Dirk Menche

University of Bonn, Bonn, North Rhine-Westphalia, Germany

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Publications (76)377.43 Total impact

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    ABSTRACT: Inspired by the bioactive natural metabolites leupyrrin A1 and B1 , two novel stereoselective methods for the highly concise synthesis of densely substituted α-chiral butyrolactones are reported. The first approach relies on an innovative three-step Ti(III) -catalyzed radical reaction that proceeds with excellent chemo-, regio-, and stereoselectivity. The alternative route utilizes sequential asymmetric alkylations and enables asymmetric synthesis of the authentic α-tetrasubstituted butyrolactone motif of the leupyrrins in only four steps from commercially available substrates.
    Chemistry - A European Journal 09/2015; DOI:10.1002/chem.201502263 · 5.73 Impact Factor
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    ABSTRACT: A general new method for the highly concise synthesis of C-1-alkylated tetrahydroisoquinolines (THIQ) is reported. The CuCl2-catalyzed procedure is based on a coupling of nonfunctionalized THIQs with organozinc reagents under aerobic conditions. It proceeds in high yields and is broadly applicable to a wide range of substrates. It relies on a regioselective sp(3) C-H bond activation allowing for an sp(3)-sp(3) bond union under mild reaction conditions in a rapid and effective manner. Mechanistically it involves an iminium ion intermediate that is formed via an organic radical involving a single-electron-transfer process. For the first time for this type of reaction a radical intermediate has been proven by EPR spectroscopy.
    Organic Letters 08/2015; 17(16). DOI:10.1021/acs.orglett.5b01845 · 6.36 Impact Factor
  • Björn Schmalzbauer · Dirk Menche
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    ABSTRACT: A concise synthesis of the tricyclic core 2 of the structurally unique marine myxobacterial natural product salimabromide has been developed. Compound 2 contains the tetraline subunit including the two quaternary centers and the eight-membered ring of salimabromide. Major features for its synthesis include a Lewis base catalyzed Denmark-crotylation for stereoselective construction of the highly hindered quaternary stereocenter, an innovative iodine/selectfluor induced endo-carbocylization, and a unique chemoselective carbonylative lactonization of the eight-membered ring.
    Organic Letters 05/2015; 17(12). DOI:10.1021/acs.orglett.5b01231 · 6.36 Impact Factor
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    ABSTRACT: The stereochemical determination of the potent antifungal agents leupyrrin A1 and B1 and the total synthesis of leupyrrin A1 are reported. The relative and absolute configuration was determined by a combination of high field NMR studies, molecular modeling and chemical derivatization. The expedient total synthesis involves a one-pot sequential Zr-mediated oxidative diyne-cyclization/regioselective opening sequence for preparation of the unique dihydrofuran ring, a highly stereoselective one-pot approach to the butyrolactone, a challenging sp2-sp3-Suzuki coupling and a high-yielding Shiina macrolactonization.
    Journal of the American Chemical Society 03/2015; 137(12). DOI:10.1021/jacs.5b01894 · 12.11 Impact Factor
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    ABSTRACT: The natural products rhizopodin and bistramide belong to an elite class of highly potent actin binding agents. They show powerful antiproliferative activities against a range of tumor cell lines, with IC50 values in the low-nanomolar range. At the molecular level they disrupt the actin cytoskeleton by binding specifically to a few critical sites of G-actin, resulting in actin filament stabilization. The important biological properties of rhizopodin and bistramide, coupled with their unique and intriguing molecular architectures, render them attractive compounds for further development. However, this is severely hampered by the structural complexity of these metabolites. We initiated an interdisciplinary approach at the interface between molecular modeling, organic synthesis, and chemical biology to support further biological applications. We also wanted to expand structure–activity relationship studies with the goal of accessing simplified analogues with potent biological properties. We report computational analyses of actin–inhibitor interactions involving molecular docking, validated on known actin binding ligands, that show a close match between the crystal and modeled structures. Based on these results, the ligand shape was simplified, and more readily accessible rhizopodin–bistramide mimetics were designed. A flexible and modular strategy was applied for the synthesis of these compounds, enabling diverse access to dramatically simplified rhizopodin–bistramide hybrids. This novel analogue class was analyzed for its antiproliferative and actin binding properties.
    ChemMedChem 01/2015; 10(3). DOI:10.1002/cmdc.201402508 · 2.97 Impact Factor
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    ABSTRACT: The macrolide archazolid inhibits vacuolar-type H(+)-ATPase (V-ATPase), a proton-translocating enzyme involved in protein transport and pH regulation of cell organelles, and potently suppresses cancer cell growth at low nanomolar concentrations. In view of the growing link between inflammation and cancer, we investigated whether inhibition of V-ATPase by archazolid may affect primary human monocytes that can promote cancer by sustaining inflammation through the release of tumor-promoting cytokines. Human primary monocytes express V-ATPase, and archazolid (10 to 100nM) increases the vesicular pH in these cells. Archazolid (10nM) markedly reduced the release of pro-inflammatory (TNF-α, interleukin-6 and -8) but also of anti-inflammatory (interleukin-10) cytokines in monocytes stimulated with LPS, without affecting cell viability up to 1000nM. Of interest, secretion of interleukin-1β was increased by archazolid. Comparable effects were obtained by the V-ATPase inhibitors bafilomycin and apicularen. The phosphorylation of p38 MAPK and ERK-1/2, Akt, SAPK/JNK or of the inhibitor of NFκB (IκBα) as well as mRNA expression of IL-8 were not altered by archazolid in LPS-stimulated monocytes. Instead, archazolid caused endoplasmic reticulum (ER) stress response visualized by increased BiP expression and accumulation of IL-8 (and TNF-α) at the ER, indicating a perturbation of protein secretion. In conclusion, by interference with V-ATPase, archazolid significantly affects the secretion of cytokines due to accumulation at the ER which might be of relevance when using these agents for cancer therapy.
    Biochemical Pharmacology 08/2014; 91(4). DOI:10.1016/j.bcp.2014.07.028 · 5.01 Impact Factor
  • Thomas Debnar · Dirk Menche
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    ABSTRACT: Polyketides are prevalent structural features in numerous natural products with a broad range of biological activities and pharmacological properties and polyketide antibiotics, antifungals, cytostatics, antiparasitics, and natural insecticides are in commercial use. Biosynthetically, they are derived by iterative condensations of acetyl and propionyl subunits giving rise to diverse assemblies of methyl and hydroxyl-bearing stereogenic centers and thus enabling very large numbers of stereochemical permutations and structures with very complexity and diversity. Despite impressive accomplishments and progress in the synthesis of these structures in recent years, there remains a high need for the development of more efficient synthetic methods to assemble these structures in a more direct and convergent manner. Sequential catalytic sequences are particularly desirable as they combine several synthetic transformations in a one-pot process and thus enable the rapid assembly of complex architectures. Herein, the design, development, and application of innovative sequential concepts are reported, including a novel domino reaction relying on a combination of a nucleophilic addition and a Tsuji–Trost reaction and a sequence relying on an oxidative diyne cyclization and regioselective opening of the intermediate metallacycles. These methods enable a highly concise synthesis of key structural elements of complex polyketides.
    Molecular Catalysts, 06/2014: pages 299-312; , ISBN: 9783527335213
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    ABSTRACT: Covering: the literature up to 2012This review presents recent advances in sequential catalytic methods developed in our group for the rapid and stereoselective synthesis of key structural features of complex polyketides. These include a novel domino reaction, based on a combination of a nucleophilic addition and a Tsuji-Trost reaction, an innovative sequence relying on an oxidative diyne cyclization and regioselective opening, as well as sequential cross coupling strategies. The design and scope of these methods are discussed and applications in complex target syntheses presented.
    Natural Product Reports 12/2013; 31(4). DOI:10.1039/c3np70093c · 10.11 Impact Factor
  • Sebastian Essig · Dirk Menche
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    ABSTRACT: Polyketides are a very diverse family of natural products with an extremely broad range of biological activities and pharmacological properties, including antiproliferative, antibiotic, antifungal, or antiplasmodial activities, and in many cases specific targets are addressed at the molecular level. Their structures are characterized by diverse assemblies of methyl- and hydroxyl-bearing stereogenic centers enabling large numbers of stereochemical permutations, which are often embedded into macrolide rings. This complexity renders the stereochemical assignment and directed total synthesis challenging tasks. Within this review, we will detail practicable approaches for the stereochemical determination of diverse complex polyketides of myxobacterial origin by using computational and NMR methods in combination with novel procedures based on bioinformatics. Furthermore, we have developed efficient preparative strategies for the synthesis of these compounds, which have culminated in several first total syntheses. Key aspects of these various endeavors, which will also focus on the importance of conformational bias in complex polyketide analysis and synthesis, will be discussed within this review in the realm of the potent macrolide antibiotics etnangien and rhizopodin. Along these lines, we will also summarize novel methods for the rapid assembly of key structural elements of polyketides including a novel domino concept relying on a combination of a nucleophilic addition and a Tsuji-Trost reaction.
    ChemInform 10/2013; 44(42). DOI:10.1002/chin.201342247
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    ABSTRACT: A highly convergent total synthesis of the potent polyketide macrolide rhizopodin has been achieved in 29 steps by employing a concise strategy that exploits the molecule's C2 symmetry. Notable features of this convergent approach include a rapid assembly of the macrocycle through a site-directed sequential cross-coupling strategy and the bidirectional attachment of the side chains by means of Horner-Wadsworth-Emmons (HWE) coupling reactions. During the course of this endeavor, scalable routes for synthesis of three main building blocks of similar complexity were developed that allowed for their stereocontrolled construction. This modular route will be amenable to the development of syntheses of other analogues of rhizopodin.
    Chemistry - A European Journal 10/2013; 19(47). DOI:10.1002/chem.201302197 · 5.73 Impact Factor
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    ABSTRACT: The aldol addition of an enol(ate) to a carbonyl compound is one of the most powerful and versatile C-C bond forming reactions. In complex target synthesis the coupling of two chiral partners may complicate the stereochemical outcome by multiple stereoinductions. Here, we report studies on pivotal aldol couplings employed in the rhizopodin synthesis, detailing the various directing effects exerted by the stereogenic centers present in this sterically hindered connection.
    Synthesis 08/2013; 45(16):2305-2315. DOI:10.1055/s-0033-1338493 · 2.69 Impact Factor
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    ABSTRACT: Marine myxobacteria (Enhygromyxa, Plesiocystis, Pseudoenhygromyxa, Haliangium) are phylogenetically distant from their terrestrial counterparts. Salimabromide is the first natural product from the Plesiocystis/Enhygromyxa clade of obligatory marine myxobacteria. Salimabromide has a new tetracyclic carbon skeleton, comprising a brominated benzene ring, a furano lactone residue, and a cyclohexane ring, bridged by a seven-membered cyclic moiety. The absolute configuration was deduced from experimental and calculated CD data. Salimabromide revealed antibiotic activity towards Arthrobacter cristallopoietes.
    Chemistry - A European Journal 07/2013; 19(28). DOI:10.1002/chem.201301379 · 5.73 Impact Factor
  • Liang Wang · Dirk Menche
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    ABSTRACT: Pd-catalyzed treatment of unsaturated alcohols of type (I) with nitro olefins provides a new and efficient approach to multisubstituted tetrahydropyrans, which are of synthetic and biological interest.
    ChemInform 06/2013; 44(23). DOI:10.1002/chin.201323126
  • Thomas Debnar · Tongtong Wang · Dirk Menche
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    ABSTRACT: Stereoselective syntheses of the Northern and the Southern fragments 2 and 3 of leupyrrin A1 are reported. The convergent preparation of 2 is highlighted by a zirconocene-mediated one-pot cyclization-regioselective opening of an advanced diyne while the route to 3 involves a Krische allylation and a one-pot Sharpless dihydroxylation-cyclization. Comparison of the spectroscopic data with those reported for the natural product supports a relative stereochemical assignment within these heterocycles.
    Organic Letters 05/2013; 15(11). DOI:10.1021/ol401110x · 6.36 Impact Factor
  • Liang Wang · Dirk Menche
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    ABSTRACT: Designed, developed, and applied: A novel domino sequence was used for the rapid assembly of acetal-protected syn 1,3-diols. The convergent synthesis of a polyol fragment of the macrolide antibiotic RK-397 demonstrates that this method is suitable for the rapid and stereoselective preparation of polyketide-type diol motifs.
    Angewandte Chemie International Edition 02/2013; 51(37):9425-7. DOI:10.1002/anie.201203911 · 11.26 Impact Factor
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    ABSTRACT: A concise total synthesis of dysidavarone A possessing the new "dysidavarane" carbon skeleton has been accomplished by a convergent strategy, involving a stereoselective reductive alkylation of a Wieland-Miescher type ketone under Birch conditions and an advantageous intramolecular palladium-catalyzed α-arylation of a sterically hindered ketone. Dysidavarone A showed potent antimicrobial and antiproliferative activities based on characteristic morphological changes of treated cells.
    Organic Letters 02/2013; 15(4). DOI:10.1021/ol400156u · 6.36 Impact Factor
  • Michael Dieckmann · Dirk Menche
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    ABSTRACT: A novel domino process for 1,3-anti diol synthesis by the union of a methyl ketone with an aldehyde is described. The operationally simple procedure is based on an Ipc-boron-aldol coupling and subsequent Ipc-mediated reduction of the intermediate β-hydroxy-ketone. The sequence proceeds with excellent anti-selectivities and enables the rapid construction of complex polyketide fragments.
    Organic Letters 12/2012; 15(1). DOI:10.1021/ol3033303 · 6.36 Impact Factor
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    ABSTRACT: An efficient protocol for the highly regioselective opening of aliphatic zirconacyclopentadienes is reported. The one-pot process involves a zirconocene-mediated cyclization of 1,6-diynes and highly selective cleavage of the metallacycles with NBS and enables a concise synthesis of the tetrahydrofuran-core of the leupyrrins.
    Chemical Communications 12/2012; 49(7). DOI:10.1039/c2cc37678d · 6.83 Impact Factor
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    ABSTRACT: An efficient procedure for the concise synthesis of hetero-bis-metallated alkenes as useful building blocks for the modular access to highly elaborate polyenes and stabilized analogues is reported. By applying these bifunctional olefins in convergent Stille/Suzuki-Miyaura couplings, novel, carefully selected side chain analogues of the potent RNA polymerase inhibitor etnangien were synthesized by a modular late stage coupling strategy and evaluated for antibacterial and antiproliferative activities.
    Organic & Biomolecular Chemistry 11/2012; 11(13). DOI:10.1039/c2ob26906f · 3.56 Impact Factor
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    ABSTRACT: A highly convergent synthesis of the central dimeric core of the potent antibiotic macrolide rhizopodin is reported. Notable features of the highly concise route include an effective preparation of the key C8-C22 building block based on an Iridium-catalyzed Krische allylation and a chemoselective cross-coupling approach toward the macrocycle involving a highly advantageous Heck reaction for macrocyclization.
    The Journal of Organic Chemistry 11/2012; 77(23). DOI:10.1021/jo302134y · 4.72 Impact Factor

Publication Stats

985 Citations
377.43 Total Impact Points


  • 2011–2015
    • University of Bonn
      • Kekulé Institute of Organic Chemistry and Biochemistry
      Bonn, North Rhine-Westphalia, Germany
  • 2008–2012
    • Universität Heidelberg
      • Institute of Organic Chemistry
      Heidelburg, Baden-Württemberg, Germany
  • 2007–2011
    • Helmholtz Centre for Infection Research
      • • Department of Chemical Biology (CBIO)
      • • Department of Medicinal Chemistry (MCH)
      Brunswyck, Lower Saxony, Germany
  • 2005
    • University of Cambridge
      Cambridge, England, United Kingdom
  • 2003
    • University of Cologne
      • Institute of Organic Chemistry
      Köln, North Rhine-Westphalia, Germany