-chain bioisosteric approach. In this study we analyzed the structure-activity-relationship (SAR) of these novel ligands based on an azo-biaryl structural motif in α1β3 GABAA receptors, indicating interesting novel properties of the compound class.
Leoligin-inspired synthetic lignans with selectivity for cell-type and bioactivity relevant for cardiovascular disease
T. Linder, R. Liu, A Atanasov, S. Geyrhofer, S. Schwaiger, H. Stuppner, M. Schnürch, V. Dirsch, M.D. Mihovilovic*
Chemical Science, 10 (2019), 5815 – 5820.
Recently, a natural compound leoligin, a furan-type lignan, was discovered as an interesting hit compound with an anti-inflammatory pharmacological activity profile. We developed a modular and stereoselective approach for the synthesis of the edelweiss-derived lignan leoligin and used the synthetic route to rapidly prepare leoligin analogs even on the gram scale. Proof of concept of this approach together with cell-based bio-assays gained structural analogs with increased selectivity towards vascular smooth muscle versus endothelial cell proliferation inhibition, a major benefit in fighting vascular neointima formation. In addition, we identified the structural features of leoligin analogs that define their ability to inhibit the pro-inflammatory NF-κB pathway. Results are discussed in the context of structural modification of these novel synthetic lignans.
Toluene and its Derivatives as Atom-Efficient Benzylating Agents for Secondary Amines
D. Schönbauer, F. Lukas, M. Schnürch*
Synlett, 30 (2019), 94 – 98.
Toluene as a replacement for common N-benzylating agents, such as benzyl bromide, can be an atom-efficient alternative reagent. Under nickel catalysis and mildly oxidative conditions, it is possible to activate toluene efficiently and use it directly for the benzylation of different 2-aminopyridines. The transformation is not restricted to simple toluene, but also substituted derivatives give the desired product in good yields. Effective cleavage of the pyridine moiety is presented.
Investigations of the generality of quaternary ammonium salts as alkylating agents in direct C-H alkylation reactions: solid alternatives for gaseous olefins
D. Schönbauer, M. Spettel, R. Pollice, E. Pittenauer, M. Schnürch*
Organic & Biomolecular Chemistry, 17 (2019), 16; 4024 – 4030.
C–H alkylation reactions using short chain olefins as alkylating agents could be operationally simplified on the lab scale by using quaternary ammonium salts as precursors for these gaseous reagents: Hofmann elimination delivers in situ the desired alkenes with the advantage that the alkene concentration in the liquid phase is high. In case a catalytic system did not tolerate the conditions for Hofmann elimination, a very simple spatial separation of both reactions, Hofmann elimination and direct alkylation, was achieved to circumvent possible side reactions or catalyst deactivation. Additionally, the truly catalytically active species of a rhodium(I) mediated alkylation reaction could be identified by using this approach.
Defined concatenated α6α1β3γ2 GABAA receptor constructs reveal dual action of pyrazoloquinolinone allosteric modulators
X. Simeone, M.T. Iorio, D. Siebert, S. Rehman, M. Schnürch, M.D. Mihovilovic, M. Ernst*
Bioorganic & Medicinal Chemistry, 27 (2019), 3167 – 3178.
Pyrazoloquinolinones (PQs) have been extensively studied as modulators of GABAA receptors with different subunit composition, exerting modulatory effects by binding at α+/β- interfaces of GABAA receptors. PQs with a substituent in position R7 have been reported to preferentially modulate α6- subunit containing GABAA receptors which are mostly expressed in the cerebellum but were also found in the olfactory bulb, in the cochlear nucleus, in the hippocampus and in the trigeminal sensory pathway. They are considered potentially interesting in the context of sensori-motor gating deficits, depressive-like behavior, migraine and orofacial pain. Here we explored the option to modify the lead ligands’ R7 position. In the compound series we observed two different patterns of allosteric modulation in recombinantly expressed α6β3γ2 receptors, namely monophasic and biphasic positive modulation. In the latter case the additional phase occurred in the nanomolar range, while all compounds displayed robust modulation in the micromolar range. Nanomolar, near silent binding has been reported to occur at benzodiazepine binding sites, but was not investigated at the diazepam insensitive α6+/γ2- interface. To clarify the mechanism underlying the biphasic effect we tested one of the compounds in concatenated receptors. In these constructs the subunits are covalently linked, allowing to form either the α6+/γ2- interface, or the α6+/β3- interface, to study the resulting modulation. With this approach we were able to ascribe the nanomolar modulation to the α6+/γ2- interface. While not all compounds display the nanomolar phase, the strong modulation at the α6+/β3 interface proved to be tolerant for all tested R7 groups. This provides the future option to introduce e.g. isotope labelled or fluorescent moieties or substituents that enhance solubility and bioavailability.
Publications in Scientific Journals
Magnolol dimer-derived fragments as PPARγ-selective probes
D. Dreier, M. Resetar, V. Temml, L. Rycek, N. Kratena, M. Schnürch, D. Schuster, V. Dirsch, M.D. Mihovilovic*
Organic & Biomolecular Chemistry, 16 (2018), 38; 7019 – 7028.
Partial agonists of the transcription factor PPARγ (peroxisome proliferator-activated receptor γ) have shown potential for the treatment of metabolic and inflammatory conditions and novel activators serve as valuable tool and lead compounds. Based on the natural product magnolol (I) and recent structural information of the ligand–target interaction we have previously developed magnolol dimer (II) which has been shown to have enhanced affinity towards PPARγ and improved selectivity over RXRα (retinoid X receptor α), PPARγ’s heterodimerization partner. In this contribution we report the synthesis and evaluation of three fragments of the dimeric lead compound by structural simplifications. Sesqui magnolol A and B (III and IV) were found to exhibit comparable activities to magnolol dimer (II) and selectivity over RXRα persisted. Computational studies suggest a common pharmacophore of the distinctive biphenyl motifs. Truncated magnolol dimer (V) on the other hand does not share this feature and was found to act as an antagonist.
One-pot synthesis of triazines as potential agents affecting cell differentiation
T. Linder, M. Schnürch*, M.D. Mihovilovic
Monatshefte für Chemie, 149 (2018), 1257 – 1284.
This paper outlines the synthesis of a number of structural analogs of 3-[(4,6-diphenoxy-1,3,5-triazin-2-yl)amino]benzoic acid which represent compounds with potential cardiogenetic activity. A one-pot protocol was developed for swift functionalization of the 1,3,5-triazine core without the need of isolating intermediates. The developed route starts from readily available 2,4,6-trichloro-1,3,5-triazine, displacing the chlorine atoms sequentially by aryloxy, arylamino, or arylthio moieties to enable access to molecules with three different substituents of this type in good yields. To facilitate purification, tert-butyl, methyl, and ethyl ester derivatives of the target compounds were initially synthesized. The tert-butyl esters could be readily hydrolyzed to the desired compounds, while reduction of the methyl and ethyl esters gave the corresponding benzylic alcohols in high yields, thereby expanding the substrate scope for future relevant cell assays.
Stereoselective Synthesis of the Isomers of Notoincisol A: Assigment of the Absolute Configuration of this Natural Product and Biological Evaluation
L. Rycek, V. Ticli, J. Pyszkowski, S. Latkolik, X. Liu, A Atanasov, T. Steinacher, R. Bauer, D. Schuster, V. Dirsch, M. Schnürch, M. Ernst, M.D. Mihovilovic*
Journal of Natural Products, 81 (2018), 2419 – 2428.
A comprehensive overview of directing groups applied in metal catalysed C-H functionalisation chemistry
Sambiagio, D. Schönbauer, R. Blieck, T. Dao-Huy, G. Pototschnig, P. Schaaf, T. Wiesinger, M.F. Zia, J. Wencel-Delord, T. Besset, B. Maes, M. Schnürch*
Chemical Society Reviews (invited), 47 (2018), 6603 – 6743.
The present review is devoted to summarizing the recent advances (2015-2017) in the field of metal catalysed group-directed C-H functionalisation. In order to clearly showcase the molecular diversity that can now be accessed by means of directed C-H functionalisation, the whole is organized following the directing groups installed on a substrate. Its aim is to be a comprehensive reference work, where a specific directing group can be easily found, together with the transformations which have been carried out with it. Hence, the primary format of this review is schemes accompanied with a concise explanatory text, in which the directing groups are ordered in sections according to their chemical structure. The schemes feature typical substrates used, the products obtained as well as the required reaction conditions. Importantly, each example is commented on with respect to the most important positive features and drawbacks, on aspects such as selectivity, substrate scope, reaction conditions, directing group removal,and greenness. The targeted readership are both experts in the field of C-H functionalisation chemistry (to provide a comprehensive overview of the progress made in the last years) and, even more so, all organic chemists who want to introduce the C-H functionalisation way of thinking for a design of straightforward, efficient and step-economic synthetic routes towards molecules of interest to them. Accordingly, this review should be of particular interest also for scientists from industrial R&D sector.
Hence, the overall goal of this review is to promote the application of C-H functionalisation reactions outside the research groups dedicated to method development and establishing it as a valuable reaction archetype in contemporary R&D, comparable to the role cross-coupling reactions play to date.
Biocompatible metal-assisted C-C cross-coupling combined with biocatalytic chiral reductions in a concurrent tandem cascade
P. Schaaf, T. Bayer, M. Koley, M. Schnürch, U. Bornscheuer, F. Rudroff*, M.D. Mihovilovic*
Chemical Communications, 54 (2018), 12978 – 12981.
Easy Access to Enantiopure (S)- and (R)-Aryl Alkyl Alcohols by a Combination of Gold(III)-Catalyzed Alkyne Hydration and Enzymatic Reduction
P. Schaaf, V. Gojic, T. Bayer, F. Rudroff, M. Schnürch, M.D. Mihovilovic*
ChemCatChem, 10 (2018), 920 – 924.
Engineered Flumazenil Recognition Site Provides Mechanistic Insight Governing Benzodiazepine Modulation in GABAA Receptors
D. Siebert, K. Bampali, R. Puthenkalam, Z. Varagic, I. Sarto-Jackson, P. Scholze, W. Sieghart, M.D. Mihovilovic, M. Schnürch, M. Ernst*
ACS Chemical Biology, 13 (2018), 2040 – 2047.
The anxiolytic, anticonvulsant, muscle-relaxant, and sedative-hypnotic effects of benzodiazepine site ligands are mainly elicited by allosteric modulation of GABAA receptors via their extracellular αx+/γ2– (x = 1, 2, 3, 5) interfaces. In addition, a low affinity binding site at the homologous α+/β– interfaces was reported for some benzodiazepine site ligands. Classical benzodiazepines and pyrazoloquinolinones have been used as molecular probes to develop structure–activity relationship models for benzodiazepine site activity. Considering all possible α+/β– and α+/γ– interfaces, such ligands potentially interact with as many as 36 interfaces, giving rise to undesired side effects. Understanding the binding modes at their binding sites will enable rational strategies to design ligands with desired selectivity profiles. Here, we compared benzodiazepine site ligand interactions in the high affinity α1+/γ2– site with the homologous α1+/β3– site using a successive mutational approach. We incorporated key amino acids known to contribute to high affinity benzodiazepine binding of the γ2– subunit into the β3– subunit, resulting in a quadruple mutant β3(4mut) with high affinity flumazenil (Ro 15-1788) binding properties. Intriguingly, some benzodiazepine site ligands displayed positive allosteric modulation in the tested recombinant α1β3(4mut) constructs while diazepam remained inactive. Consequently, we performed in silico molecular docking in the wildtype receptor and the quadruple mutant. The results led to the conclusion that different benzodiazepine site ligands seem to use distinct binding modes, rather than a common binding mode. These findings provide structural hypotheses for the future optimization of both benzodiazepine site ligands, and ligands that interact with the homologous α+/β– sites.
SAR-Guided Scoring Function and Mutational Validation Reveal the Binding Mode of CGS-8216 at the α1+/γ2- Benzodiazepine Site
D. Siebert, M. Wieder, L. Schlener, P. Scholze, S. Boresch, T. Langer, M. Schnürch, M.D. Mihovilovic, L. Richter*, M. Ernst, G. Ecker
Journal of Chemical Information and Modeling, 58 (2018), 1682 – 1696.
The structural resolution of a bound ligand–receptor complex is a key asset to efficiently drive lead optimization in drug design. However, structural resolution of many drug targets still remains a challenging endeavor. In the absence of structural knowledge, scientists resort to structure–activity relationships (SARs) to promote compound development. In this study, we incorporated ligand-based knowledge to formulate a docking scoring function that evaluates binding poses for their agreement with a known SAR. We showcased this protocol by identifying the binding mode of the pyrazoloquinolinone (PQ) CGS-8216 at the benzodiazepine binding site of the GABAA receptor. Further evaluation of the final pose by molecular dynamics and free energy simulations revealed a close proximity between the pendent phenyl ring of the PQ and γ2D56, congruent with the low potency of carboxyphenyl analogues. Ultimately, we introduced the γ2D56A mutation and in fact observed a 10-fold potency increase in the carboxyphenyl analogue, providing experimental evidence in favor of our binding hypothesis.
Towards functional selectivity for α6β3γ2 GABAA receptors: a series of novel pyrazoloquinolinones
M. Treven, D. Siebert, R. Holzinger, K. Bampali, J. Fabjan, Z. Varagic, L. Wimmer, F. Steudle, P. Stolze, M. Schnürch, M.D. Mihovilovic, M. Ernst*
British Journal of Clinical Pharmacology, 175 (2018), 419 – 428.
Publications in Scientific Journals
Linked magnolol dimer as a selective PPARγ agonist – Structure-based rational design, synthesis, and bioactivity evaluation
D. Dreier, S. Latkolik, L. Rycek, M. Schnürch, A. Dymáková, A Atanasov, A. Ladurner, E. Heiss, H. Stuppner, D. Schuster*, M.D. Mihovilovic, V. Dirsch*
Scientific Reports, 7 (2017), 13002; 1 – 10.
The nuclear receptors peroxisome proliferator-activated receptor γ (PPARγ) and its hetero-dimerization partner retinoid X receptor α (RXRα) are considered as drug targets in the treatment of diseases like the metabolic syndrome and diabetes mellitus type 2. Effort has been made to develop new agonists for PPARγ to obtain ligands with more favorable properties than currently used drugs. Magnolol was previously described as dual agonist of PPARγ and RXRα. Here we show the structure-based rational design of a linked magnolol dimer within the ligand binding domain of PPARγ and its synthesis. Furthermore, we evaluated its binding properties and functionality as a PPARγ agonist in vitro with the purified PPARγ ligand binding domain (LBD) and in a cell-based nuclear receptor transactivation model in HEK293 cells. We determined the synthesized magnolol dimer to bind with much higher affinity to the purified PPARγ ligand binding domain than magnolol (K i values of 5.03 and 64.42 nM, respectively). Regarding their potency to transactivate a PPARγ-dependent luciferase gene both compounds were equally effective. This is likely due to the PPARγ specificity of the newly designed magnolol dimer and lack of RXRα-driven transactivation activity by this dimeric compound.
Cu(I)-catalyzed one-pot decarboxylation-alkynylation reactions on1,2,3,4-tetrahydroisoquinolines and one-pot synthesis oftriazolyl-1,2,3,4-tetrahydroisoquinolines
B. Gröll, P. Schaaf, M.D. Mihovilovic, M. Schnürch
Journal of Molecular Catalysis A: Chemical, 426 (2017), 398 – 406.
A facile and efficient method to introduce alkyne groups to the C-1 position of biologically interesting 1,2,3,4-tetrahydroisoquinolines via direct CH-functionalization is reported. Various alkynylated N-substituted 1,2,3,4-tetrahydroisoquinolines could be obtained by using copper(I)-chloride as catalyst, alkynoic acids as alkyne source and t-BuOOH as oxidant, in a one-pot two-step decarboxylation- alkynylation reaction in moderate to high yields. Furthermore, a one-pot protocol of a three-step decarboxylation-alkynylation-1,3-dipolar cycloaddition reaction leading to 1-triazolyl-tetrahydroisoquinolines was developed, a hitherto unknown reaction cascade.
Improved simplicity and practicability in copper-catalyzed alkynylation of tetrahydroisoquinoline
B. Gröll, P. Schaaf, M. Schnürch*
Monatshefte für Chemie, 148 (2017), 91 – 104.
Alkynylation reactions of N-protected tetrahydroisoquinolines have been performed using several different protocols of cross dehydrogenative coupling. Initially, a CuCl-catalyzed method was investigated, which worked well with three different N-protecting groups, namely phenyl, PMP, and benzyl and t-BuOOH as oxidant in acetonitrile as solvent. The peroxide could then be replaced by simple air and acetonitrile for water, leading to an overall very environmentally friendly protocol. Finally, a decarboxylative alkynylation protocol starting from alkynoic acids was also developed using again air as oxidant. This avoids the use of gaseous alkynes in the introduction of short-chained alkyne substituents.
Direct Functionalization of C−H Bonds by Iron, Nickel, and Cobalt Catalysis
G. Pototschnig, N. Maulide, M. Schnürch*
Chemistry – A European Journal, 23 (2017), 9206 – 9232.
Non‐precious‐metal‐catalyzed reactions are of increasing importance in chemistry due to the outstanding ecological and economic properties of these metals. In the subfield of metal‐catalyzed direct C−H functionalization reactions, recent years have shown an increasing number of publications dedicated to this topic. Nickel, cobalt, and last but not least iron, have started to enter a field which was long dominated by precious metals such as palladium, rhodium, ruthenium, and iridium. The present review article summarizes the development of iron‐, nickel‐, and cobalt‐catalyzed C−H functionalization reactions until the end of 2016, and discusses the scope and limitations of these transformations.
Molecular tools for GABAA receptors: High affinity ligands for β1-containing subtypes
X. Simeone, D. Siebert, K. Bampali, Z. Varagic, M. Treven, S. Rehman, J. Pyszkowski, R. Holzinger, F. Steudle, P. Scholze, M.D. Mihovilovic, M. Schnürch, M. Ernst*
Scientific Reports, 7 (2017), 5674.
γ-Aminobutyric acid type A (GABAA) receptors are pentameric GABA-gated chloride channels that are, in mammalians, drawn from a repertoire of 19 different genes, namely α1-6, β1-3, γ1-3, δ, ε, θ, π and ρ1-3. The existence of this wide variety of subunits as well as their diverse assembly into different subunit compositions result in miscellaneous receptor subtypes. In combination with the large number of known and putative allosteric binding sites, this leads to a highly complex pharmacology. Recently, a novel binding site at extracellular α+/β− interfaces was described as the site of modulatory action of several pyrazoloquinolinones. In this study we report a highly potent ligand from this class of compounds with pronounced β1-selectivity that mainly lacks α-subunit selectivity. It constitutes the most potent β1-selective positive allosteric modulatory ligand with known binding site. In addition, a proof of concept pyrazoloquinolinone ligand lacking the additional high affinity interaction with the benzodiazepine binding site is presented. Ultimately, such ligands can be used as invaluable molecular tools for the detection of β1-containing receptor subtypes and the investigation of their abundance and distribution.
Quaternary Ammonium Salts as Alkylating Reagents in C–H Activation Chemistry
M. Spettel, R. Pollice, M. Schnürch*
Organic Letters, 19 (2017), 4287 – 4290.
A rhodium(I)-catalyzed alkylation reaction of benzylic amines via C(sp3)–H activation using quaternary ammonium salts as alkyl source is described. The reaction proceeds via in situ formation of an olefin via Hofmann elimination, which is the actual alkylating reagent. This represents an operationally simple method for substituting gaseous and liquid olefins with solid quaternary ammonium salts as alkylating reagents, which is transferable to other C–H activation protocols as well.
(Z)-4,6-Di¬chloro-N-(4-chlorophenyl)quinoline-3-carbimidoyl chloride
M. Weil, D. Siebert, M. Schnürch*
IUCrData, 2 (2017), x170274.
The title imidoyl chloride, C16H8Cl4N2, has formed accidentally as a side product during the synthesis of a quinolin-3-one derivative. The molecule is not flat [the dihedral angle between the 4,6-dichloroquinoline and the imidoyl chloride planes is 53.43 (5)°], preventing π-conjugation over the complete entity. In the crystal, C—HN hydrogen bonding between a chlorophenyl C—H group and the quinoline N atom, as well as π–π stacking between neighbouring quinoline rings, consolidate the packing.
Michael Schnürch
