Publications by authors named "Bernhard Breit"

174 Publications

Regio-, Diastereo-, and Enantioselective Decarboxylative Hydroaminoalkylation of Dienol Ethers Enabled by Dual Palladium/Photoredox Catalysis.

Angew Chem Int Ed Engl 2022 May 16;61(20):e202200105. Epub 2022 Mar 16.

Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertstraße 21, 79104, Freiburg im Breisgau, Germany.

Intermolecular photocatalytic hydroaminoalkylation (HAA) of alkenes have emerged as a powerful method for the construction of alkyl amines. Although there are some studies aiming at stereoselective photocatalytic HAA reactions, the alkenes are limited to electrophilic alkenes. Herein, we report a highly regio-, diastereo-, and enantioselective HAA of electron-rich dienol ethers and α-amino radicals derived from α-amino acids using a unified photoredox and palladium catalytic system. This decarboxylative 1,2-Markovnikov addition enables the construction of vicinal amino tertiary ethers with high levels of regio- (up to >19 : 1 rr), diastereo- (up to >19 : 1 dr), and enantioselectivity control (up to >99 % ee). Mechanistic studies support a reversible hydropalladation as a key step.
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http://dx.doi.org/10.1002/anie.202200105DOI Listing
May 2022

Stereodivergent Palladium- and Rhodium-Catalyzed Intramolecular Addition of Tosylureas to Allenes: Diastereoselective Synthesis of Tetrahydropyrimidinones.

Org Lett 2021 Dec 22;23(23):9168-9172. Epub 2021 Nov 22.

Institute of Organic Chemistry, Albert-Ludwigs-Universität Freiburg, Albertstr. 21, 79104 Freiburg, Germany.

The intramolecular addition of tosylureas to allenes is highly -/-diastereoselective when employing a palladium or rhodium-based catalytic system and affords 1,3-cyclic ureas. Under palladium catalysis a range of thermodynamic -tetrahydropyrimidinones are accessible, while rhodium catalysis allows synthesis of the kinetic -tetrahydropyrimidinones. For a representative scope of substrates both cyclic ureas were obtained in excellent yields and diastereoselectivities. The obtained tetrahydropyrimidinones were shown to be easily deprotected and modified to demonstrate the synthetic value.
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http://dx.doi.org/10.1021/acs.orglett.1c03482DOI Listing
December 2021

Pharmacokinetic study of the novel phosphocholine derivative 3-dibutylaminopropylphosphonic acid by LC-MS coupling.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Dec 8;1186:122998. Epub 2021 Nov 8.

Centre for Integrative Signalling Analysis CISA, University of Freiburg, Habsburger Straße 49, 79104 Freiburg, Germany; Institute of Organic Chemistry, University of Freiburg, Albertstraße 21, 79104 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, Schänzlestr. 16, 79104 Freiburg, Germany; Spemann Graduate School of Biology and Medicine, University of Freiburg, Albertstr. 19a, 79104 Freiburg, Germany.

CRP is an important mediator of the inflammatory response. Pro-inflammatory CRP effects are mediated by pCRP* and mCRP, dissociation products of the native pCRP. The concentration of pCRP during inflammation may rise up to concentrations 1000-fold from baseline. By prevention of the conformational change from pCRP to pCRP*, pro-inflammatory immune responses can be inhibited and local tissue damage reduced. 3-(Dibutylamino)propylphosphonic acid (C10m) is a new substance that can suppress ischemic-reperfusion injury by targeting CRP in the complement cascade. It hampers dissociation of pCRP into its monomers, thus preventing exacerbation of tissue inflammation subsequent to reperfusion injury. In this study, the pharmacokinetics and metabolism of the new drug candidate C10m was investigated. A sensitive and selective method for detection of C10m and its metabolites from plasma and urine was developed with LC-MS and LC-MS/MS coupling. The LLOQ is at 0.1 µg mL and recovery at 87.4% ± 2.8%. Accuracy and precision were within 15% coefficient of variation and nominal concentrations, respectively. Concentration time profile after i.v. bolus injection of C10m was analyzed by LC-MS/MS. Bioavailability has shown to be below 30%. Most likely due to the compounds' very polar chemical properties, no phase-I or phase-II metabolism could be observed. Absence of phase-I metabolism was cross-checked by performing microsomal incubations. Our study revealed that C10m is rapidly eliminated via urine excretion and that half-times appear to be increased with coadministration of the target pCRP.
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http://dx.doi.org/10.1016/j.jchromb.2021.122998DOI Listing
December 2021

Cobalt-Catalyzed Hydroboration of Terminal and Internal Alkynes.

Org Lett 2021 Nov 7;23(21):8199-8203. Epub 2021 Oct 7.

Institut für Organische Chemie, Albert-Ludwigs-Universität 21, 79104 Freiburg, Germany.

A novel methodology to access synthetically versatile vinylboronic esters through a ligand-controlled cobalt-catalyzed hydroboration of terminal and internal alkynes is reported. The approach relies on the reduction of Co(II) by H-BPin in the presence of bisphosphine ligands generating catalytically active Co(I) hydride complexes. This procedure avoids the use of stoichiometric amounts of base, and no boron-containing byproducts are generated which is translated into high functional group tolerance and atom economy.
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http://dx.doi.org/10.1021/acs.orglett.1c02854DOI Listing
November 2021

4-Acyl Pyrrole Capped HDAC Inhibitors: A New Scaffold for Hybrid Inhibitors of BET Proteins and Histone Deacetylases as Antileukemia Drug Leads.

J Med Chem 2021 10 28;64(19):14620-14646. Epub 2021 Sep 28.

Institut für Wirkstoffentwicklung, Medizinische Fakultät, Universität Leipzig, Brüderstraße 34, D-04103 Leipzig, Germany.

Multitarget drugs are an emerging alternative to combination therapies. In three iterative cycles of design, synthesis, and biological evaluation, we developed a novel type of potent hybrid inhibitors of bromodomain, and extra-terminal (BET) proteins and histone deacetylases (HDACs) based on the BET inhibitor and well-established HDAC inhibitors. The most promising new hybrids, and , displayed submicromolar inhibitory activity against HDAC1-3 and 6, and BRD4(1), and possess potent antileukemia activity. induced apoptosis more effectively than the combination of ricolinostat and birabresib (1:1). The most balanced dual inhibitor, , induced significantly more apoptosis than the related control compounds (no BRD4(1) affinity) and (no HDAC inhibition) as well as the 1:1 combination of both. Additionally, was well tolerated in an zebrafish toxicity model. Overall, our data suggest an advantage of dual HDAC/BET inhibitors over the combination of two single targeted compounds.
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http://dx.doi.org/10.1021/acs.jmedchem.1c01119DOI Listing
October 2021

Cu-Catalyzed C-H Allylation of Benzimidazoles with Allenes.

Org Lett 2021 09 20;23(17):6765-6769. Epub 2021 Aug 20.

Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, 79104 Freiburg im Breisgau, Germany.

CuH-catalyzed intramolecular cyclization and intermolecular allylation of benzimidazoles with allenes have been described. The reaction proceeded smoothly with the catalytic system of Cu(OAc)/Xantphos and catalytic amount of (MeO)MeSiH. This protocol features mild reaction conditions and a good tolerance of substrates bearing electron-withdrawing, electron-donating, or electron-neutral groups. A new catalytic mechanism was proposed for this copper hydride catalytic system.
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http://dx.doi.org/10.1021/acs.orglett.1c02346DOI Listing
September 2021

Catalyst Deactivation During Rhodium Complex-Catalyzed Propargylic C-H Activation.

Chemistry 2021 Oct 1;27(56):14034-14041. Epub 2021 Aug 1.

Leibniz-Institut für Katalyse e.V., Albert-Einstein-Str. 29a, 18059, Rostock, Germany.

Detailed mechanistic investigations on our previously reported synthesis of branched allylic esters by the rhodium complex-catalyzed propargylic C-H activation have been carried out. Based on initial mechanistic studies, we present herein more detailed investigations of the reaction mechanism. For this, various analytical (NMR, X-ray crystal structure analysis, Raman) and kinetic methods were used to characterize the formation of intermediates under the reaction conditions. The knowledge obtained by this was used to further optimize the previous conditions and generate a more active catalytic system.
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http://dx.doi.org/10.1002/chem.202102219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8518492PMC
October 2021

Asymmetric hydroalkylation of alkynes and allenes with imidazolidinone derivatives: α-alkenylation of α-amino acids.

Chem Sci 2021 Apr 22;12(21):7388-7392. Epub 2021 Apr 22.

Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg Albertstraße 21 79104 Freiburg im Breisgau Germany

This work reports a new method for the synthesis of quaternary α-alkenyl substituted amino acids by the enantio- and diastereoselective addition of imidazolidinone derivatives to alkynes and allenes. Further hydrolysis of the imidazolidinone products under acidic conditions afforded biologically relevant amino acid derivatives. This method is geometry-selective (-isomer), enantio- and diastereoselective, and products were obtained in good to excellent yields. The utility of this new methodology is proved by its operational simplicity and the successful accomplishment of gram-scale reactions. Experimental and computational studies suggest the key role of Li in terms of selectivity and support the proposed reaction mechanism.
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http://dx.doi.org/10.1039/d1sc00240fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171337PMC
April 2021

Tandem Photocatalysis Protocol for Hydrogen Generation/Olefin Hydrogenation Using Pd-g-CN-Imine/TiO Nanoparticles.

Inorg Chem 2021 Jul 16;60(13):9484-9495. Epub 2021 Jun 16.

Institut für Organische Chemie, Albert-Ludwigs-Universität-Freiburg, Albertstrasse 21, Freiburg im Breisgau 79104, Germany.

An unprecedented visible-light-driven photocatalytic system consisting of Pd nanoparticles stabilized on g-CN-imine-functionalized TiO nanoparticles was discovered for photoassisted hydrogen generation followed by olefin hydrogenation under mild conditions. The structural integrity of the as-synthesized photocatalyst was corroborated by Fourier transform infrared spectroscopy, X-ray powder diffraction, energy-dispersive X-ray spectroscopy, inductively coupled plasma atomic emission spectroscopy, X-ray photoelectron spectroscopy, ultraviolet-diffuse reflectance spectroscopy, Brunauer-Emmett-Teller measurements, and thermogravimetric analysis (TGA). Transmission electron microscopy and high-resolution scanning electron microscopy revealed the nanoscopic nature of the catalyst. The photocatalyst promoted several different transformations in a one-pot reaction sequence: hydrogen evolution through photocatalytic acceptorless formation of benzimidazoles as important therapeutic agents followed by visible-light-driven photocatalytic reduction of olefins with a high hydrogen utilization efficiency of up to 92% under mild conditions. A significant volume of H was produced under blue light-emitting diode (LED) irradiation during the selective formation of benzimidazole, while the selectivity reduced significantly under a Xe lamp or in the dark. The in situ-generated H could be activated by the as-prepared Pd-CN-imine/TiO photocatalyst to effectively hydrogenate olefins under mild conditions at appropriate time exposed to blue LED irradiation. The light-dependent photocatalytic performance of the title catalyst was assessed using action spectra by calculating the apparent quantum efficiency (AQE), which exhibited the maximum AQEs at 410 and 550 nm, at which the highest performance for styrene hydrogenation was obtained. The improved photoredox activity of the title nanohybrid could be caused by the synergistic effects of the heterojunction of carbon nitride-Pd on TiO nanoparticles evidenced by photoluminescence spectra and catalytic reactions. The catalyst proved to be air-stable, robust, recyclable, and very active in the absence of any undesirable additives and reducing agents. Thus, this work presents a new protocol for improving the photocatalytic properties of semiconducting materials for various photocatalytic applications under environmentally friendly conditions.
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http://dx.doi.org/10.1021/acs.inorgchem.1c00603DOI Listing
July 2021

Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors.

Int J Mol Sci 2021 May 31;22(11). Epub 2021 May 31.

Institute of Pharmacy, Martin Luther University of Halle-Wittenberg, Kurt-Mothes-Str.3, 06120 Halle/Saale, Germany.

The chromatin reader protein Spindlin1 plays an important role in epigenetic regulation, through which it has been linked to several types of malignant tumors. In the current work, we report on the development of novel analogs of the previously published lead inhibitor . In an effort to improve the activity and explore the structure-activity relationship (SAR), a series of 21 derivatives was synthesized, tested in vitro, and investigated by means of molecular modeling tools. Docking studies and molecular dynamics (MD) simulations were performed to analyze and rationalize the structural differences responsible for the Spindlin1 activity. The analysis of MD simulations shed light on the important interactions. Our study highlighted the main structural features that are required for Spindlin1 inhibitory activity, which include a positively charged pyrrolidine moiety embedded into the aromatic cage connected via a propyloxy linker to the 2-aminoindole core. Of the latter, the amidine group anchor the compounds into the pocket through salt bridge interactions with Asp184. Different protocols were tested to identify a fast in silico method that could help to discriminate between active and inactive compounds within the series. Rescoring the docking poses with MM-GBSA calculations was successful in this regard. Because is known to be a G9a inhibitor, the most active developed Spindlin1 inhibitors were also tested over G9a and GLP to verify the selectivity profile of the analogs. This resulted in the discovery of diverse selective compounds, among which and showed Spindlin1 activity in the nanomolar range and selectivity over G9a and GLP. Finally, future design hypotheses were suggested based on our findings.
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http://dx.doi.org/10.3390/ijms22115910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199216PMC
May 2021

Metabolic reprogramming of inner ear cell line HEI-OC1 after dexamethasone application.

Metabolomics 2021 05 24;17(6):52. Epub 2021 May 24.

Department of Otorhinolaryngology-Head and Neck Surgery, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, 06120, Halle (Saale), Germany.

Introduction: One approach to dampen the inflammatory reactions resulting from implantation surgery of cochlear implant hearing aids is to embed dexamethasone into the matrix of the electrode carrier. Possible side effects for sensory cells in the inner ear on the metabolomics have not yet been evaluated.

Objective: We examined changes in the metabolome of the HEI-OC1 cell line after dexamethasone incubation as a cell model of sensory cells of the inner ear.

Results And Conclusion: Untargeted GC-MS-profiling of metabolic alterations after dexamethasone treatment showed that dexamethasone had antithetical effects on the metabolic signature of the cells depending on growth conditions. The differentiated state of HEI-OC1 cells is better suited for elucidating metabolic changes induced by external factors. Dexamethasone treatment of differentiated cells led to an increase in intracellular amino acids and enhanced glucose uptake and β-oxidation in the cells. Increased availability of precursors for glycolysis and ATP production by β-oxidation stabilizes the energy supply in the cells, which could be assumed to be beneficial in coping with cellular stress. We found no negative effects of dexamethasone on the metabolic level, and changes may even prepare sensory cells to better overcome cellular stress following implantation surgery.
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http://dx.doi.org/10.1007/s11306-021-01799-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144088PMC
May 2021

Rhodium-Catalyzed Stereoselective Cyclization of 3-Allenylindoles and -Allenyltryptamines to Functionalized Vinylic Spiroindolenines.

Org Lett 2021 05 26;23(9):3788-3792. Epub 2021 Apr 26.

Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertstr. 21, 79104 Freiburg, Germany.

Herein, we report a highly enantio- and diastereoselective rhodium-catalyzed cyclization of -allenyltryptamines and 3-allenylindoles to 6-membered spirocyclic indolenines. This allylic addition methodology offers the advantage of using a comparably cheap commercially available ligand with low loadings of an affordable rhodium precursor. The products can be converted into functionalized spirooxindoles and spiroindolines, which are regarded as important building blocks for the synthesis of a lot of natural products with biological activities.
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http://dx.doi.org/10.1021/acs.orglett.1c01234DOI Listing
May 2021

Copper-Catalyzed Cycloisomerization of Unactivated Allene-Tethered -Propargyl Oximes: A Domino Reaction Sequence toward the Synthesis of Hexahydropyrrolo[3,4-]azepin-5(4)-ones.

Org Lett 2021 May 12;23(9):3343-3348. Epub 2021 Apr 12.

Institut fur Organische Chemie, Albert-Ludwigs-Universitat Freiburg Albertstrasse 21, 79104 Freiburg im Breisgau, Germany.

A novel copper-catalyzed cycloisomerization of unactivated allene-tethered propargyl oximes has been developed for the synthesis of hexahydropyrrolo[3,4-]azepin-5(4)-ones. This one-pot domino reaction proceeds via a [2,3]-sigmatropic rearrangement, a [3 + 2] cycloaddition, and another [3,3]-sigmatropic rearrangement. The methodology offers a practical and straightforward route for the rapid assembly of both ring components of the fused bicyclic motifs from acyclic precursors by simultaneously forming four new bonds (a C═O, a C═N, and two C-C bonds) in a single step.
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http://dx.doi.org/10.1021/acs.orglett.1c00837DOI Listing
May 2021

Addition of Chloroprene Grignards to Aromatic Aldehydes: Synthesis of Homoallenyl Alcohols.

Org Lett 2021 04 17;23(7):2621-2625. Epub 2021 Mar 17.

Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertstrasse 21, Freiburg 79104, Germany.

A general procedure for the one-pot synthesis of racemic homoallenyl alcohols from the corresponding aldehyde and chloroprene-derived Grignards is described. Employing bis[2-dimethylaminoethyl]ether (BDMAEE) as an additive at low temperatures shifts the selectivity of the chloroprene Grignard addition to aldehydes such that it is almost exclusive toward allene formation. In a set of follow-up experiments, simple and more elaborate methods for further derivatization have been demonstrated, allowing quick access to more complex structures.
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http://dx.doi.org/10.1021/acs.orglett.1c00527DOI Listing
April 2021

Metal-Free Domino Oligocyclization Reactions of Enynals and Enynones with Molecular Oxygen.

Org Lett 2021 Feb 4;23(4):1291-1295. Epub 2021 Feb 4.

Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertstrasse 21, D-79104 Freiburg im Breisgau, Germany.

A novel metal-free direct addition of molecular oxygen to the C-C triple bond toward benzannulated oxygen-bridged seven-membered ring systems and aza[3.1.0]bicycle skeletons under O atmosphere has been described. The reaction proceeds through at least three intramolecular C-O and C-C bond forming steps via green, simple, and unprecedented domino radical processes with high selectivity and good yields.
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http://dx.doi.org/10.1021/acs.orglett.0c04272DOI Listing
February 2021

Urea-Substituted Tetramethylcyclopentadienyl Ligands for Supramolecularly Accelerated Rh -Catalyzed ortho-C-H Olefination of Benzoic Acid Derivatives.

Chemistry 2021 Feb 18;27(8):2643-2648. Epub 2021 Jan 18.

Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertstraße 21, 79104, Freiburg, Germany.

The design and synthesis of air-stable and conveniently crystallizable Rh -cyclopentadienyl catalysts substituted with a urea moiety, which are able to accelerate the C-H olefination of benzoic acid derivatives, is reported. Through kinetic studies and NMR titration experiments, the catalysts' substrate recognition ability mediated by hydrogen bonding was identified to be the reason for this effect. Introduction of pyridone-phosphine ligands capable of forming additional H-bond interactions increased the catalytic performance even further. By unveiling a proportionality between reaction rate and relative complex formation enthalpy the hypothesis of a supramolecular catalyst preformation was supported. Its application to a variety of substrates proved the catalyst system's advantages, generally increasing the yields when compared to the results obtained with widely used [RhCp*Cl ] .
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http://dx.doi.org/10.1002/chem.202005130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898290PMC
February 2021

4-Acyl Pyrroles as Dual BET-BRD7/9 Bromodomain Inhibitors Address BETi Insensitive Human Cancer Cell Lines.

J Med Chem 2020 12 4;63(24):15603-15620. Epub 2020 Dec 4.

Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, Hermann-Herder-Str. 8, D-79104 Freiburg, Germany.

Various malignant human diseases show disturbed signaling pathways due to increased activity of proteins within the epigenetic machinery. Recently, various novel inhibitors for epigenetic regulation have been introduced which promise a great therapeutic benefit. Inhibitors for the bromo- and extra-terminal domain (BET) family were of particular interest after inhibitors had shown a strong antiproliferative effect. More recently, the focus has increasingly shifted to bromodomains (BDs) outside the BET family. Based on previously developed inhibitors, we have optimized a small series of 4-acyl pyrroles, which we further analyzed by ITC, X-ray crystallography, selectivity studies, the NCI60 cell-panel, and GI determinations for several cancer cell lines. The inhibitors address both, BET and BRD7/9 BDs, with very high affinity and show a strong antiproliferative effect on various cancer cell lines that could not be observed for BD family selective inhibitors. Furthermore, a synergistic effect on breast cancer (MCF-7) and melanoma (SK-MEL-5) was proven.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00478DOI Listing
December 2020

Rhodium-Catalyzed Cyclization of Terminal and Internal Allenols: An Atom Economic and Highly Stereoselective Access Towards Tetrahydropyrans.

Angew Chem Int Ed Engl 2020 12 26;59(52):23485-23490. Epub 2020 Oct 26.

Institute for Organic Chemistry, Albert-Ludwigs-Universität Freiburg, Albertstraße 21, 79104, Freiburg im Breisgau, Germany.

A comprehensive study of a diastereoselective Rh-catalyzed cyclization of terminal and internal allenols is reported. The methodology allows the atom economic and highly syn-selective access to synthetically important 2,4-disubstituted and 2,4,6-trisubstituted tetrahydropyrans (THP). Furthermore, its utility and versatility are demonstrated by a great functional-group compatibility and the enantioselective total synthesis of (-)-centrolobine.
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http://dx.doi.org/10.1002/anie.202009166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756761PMC
December 2020

Syntheses of Thailandepsin B Pseudo-Natural Products: Access to New Highly Potent HDAC Inhibitors via Late-Stage Modification.

Chemistry 2020 Dec 3;26(69):16241-16245. Epub 2020 Nov 3.

Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertstr. 21, 79104, Freiburg, Germany.

New Thailandepsin B pseudo-natural products have been prepared. Our synthetic strategy offers the possibility to introduce varying warheads via late stage modification. Additionally, it gives access to the asymmetric branched allylic ester moiety of the natural product in a highly diastereoselective manner applying rhodium-catalyzed hydrooxycarbonylation. The newly developed pseudo-natural products are extremely potent and selective HDAC inhibitors. The non-proteinogenic amino acid d-norleucine was obtained enantioselectively by a recently developed method of rhodium-catalyzed hydroamination.
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http://dx.doi.org/10.1002/chem.202002449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756392PMC
December 2020

Ionic-liquid-modified CMK-3 as a support for the immobilization of molybdate ions (MoO): Heterogeneous nanocatalyst for selective oxidation of sulfides and benzylic alcohols.

Mater Sci Eng C Mater Biol Appl 2020 May 7;110:110577. Epub 2020 Jan 7.

Department of Chemistry, Payame Noor University, Tehran, Iran. Electronic address:

A nanometric carbon CMK-3 modified with octylimidazolium ionic liquid and MoO as a new hybrid catalyst was synthesized. The study is the first to report a successful immobilization of MoO on the CMK-3/OctIm as a hybrid nanocatalyst. A variety of analytical methods were utilized to determine the properties of the structure and morphology of the synthesized nanocatalyst [CMK-3/Im/MoO]. The analytical techniques were transmission electron microscopy (TEM), scanning electron microscope (SEM), energy-dispersive X-ray spectroscopy (EDS), inductively coupled plasma (ICP), X-ray diffraction (XRD), N isotherms (BET), IR spectroscopy and thermogravimetric analysis (TGA). CMK-3/OctIm/MoO hybrid catalyst demonstrated a considerable catalytic activity. It is a recyclable nanocatalyst that is utilized to chemoselectively oxidize different types of sulfides to the corresponding sulfoxides and benzylic alcohols to aldehydes using the green oxidant, hydrogen peroxide (HO) in high-yields. With a little leaching and variation in activity, it is possible to recover and reuse the catalyst frequently. A combination of molybdate anion and the CMK-3 order mesoporous carbon resulted in an improvement in the performance of catalysis and ease of separation for the reaction procedure.
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http://dx.doi.org/10.1016/j.msec.2019.110577DOI Listing
May 2020

Rhodium-catalyzed asymmetric intramolecular hydroarylation of allenes: access to functionalized benzocycles.

Chem Sci 2019 Nov 10;10(43):10048-10052. Epub 2019 Sep 10.

Institut für Organische Chemie , Albert-Ludwigs-Universität Freiburg , Albertstrasse 21 , 79104 Freiburg im Breisgau , Germany . Email:

A rhodium-catalyzed regio- and enantioselective cyclization of tethered allenylbenzenes is reported. Employing a Rh/Josiphos catalytic system a diverse set of 6-membered, α-chiral benzocycles were obtained, scaffolds found in many bioactive compounds. Moreover, a gram scale reaction as well as the application of suitable transformations are demonstrated.
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http://dx.doi.org/10.1039/c9sc03894aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977554PMC
November 2019

Asymmetric Total Syntheses of (-)-Angustureine and (-)-Cuspareine via Rhodium-Catalyzed Hydroamination.

Org Lett 2020 01 26;22(2):565-568. Epub 2019 Dec 26.

Institut für Organische Chemie , Albert-Ludwigs-Universität Freiburg , Albertstr. 21 , 79104 Freiburg im Breisgau , Germany.

Concise syntheses of the Hancock alkaloids (-)-angustureine and (-)-cuspareine are presented, applying and refining a recently developed rhodium-catalyzed hydroamination for the stereoselective construction of the chiral secondary amine. Furthermore, the syntheses include an allene synthesis via boron-magnesium exchange as well as the construction of the tetrahydroquinoline motive via a hydroboration/Suzuki-Miyaura coupling sequence.
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http://dx.doi.org/10.1021/acs.orglett.9b04334DOI Listing
January 2020

Ligand-Mediated Regioselective Rhodium-Catalyzed Benzotriazole-Allene Coupling: Mechanistic Exploration and Quantum Chemical Analysis.

Chemistry 2020 Feb 4;26(11):2342-2348. Epub 2020 Feb 4.

Department of Theoretical Chemistry, Amsterdam Center for Multiscale Modeling (ACMM), Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081, HV, Amsterdam, The Netherlands.

The ligand-controlled rhodium-catalyzed regioselective coupling of 1,2,3-benzotriazoles and allenes was investigated by DFT calculations. Because allylation can occur at either the N1 or N2 position of the 1,2,3-benzotriazole, the complete Gibbs free energy profiles for both pathways were computed. A kinetic preference emerged for the experimentally observed N1 allylation with the JoSPOphos ligand, whereas N2 allylation was favored with DPEphos. Analysis of the regiodetermining oxidative addition step by using the activation strain model in conjunction with a matching energy decomposition analysis has revealed that the unprecedented N2 reaction regioselectivity is dictated by the strength of the electrostatic interactions between the 1,2,3-benzotriazole and the rhodium catalyst. The nature of the electrostatic interaction was rationalized by analysis of the electrostatic potential maps and Hirshfeld charges: a stabilizing electrostatic interaction was found between the key atoms involved in the oxidative addition for the N2 pathway, analogous interactions are weaker in the N1 case.
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http://dx.doi.org/10.1002/chem.201905359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064967PMC
February 2020

Rhodium-Catalyzed Diastereo- and Enantioselective Tandem Spirocyclization/Reduction of 3-Allenylindoles: Access to Functionalized Vinylic Spiroindolines.

Org Lett 2019 12 26;21(23):9672-9676. Epub 2019 Nov 26.

Institut für Organische Chemie , Albert-Ludwigs-Universität Freiburg , Albertrstr. 21 , 79104 Freiburg , Germany.

A highly selective rhodium-catalyzed tandem spirocyclization/reduction of 3-allenylindoles is reported. By employing a Hantzsch ester as reductant, vinylic spiroindolines are obtained in excellent yields as well as diastereo- and enantioselectivity. In addition, the reaction's synthetic utility is highlighted by broad functional group compatibility and exemplified by a gram scale reaction with subsequent assorted transformations.
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http://dx.doi.org/10.1021/acs.orglett.9b03835DOI Listing
December 2019

A domino reaction for generating β-aryl aldehydes from alkynes by substrate recognition catalysis.

Nat Commun 2019 10 25;10(1):4868. Epub 2019 Oct 25.

Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.

The development of universal catalyst systems that enable efficient, selective, and straightforward chemical transformations is of immense scientific importance. Here we develop a domino process comprising three consecutive reaction steps based on the strategy of supramolecular substrate recognition. This approach provides valuable β-aryl aldehydes from readily accessible α-alkynoic acids and arenes under mild reaction conditions, employing a supramolecular Rh catalyst containing an acylguanidine-bearing phosphine ligand. Furthermore, the synthesis of a key intermediate of Avitriptan using this protocol is accomplished. The first step of the reaction sequence is proved to be the regioselective hydroformylation of α-alkynoic acids. Remarkably, molecular recognition of the ligand and the substrate via hydrogen bonding plays a key role in this step. Control experiments indicate that the reaction further proceeds via 1,4-addition of an arene nucleophile to the unsaturated aldehyde intermediate and subsequent decarboxylation.
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http://dx.doi.org/10.1038/s41467-019-12770-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814718PMC
October 2019

Visible-Light-Driven Intermolecular Reductive Ene-Yne Coupling by Iridium/Cobalt Dual Catalysis for C(sp )-C(sp ) Bond Formation.

Chemistry 2019 Dec 8;25(69):15746-15750. Epub 2019 Nov 8.

Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertstr. 21, 79104, Freiburg, Germany.

A new methodology to form C(sp )-C(sp ) bonds by visible-light-driven intermolecular reductive ene-yne coupling has been successfully developed. The process relies on the ability of the Hantzsch ester to contribute in both SET and HAT processes through a unified cobalt and iridium catalytic system. This procedure avoids the use of stoichiometric amounts of reducing metallic reagents, which is translated into high functional-group tolerance and atom economy.
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http://dx.doi.org/10.1002/chem.201903708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916364PMC
December 2019

Synthesis of 2-(Isoquinolin-1-yl)prop-2-en-1-ones via Silver(I)-Catalyzed One-Pot Tandem Reaction of -Alkynylbenzaldoximes with Propargylic Alcohols.

Org Lett 2019 Sep 9;21(18):7645-7648. Epub 2019 Sep 9.

Institut für Organische Chemie , Albert-Ludwigs-Universität Freiburg , Albertstrasse 21 , 79104 Freiburg im Breisgau , Germany.

The silver(I)-catalyzed reaction of -alkynylbenzaldoximes with propargylic alcohols represents a new strategy for the divergent one-pot synthesis of 2-(isoquinolin-1-yl) prop-2-en-1-ones via tandem 6--cyclization, 1,3-dipolar cycloaddition, and intramolecular dehydrative opening of the 2,3-dihydroisoxazole ring. This synthetic protocol tolerates a wide variety of -alkynylbenzaldoximes and propargylic alcohols and affords the corresponding products in excellent yields.
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http://dx.doi.org/10.1021/acs.orglett.9b02952DOI Listing
September 2019

Needle ball-like nanostructured mixed Cu-Ni-Co oxides: Synthesis, characterization and application to the selective oxidation of sulfides to sulfoxides.

Mater Sci Eng C Mater Biol Appl 2019 Oct 30;103:109814. Epub 2019 May 30.

Department of Chemistry, Payame Noor University, Tehran, Iran.

A mixed nano-metal oxides of Cu-Ni-Co has been synthesized. Several characterization techniques (EDS, XRD, TEM, and SEM) have been used to provide insight into the nature and structure of the catalyst. The size of this mixed metal oxide is 22 nm. The SEM images indicate that the sample with spherical particles, of which spherical assembly is comprised of elongated rod/needle-like subunits pointing radially outward, creates a needle ball-like structure. To efficiently catalyze the selective oxidation of sulfide towards sulfoxide, this heterogeneous catalyst uses an oxidizing agent (hydrogen peroxide- HO) and a solvent (acetonitrile) in mild conditions. The influence of reaction temperature and sulfide/oxidant molar ratio was evaluated with respect to sulfide conversion and chemoselectivity towards the sulfoxide product. Under optimized conditions, product yields in the range from 70 to 97% were obtained.
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http://dx.doi.org/10.1016/j.msec.2019.109814DOI Listing
October 2019

Chemo-, regio-, and enantioselective synthesis of allylic nitrones via rhodium-catalyzed addition of oximes to allenes.

Chem Commun (Camb) 2019 Jul 13;55(53):7619-7622. Epub 2019 Jun 13.

Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertstrasse 21, 79104 Freiburg im Breisgau, Germany.

The first chemo-, regio-, and enantioselective rhodium-catalyzed addition of oximes to allenes is reported. Using a Rh(i)/Josiphos catalyst system under mild conditions, the construction of allylic C-N bonds instead of C-O bonds was achieved. This method permits the atom-economic synthesis of branched allylic nitrones in good to quantitative yields with excellent enantioselectivities.
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http://dx.doi.org/10.1039/c9cc03391bDOI Listing
July 2019

A rhodium catalyzed cycloisomerization and tandem Diels-Alder reaction for facile access to diverse bicyclic and tricyclic heterocycles.

Chem Sci 2019 May 3;10(18):4805-4810. Epub 2019 Apr 3.

Institut für Organische Chemie und Biochemie , Albert-Ludwigs-Universität , Alberstr. 21 , 79104 Freiburg , Germany . Email:

A regioselective distal cycloisomerization of 1,6-allenenes was successfully developed to afford six-membered ring exocyclic 1,3-dienes employing a rhodium/diphosphine catalyst system. Deuterium labelling experiments and DFT calculations were performed to provide insights into the reaction mechanism of this unprecedented transformation. In addition, one-pot tandem Diels-Alder reactions with various dienophiles could readily construct diverse bicyclic and tricyclic nitrogen heterocycles, which are ubiquitous core scaffolds for a variety of natural products and bioactives. High efficiency and exclusive chemo and regioselectivities for a broad substrate scope were achieved under mild conditions using a low catalyst loading of 0.5 mol%.
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http://dx.doi.org/10.1039/c9sc00980aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521805PMC
May 2019
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