Intern
    Prof. Dr. G. Bringmann

    Computational Methods in Natural Products Chemistry

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    1. Key Words:

    Use of force field, semiempirical, density functional, and ab-initio methods for the computational calculation of structures, dynamics, and chemical reactivities of molecules; computational correlation of biological activities with molecular structures (SAR) (see 'Naphthylisoquinoline Alkaloids', see also www.sfb630.de), prediction of NMR shifts; simulation of IR, Raman, and UV spectra; quantum chemical calculations of circular dichroism (CD) spectra for the assignment of the absolute configuration of novel-type compounds with stereogenic centers, or with elements of axial, planar, or helical chirality, or combinations thereof (see also 'Naphthylisoquinoline Alkaloids', 'Anthraquinones and Knipholones', 'Marine Natural Products', 'The TaClo Concept', 'The Lactone Concept', and 'Natural Product Synthesis'); combination of LC-CD coupling with quantum chemical CD calculations for the online elucidation of the absolute stereostructures of chiral compounds, directly from the peak in the chromatogram (see also 'Natural Product Analysis'); intense collaboration between experimentally and theoretically working researchers within the group, and numerous collaborations with external scientists from organic, inorganic, and physical chemistry, natural product chemistry, pharmacy, pharmaceutical biology, plant biochemistry, marine research, and microbiology.


    For the calculations of ground-state properties, the following methods are in use:

    •    force fields (TRIPOS, MM3),
    •    semiempirical Hamiltonians (AM1, PM3),
    •    ab initio approaches (HF, MPn), and
    •    density functional theory (DFT).

    The excited-states computations are performed with:

    •    semiempirical Hamiltonians (CNDO/S, INDO/S, OM2) combined with CI calculations,
    •    time-dependent density functional theory (TDDFT), and
    •    multi-reference methods (DFT/MRCI, MR-MP2).

    2. Graphical Abstract:

    Subtopic A: Circular Dichroism (CD) Calculations – Theoretical Background

    Figure 1: Approaches for simulating the circular dichroism (CD): For the prediction of a most reliable theoretical CD spectrum, all possible conformational species that may influence the overall CD behavior of a chiral molecule have to be taken into consideration. To characterize these conformers, two different methods are in use: a classical conformational analysis (CA) and a molecular dynamics (MD) approach. From the resulting structures, single UV and CD spectra are calculated, summed up following the Boltzmann statistics, or averaged over the trajectory results of the MD-based simulations, to yield the overall theoretical spectrum. After UV correction, the comparison of the computationally predicted CD curve with the epxerimentally obtained CD spectrum finally permits attribution of the absolute configuration of a chiral natural or snythetic product. The quantum chemical calculations of CD spectra are not limited by structural restrictions, but can be performed for virtually any compound exhibiting central, axial, or planar chirality [1,4].

    Subtopic B: Absolute Stereostructures of Chiral Compounds by Quantum Chemical Calculation of CD Spectra

    Figure 2: Attribution of the absolute axial configurations of the configuratively stable biaryl amides 3 resulting from the atropo-diastereoselective cleavage of the configurationally unstable biaryl lactone 1 with L-valine methyl ester (2), by comparison of the measured CD spectra with the ones theoretically predicted for the two atropo-diastereomers, (P,S)-3 and (M,S)-3. The CD sprectra were obtained by semiempirical CNDO/S-Cl computations, based on a conformational analysis using the semiempirical AM1 method. – Single-crystal X-ray structure analysis of (P,S)-3 confirmed the constitution and the relative configuration and thus, given the known absolute L-configuration of the amino acid part, also fully corroborated the absolute axial P-configurational assignment by CD calculations [5].
    Figure 3: Attribution of the absolute configurations of the new dimeric anthracene derivatives abyquinone A (4) and B (5) from the fruits of the African plant Bulbine abyssinica (Asphodelaceae), by comparison of the experimental CD spectra with those obtained from semiempirical CD calculations, using the CNDO/S-CI approach as well as the OM2 Hamiltonian on the SCI and the SDCI levels. Obviously of biosynthetic relevance, abyquinone B (5) is converted to the axially chiral abyquinone A (4) upon aerial oxidation under basic conditions without any loss of enantiomeric purity, hinting at a highly efficient center-to-axis chiraltiy transfer as yet unprecedented for natural products [6].
    Figure 4: Determination of the absolute configuration of gephyromycin (6), the first angucyclinone with an intramolecular ether bridge, isolated from an extract of the antarctic Streptomyces griseus strain NTK 14, by comparison of the experimental CD spectrum of 6 (a) with the CD curves semiempirically (OM2) predicted for the two possible enantiomers of its tetraacetate 7, and (b) with the CD spectra calculated for the two possible enantiomers of 6 applying the time-dependent DFT (TDDFT) method using Becke's hybrid exchange correlation B3LYP functional and a TZVP basis set (triple-zeta valence basis set including polarization functions). The three-dimensional structure of gephyromycin was elucidated by NMR methods such as ROESY (full arrows) and COSY (dotted arrows) couplings, and substantiated by single-crystal X-ray diffraction [7].
    Figure 5: Assignment of the absolute configuration of sorbicillactone B (8), isolated from the saltwater culture of a Penicillium chrysogenum strain from the Mediterranean sponge Ircinia fasciculata (see also 'Marine Natural Products'), by comparison of the experimental CD spectrum with the spectra quantum chemically calculated for its two possible enantiomers, (5S,6R,9S)-8 and (5R,6S,9R)-8, computed by means of the CNDO/S Hamiltonian based on a molecular dynamics (MD) simulation using the TRIPOS force field. The MD simulation was carried out at a virtual temperature of 600 K. During a single MD run with a total period of 500 ps, 1000 single structures were collected. The calculations of these structures and their arithmetical averaging provided the overall theoretical CD spectra. Comparison with the experimental data showed a good agreement of the spectrum calculated for (5S,6R,9S)-8 with the one of the natural product, and a near-opposite curve of the one computed for (5R,6S,9R)-8 [8].
    Figure 6: Some chiral natural and synthetic products stereochemically attributed by theoretical CD investigations in our research group – a selection [9-18].

    Subtopic C: Combination of LC-CD Coupling with Quantum Chemical CD Calculations

    Figure 7: Simple and versatile one-pot synthetic pathway to a new type of functionalized axially chiral quateraryls like e.g., 9 (by Goel et al.), and its enantiomeric resolution by HPLC on a chiral OD-H phase with online CD analysis. Attribution of the configurationally stable atropoenantiomers was achieved by quantum chemical CD calculations, applying the semiempirical CNDO/S Hamiltonian and TDDFT (B3LYP/TZVP) method [19].
    Figure 8: Selected examples of stereochemical assignments by LC-CD coupling (chiral phases used for the respective enantiomeric resolutions shown in parantheses), combined with quantum chemical CD calculations [20-27].

    Subtopic D: Natural Products with Unusual CD Effects – Two Examples

    Figure 9: "Molecular Chirality": Stereochemistry of isoplagiochin C (10), a macrocyclic bisbibenzyl from liverworts. – A small asymmetry in the structure of isoplagiochin C – the blue drawn hydroxy function (see bottom part) – is responsible for the formation of a chiral compound with a distinctive CD effect: even though isoplagiochin C passes through all possible diastereomeric and pseudo-enantiomeric geometries, the ratio of their population is determined only by the above mentioned hydroxy function. Quantum chemical calculations, in particular investigations on the conformational space and molecular dynamics simulations, clearly revealed the helicity to be a property of the entire molecule, whose ring strain makes the molecule configurationally stable overall, with (formally) three stereogenic centers (two biaryl axes, A and B, and one helical stilbene unit, C). Only one of the biaryl axes (the 'upper' one), axis A, has a stable configuration, leading to a population of four interconverting diastereomers, yet without racemization at room temperature. The experimental overall enantiomerization barrier of 101.6 kJ/mol and the theoretically calculated one of 115.1 kJ/mol confirmed the expectation of a molecule that is configurationally stable at room temperature. On the basis on these conformational and dynamic calculations, quantum chemical CD calculations permitted assignment of the absolute configuration of isoplagiochin C and established its main stereoisomeric form to be P-configured at the stereochemically stable axis. Accordingly, isoplagiochin C is a mixture of diastereomers with respect to the other biaryl axis and the helical stilbene unit. The calculations further confirmed the helical structure of the molecule to be responsible for the distinct CD spectrum of isoplagiochin C. Determination of the enantiomeric ratio of this natural product, by chromatography on a chiral phase with CD-coupling, revealed that in Plagiochilla deflexa, isoplagiochin C occurs in a 85:15 ratio in favor of the enantiomer with P-configuration at the stereochemically stable axis [28,29].
    Figure 10: Cyclorocaglamide (12) from the tropical plant Aglaia oligophylla (Meliaceae) is the first bridged cyclopentatetrahydrobenzofuran, and it exhibits a CD spectrum virtually opposite that of all the other rocaglamide natural products known so far, but it still has the same absolute configuration at all stereogenic centers of the basic molecular framework. This was shown unequivocally by CD calculations (here based on MD-weighted force field structures) and was confirmed experimentally, by a biomimetic-type cyclization of the related 'open-chain' rocaglamide 11 to give 12, with the expected 'inversion' of the CD spectrum. The reason for this chiroptical 'inversion' is that in this case just a ring closure that does not involve any stereogenic center causes a near-enantiomeric preferential array of the chromophores and thus an inversion of the CD behavior. By freezing the rotation of one of the aromatic rings in 12, the molecule is forced into a conformation whose chromophores are a near-mirror image of those of 11 [30].

    3. Brief Description:

    One of the most efficient if not ideal methods for the attribution of the absolute configuration of chiral compounds is the investigation of their circular dichroism (CD), which is often done by an empirical comparison with the spectral data of related compounds of known absolute configurations. More specific approaches to the interpretation of CD spectra are the application of the octant rule or of the exciton chirality method; the use of the former however is restricted to centrochiral ketones, the second one to systems containing two (near-)identical chromophores. By contrast, these restrictions are avoided by the quantum chemical calculation of the CD spectra for both enantiomers of a chiral molecule and comparison of these predicted spectra with the experimental ones [1-4]. This procedure has become a most valuable tool for assigning absolute configurations to a broad variety of chiral compounds of synthetic or natural origin, involving all kinds of chirality, not only stereogenic centers, but also axial and / or planar chirality [5-30]. The consistently extended approach to calculate the circular dichroism of organic molecules often facilitated the experimental work of natural product chemists of our research group [i.a., 5,7,8,17,20-25] and that of our scientific partners [i.a., 6,10,12,14,18,19,28,30]. The chiral structures shown in the Figures 2-10 represent a selection of compounds whose absolute configurations had previously been unkown, but were clearly assigned by theoretical CD investigations in our group.
    Since the CD spectrum strongly depends on the molecular flexibility of the chromophors, more than for any other spectroscopic method, a detailed investigation of the conformational space is indispensable for the simulation of a CD curve. Starting with an arbitrarily chosen enantiomer of the chiral compound, a set of reasonable starting structures of the molecular framework is generated manually by taking into account the most relevant conformational freedom degrees of flexible substituents. These are then subjected to a refinement by investigating the corresponding rotations, usually at a semiempirical level (AM1, PM3), in order to find all minimum geometries that are significantly populated at ambient temperature. For all conformers thus obtained within an energetic cut-off of 3 kcal/mol above the global minimum, the single CD spectra are calculated and added up following the Boltzmann statistics, i.e., according to their energetic contents (see examples in Figure 2, Figure 3, Figure 4, and Figure 7).
    For more flexible molecules, the absolute configuration can be assigned by replacing the AM1-/Boltzmann-based calculation by a molecular dynamics (MD) simulation, using different force fields like TRIPOS or MM3. Within this approach the different geometries for the calculation of the single CD spectra are extracted from the trajectory of the MD simulation. Averaging these single spectra over the trajectory results in the MD-based theoretical overall CD spectrum (see examples in Figure 5, Figure 9, and Figure 10).
    In order to receive trustable wave functions for the ground state and the excited states, together with the corresponding energies, several methodologies are applicable. The most common one is the configuration interaction (CI) approach. Based on this method, our group has frequently applied the semiempirical CNDO/S and OM2 Hamiltonians with a CI expansion that covers single excitations (e.g., see Figure 2, Figure 3, Figure 4, and Figure 5). However, to account for the dynamic electron correlation, at least the double excitations have to be included in the CI progression, since the mere single ones do not interact with the ground state wave function. This is accounted for by likewise performing OM2-CISD calculations (see, e.g., Figure 3 and Figure 7) [1,2,4].
    Another technique to compute electronic transitions uses the propagator method, which applies a time-dependent (TD) perturbation to the system, generated by a fluctuating linear electric field. This approach has been applied to both, the Hartree Fock (HF) and the density functional theory (DFT) method, while the latter one, TDDFT (TD = time dependent), is undoubtedly superior and nowadays frequently used. Besides the aforementioned semiempirical techniques, we also use TDDFT by default, adopting the B3LYP hybrid functional or BLYP, the latter one together with the resolution-of-the-identity (RI) approximation, each with a triple-zeta valence polarized basis set (TZVP) (see, e.g., Figure 4 and Figure 7) [3,4].
    Before simulated and experimental CD curves are compared in order to attribute the respective absolute configuration, a correction step is performed that is able to compensate systematic computational errors. For that purpose the overall UV spectrum calculated by the same conformational analysis is compared with the measured UV curve and the shift necessary to match the peaks of the two graphs is determined. This wavelength scaling by UV matching (‘UV correction’) is easier and more unequivocal than for the CD spectra because of the usually larger number of – positive and negative – peaks of the latter. Our general strategy for quantum chemical calculation of CD spectra is schematically displayed in Figure 1 [1,4].
    Besides the more detailed presentations in the Figures 2-5 [5-8], in Figure 7 [19], Figure 9 [28,29], and Figure 10 [30], a further selection of structurally most diverse natural and synthetic products with stereogenic centers or elements of axial or planar chirality stereochemically attributed by our CD calculations is given in Figure 6 [9-18] and Figure 8 [20-27], the latter one shows intriguing compounds whose absolute configurations have been established by LC-CD in combination with quantum chemical CD calculations [4]. The application of hyphenated techniques like high-performance liquid chromatography (HPLC) coupled to nuclear magnetic resonance spectroscopy (NMR), to electrospray ionization tandem mass spectrometry (ESI-MS/MS), and to circular dichroism spectroscopy (CD) is a sensitive and powerful tool in natural product chemistry permitting a fast screening of the metabolic profiles of plant extracts, with a minimum amount of material. In particular, by the combined application of HPLC-NMR, HPLC-ESI-MS/MS, and HPLC-CD as established in our group, it is not only possible to rapidly identify known structures, but also to investigate new metabolites and to establish their full absolute stereostructures online, directly from crude extracts, without the necessity of isolation and purification (see also 'Natural Product Analysis').
    Summarizing, in many of the cases presented here, an assignment of the absolute stereostructure would not have been possible by any of the existing conventional methods for the interpretation of CD spectra. Without having to rely on empirical data or reference material, the CD calculations can be done directly, without the necessity of chemically introducing additional chromophores – which, for several of the cases investigated, would not have been possible, anyhow. The quantum chemical attribution of the absolute stereostructures of further classes of compounds is underway.

    4. Selected Publications:

    [1] G. Bringmann, S. Busemann; The quantumchemical calculation of CD Spectra: the absolute configuration of chiral compounds from catural or synthetic origin. In: Natural Product Analysis (P. Schreier, M. Herderich, H.-U. Humpf, W. Schwab, eds.), Vieweg, Braunschweig, 1998, pp. 195-211.
    [2] J. Sandström; Determination of absolute configurations and conformations of organic compounds by theoretical calculations of CD spectra. Chirality 2000, 12, 162-171.
    [3] C. Diedrich, S. Grimme; Systematic investigation of modern quantum chemical methods to predict electronic circular dichroism spectra. J. Phys. Chem. A 2003, 107, 2524-2539.
    [4] G. Bringmann, T.A.M. Gulder, M. Reichert, T. Gulder; The online assignment of the absolute configuration of natural products: HPLC-CD in combination with quantum chemical CD calculations. Chirality 2008, 20, 628-642.
    [5] G. Bringmann, H. Scharl, K. Maksimenka, K. Radacki, H. Braunschweig, P. Wich, C. Schmuck; Atropodiastereoselective cleavage of configurationally unstable biaryl lactones with amino acid esters. Eur. J. Org. Chem. 2006, 4349-4361.
    [6] J.M. Wanjohi, A. Yenesew, J.O. Midiwo, M. Heydenreich, M.G. Peter, M. Dreyer, M. Reichert, G. Bringmann; Three dimeric anthracene derivatives from the fruits of Bulbine abyssinica. Tetrahedron 2005, 61, 2667-2674.
    [7] G. Bringmann, G. Lang, K. Maksimenka, A. Hamm, T.A.M. Gulder, A. Dieter, A.T. Bull, J.E.M. Stach, N. Kocher, W.E.G. Müller, H.P. Fiedler; Gephyromycin, the first bridged angucyclinone from Streptomyces griseus strain NTK 14. Phytochemistry 2005, 66, 1366-1373.
    [8] G. Bringmann, G. Lang, T.A.M. Gulder, H. Tsuruta, J. Mühlbacher, K. Maksimenka, S. Steffens, K. Schaumann, R. Stöhr, J. Wiese, J.F. Imhoff, S. Perović-Ottstadt, O. Boreiko, W.E.G. Müller; The first sorbicillinoid alkaloids, the antileukemic sorbicillactones A and B, from a sponge-derived Penicillium chrysogenum strain. Tetrahedron 2005, 61, 7252-7265.
    [9] T. Mülhaupt, H. Kaspar, S. Otto, M. Reichert, G. Bringmann, T. Lindel; Isolation, structural elucidation, and synthesis of curcutetraol. Eur. J. Org. Chem. 2005, 334-341.
    [10] M.C. Kozlowski, E.C. Dugan, E.S. Divirgilio, K. Maksimenka, G. Bringmann; Asymmetric total synthesis of nigerone and ent-nigerone: enantioselective oxidative biaryl coupling of highly hindered naphthols. Adv. Synth. Catal. 2007, 349, 583-594.
    [11] G. Bringmann, M. Reichert, Y. Hemberger; The absolute configuration of streptonigrin. Tetrahedron 2008, 64, 515-521.
    [12] F. Bracher, W.J. Eisenreich, J. Mühlbacher, M. Dreyer, G. Bringmann; Saludimerines A and B, novel-type dimeric alkaloids with stereogenic centers and configurationally semistable biaryl axes. J. Org. Chem. 2004, 69, 6802-6808.
    [13] J. Wu, S. Zhang, T. Bruhn, Q. Xiao, H. Ding, G. Bringmann; Xylogranatins F-R: Antifeedants from the Chinese mangrove, Xylocarpus granatum, a new biogenetic pathway to tetranortriterpenoids. Chem. Eur. J. 2008, 14, 1129-1144.
    [14] K. Ishida, K. Maksimenka, K. Fritzsche, K. Scherlach, G. Bringmann, C. Hertweck; The boat-shaped polyketide resistoflavin results from re-facial central hydroxylation of the discoid metabolite resistomycin. J. Am. Chem. Soc. 2006, 128, 14619-14624.
    [15] M. Xu, G. Gessner, I. Groth, C. Lange, A. Christner, T. Bruhn, Z. Deng, X. Li, S.H. Heinemann, S. Grabley, G. Bringmann, I. Sattler, W. Lin; Shearinines D-K, new indole triterpenoids from an endophytic Penicillium sp. (strain HKI0459) with blocking activity on large-conductance calcium-activated potassium channels. Tetrahedron 2007, 63, 435-444.
    [16] D. Hölscher, M. Reichert, H. Görls, O. Ohlenschläger, G. Bringmann, B. Schneider; Monolaterol, the first configurationally assigned phenylphenalenone derivative with a stereogenic center at C-9, from Monochoria elata. J. Nat. Prod. 2006, 69, 1614-1617.
    [17] G. Bringmann, K. Maksimenka, J. Mutanyatta-Comar, M. Knauer, T. Bruhn; The absolute axial configuration of knipholone and knipholone anthrone by TDDFT and DFT/MRCI CD calculations: a revision. Tetrahedron 2007, 63, 9810-9824.
    [18] G. Bringmann, J. Mutanyatta-Comar, K. Maksimenka, J.-M. Wanjohi, M. Heydenreich, R. Brun, W.E.G. Müller, M.G. Peter, J.O. Midiwo, A. Yenesew; Joziknipholones A and B: the first dimeric phenylanthraquinones, from the roots of Bulbine frutescens. Chem. Eur. J. 2008, 14, 1420-1429.
    [19] A. Goel, F.V. Singh, V. Kumar, M. Reichert, T.A.M. Gulder, G. Bringmann; Synthesis, optical resolution, and configurational assignment of novel axially chiral quateraryls. J. Org. Chem. 2007, 72, 7765-7768.
    [20] G. Bringmann, I. Kajahn, M. Reichert, S.E.H. Pedersen, J.H. Faber, T. Gulder, R. Brun, S.B. Christensen, A. Ponte-Sucre, H. Moll, G. Heubl, V. Mudogo; Ancistrocladinium A and B, the first N,C-coupled naphthydihydroisoquinoline alkaloids, from a Congolese Ancistrocladus species. J. Org. Chem. 2006, 71, 9348-9356.
    [21] G. Bringmann, D. Feineis, R. God, K. Maksimenka, J. Mühlbacher, K. Messer, M. Münchbach, K.-P. Gulden, E.-M. Peters, K. Peters; Resolution and chiroptical properties of the neurotoxin 1-trichloromethyl-1,2,3,4-tetrahydro-β-carboline (TaClo) and related compounds: quantum chemical CD calculations and X-ray diffraction analysis. Tetrahedron 2004, 60, 8143-8151.
    [22] G. Bringmann, S. Rüdenauer, D.C.G. Götz, T.A.M. Gulder, M. Reichert; Axially chiral directly β,β-linked bisporphyrins: synthesis and stereostructure. Org. Lett. 2006, 8, 4743-4746.
    [23] G. Bringmann, S. Tasler, H. Endress, J. Kraus, K. Messer, M. Wohlfarth, W. Lobin; Murrastifoline-F: First total synthesis, atropo-enantiomer resolution, and stereoanalysis of an axially chiral N,C-coupled biaryl alkaloid. J. Am. Chem. Soc. 2001, 123, 2703-2711.
    [24] G. Bringmann, K. Messer, K. Wolf, J. Mühlbacher, M. Grüne, R. Brun, A.M. Louis; Dioncophylline E from Dioncophyllum thollonii, the first 7,3'-coupled dioncophyllaceous naphthylisoquinoline alkaloid. Phytochemistry 2002, 60, 389-397.
    [25] G. Bringmann, T. Gulder, M. Reichert, F. Meyer; Ancisheynine, the first N,C-coupled naphthylisoquinoline alkaloid: total synthesis and stereochemical analysis. Org. Lett. 2006, 8, 1037-1040.
    [26] X. Yang, T.A.M. Gulder, M. Reichert, C. Tang, C. Ke, G. Bringmann; Parvistemins A-D, a new type of dimeric phenylethyl benzoquinones from Stemona parviflora Wright. Tetrahedron 2007, 63, 4688-4694.
    [27] G. Bringmann, T.A.M. Gulder, K. Maksimenka, D. Kuckling, W. Tochtermann; A borderline case between meso and C1: an axially chiral, yet configurationally semi-stable biphenyl with two oppositely configured [10]paracyclophane portions. Tetrahedron 2005, 61, 7241-7246.
    [28] G. Bringmann, J. Mühlbacher, M. Reichert, M. Dreyer, J. Kolz, A. Speicher; Stereochemistry of isoplagiochin C, a macrocyclic bisbibenzyl from liverworts. J. Am. Chem. Soc. 2004, 126, 9283-9290.
    [29] J.M. Scher, J. Zapp, H. Becker, N. Kather, J. Kolz, A. Speicher, M. Dreyer, K. Maksimenka, G. Bringmann; Optically active bisbibenzyls from Bazzania trilobata: isolation and stereochemical analysis by chromatographic, chiroptical, and computational methods. Tetrahedron 2004, 60, 9877-9881.
    [30] G. Bringmann, J. Mühlbacher, K. Messer, M. Dreyer, R. Ebel, B.W. Nugroho, V. Wray, P. Proksch; Cyclorocaglamide, the first bridged cyclopentatetrahydrobenzofuran, and a related "open chain" rocaglamide derivative from Aglaia oligophylla. J. Nat. Prod. 2003, 66, 80-85.

    5. Cooperations and Research Grants

    a) Within a special research project entitled "A New Class of Active Agents against Infectious Diseases" incorporated into the Collaborative Research Centre „Recognition, Preparation, and Functional Analysis of Agents against Infectious Diseases“ (Sonderforschungsbereich 630), sponsored by the Deutsche Forschungsgemeinschaft (DFG).

    b) Within a special research project entitled "Enantioselective Synthesis of Bisbibenzyl Natural Products of the Isoplagiochin-Type with Combined Axially and Helical Chirality", in collaboration with PD Dr. Andreas Speicher (Universität des Saarlandes, Fachrichtung 8.1. Chemie – Organische Chemie), sponsored by the DFG (Individual Grant Br 699/12);

    c) Within a special research project entitled "Natural Products from African Plants ", in collaboration with Prof. Dr. M.G. Peter (Institut für Chemie der Univerisität Potsdam) and Dr. A. Yenesew (Department of Chemistry, University of Nairobi, Kenya), sponsored by the DFG (Individual Grant Br 699/13-5);

    d) Within a special research project entitled "Convergence in the Biosynthesis of Acetate- or Prenyl-Derived Natural Products", incorporated into the DFG priority programme 1152 "Evolution of Metabolic Diversity", Individual Grant Br 699/9-3);

    e) Within a special research project entitled "Molecular Phylogeny and Chemotaxonomy of the Ancistrocladaceae Plant Family", in collaboration with Prof. Dr. G. Heubl (Institut für Systematische Botanik der LMU München), sponsored by the DFG (Individual Grants Br 699/7 and Br 699/14-2);

    f) Within the special research project entitled „BIOTECmarin – Center of Competence: Molecular Biotechnology and New Agents from Marine Sponges and Associated Microorganisms“, sponsored by the Bundesminsterium für Bildung, Forschung, Wissenschaft und Technologie (BMBF), in collaboration with

    g) Within the Research Training Group "Modification of the Electron Density in Chemical and Biological Systems – a Symbiosis between Theory and Experiment for Postgraduate Education" (Graduiertenkolleg 690, coordinator: Prof. Dr. B. Engels, Institut für Organische Chemie der Universität Würzburg), sponsored by the DFG (completed).

    h) Within a special research project entitled "Metal-Induced Synthesis and Utilization of Axially Chiral Biaryls" incorporated into the collaborative research centre „Selective Reactions of Metal-Activated Molecules“ (Sonderforschungsbereich 347), sponsored by the DFG (completed).

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