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Research Keypoints of the Institute of Organic Chemistry

Catalytic Rearrangements as tools for bond formation (N. Maulide)

Our research has mostly focused on unusual or "unconventional" reactivity profiles of organic compounds. We have taken particular interest in high-energy reactive intermediates that can be generated under mild conditions and subsequently lead to rearrangements, domino reaction sequences or catalytic asymmetric transformations. A broad scope of research has emerged from these efforts, spanning a large subset of areas within Organic Chemistry.

 

For more information, the reader is invited to visit the following linked pages.

Domino Electrophilic Activation of Amides

Catalytic Asymmetric Synthesis of Cyclobutenes

New Perspectives on Sulfur (IV) Chemistry

 

Syntheses of bioactive carbohydrates and fluorinated analogs thereof (W. Schmid)

Glycopolymers influence biological functions and effect communication between different cells including host-pathogen interactions and immunological processes. Especially the functions of Gram-positive bacteria glycopolymers, the teichoic (TA) and lipoteichoic acids (LTA) are still poorly understood. The LTA of S. pneumonia, a Gram-positive bacterium which is still a life threatening pathogen, affects the innate immune system. It contains a rather unique 2,4-diamino-2,4,6-trideoxy-d-galactose, which is either mono or di‑N‑acetylated. We developed a short and efficient synthesis of this sugar thus making this interesting monosaccharide accessible on a gram scale.

Carbohydr. Res. 2013, 367  

Other synthetic targets include fluorinated amino-deoxy-carbohydrates, in which fluorine substitution represents a valuable tool for probing the critical binding aspects of macromolecule complexes such as antigen-antibody adducts. An important advantage of fluorine is the possibility to perform facile NMR based investigations. The naturally 100 % abundant isotope 19F has proven to be an excellent nucleus for NMR experiments.

Eur. J. Org. Chem. 2014, 2451-2459; Beilstein J. Org. Chem. 2012, 8, 448–455

Selective isotope labeling of proteins by using selected labeled precursor compounds (W. Schmid)

NMR spectroscopy is a valuable tool to study the structure and dynamic properties of high molecular weight proteins and provides insight to complex molecular processes. Most of the NMR experiments require tailored isotope patterns of 13C, 15N and 2H in order to reduce spectra complexity, improve resolution, or enable effective magnetization transfer. We develop novel methods to synthesize labeled metabolic amino acid precursors, which can be added to the minimal growth media of in-cell protein overexpression systems. In collaboration with Prof. Konrat’s group at the MFPL, the labeling patterns are designed tailor-made for sophisticated NMR experiments thus enabling structure- dynamic- and binding-studies of large protein complexes.

(a) Independent valine and leucine labeling / methionine labeling

ChemBioChem 2013, 14 (7), 818-821; J. Biomol. NMR 2013, 57(3), 205-209; J. Am. Chem. Soc. 2004, 126(17), 5348-5349; ChemBioChem 2007, 8, 610-612  

(b) Novel precursors for phenylalanine and tyrosine labeling


J. Biomol. NMR 2013, 57 (4), 327-331; Eur. J. Org. Chem. 2014, submitted


Biosynthesis and biodegradation of natural products containing a P-C bond (F. Hammerschmidt)

The phosphonates 1, 2, 3, and 4 are some of the natural products containing a P-C bond. Two, the antibiotic phosphomycin (2) and the herbicide phosphinothricin (4), are of commercial importance. The biosynthesis and biodegradation of these small molecules are highly interesting. Phosphonates are made and used to unravel enzymatic steps of these processes.

J. T. Whitteck, P. Malova, S. C. Peck, R. M. Cicchillo, F. Hammerschmidt, W. A. van der Donk, J. Am. Chem. Soc. 2011, 133, 4236-4239
L. M. van Staalduinen, F. R. McSorley, K. Schiessl, P. B. Wyatt, F. Hammerschmidt, D. L. Zechel, Z. Jia, PNAS, 2014, 111, 5171-5176

 

Determination of configurational stability of heteroatom-substituted chiral [D1]methyllithiums and palladiums (F. Hammerschmidt)

alpha-Heteroatoms, especially oxygen and nitrogen, increase the configurational stability of alkyllithiums relative to the unsubstituted species. The smallest chiral alkylmetals prepared are the [D1]methyllithiums and palladiums. They were accessed from (R)- and (S)-tributyl- stannyl-[D1]methanol of 99% ee. All [D1]methyllithiums 3 and 5 were found to be microscopically configurationally stable at –78 °C except those with nitrogen, sulphur and iodine as heteroelement. 



P. Malova, F. Hammerschmidt, Eur. J. Org. Chem. 2013, 5143-5148
D. C. Kail, P. Malova Krizkova, A. Wieczorek, F. Hammerschmidt, Chem. Eur. J. 2014, 20, 4086-4091

 

Studying Enzyme Catalyzed Reactions by NMR spectroscopy (L. Brecker)

The importance of biocatalysed reactions in organic synthesis and biological chemistry is steadily growing. Using in situ NMR spectroscopy a biocatalysed reaction can easily and efficiently be analysed without sampling a reaction. In particular 1H-, 13C-, and 31P-NMR provide information about the acceptance of different substrates, the occurrence of intermediates, and the time course of the reaction. Therefore this technique enables a direct investigation of metabolisms in living cell cultures and allows conclusions about regio- and stereoselectivity of a transformation. Furthermore kinetic data of reactions can be determined.[1] High enzymatic activity is based on optimal substrate enzyme binding. Hence fundamental knowledge about binding pattern of substrates and products is important for a sensible selection of optimal biocatalysts. Saturation transfer difference NMR spectroscopy (STD NMR) can be used as time efficient method to study comprehensive mapping of enzyme/substrate interactions in global as well as in site-specific fashion. The resulting binding patterns represent a molecular foundation of specific substrate, co-substrate, and co-enzyme binding to an enzyme. These interactions are determined during catalysis (Figure 1) as well as under binding-only conditions.[2] Further, we occasionally use NMR spectroscopic determination of 13C-kinetic isotope effects to get insight into details of bond breaking and formation during the rate determining step in a mechanism. [3] Combination of all three NMR based techniques allows comprehensive studies of mechanistic details, which can be supported and visualized by in silico molecular docking (Figure 2). Actually transformations catalysed by glycosidases, phosphorylases, oxidoreductases and decarboxylases are exemplary investigated.[2e,4] NADH/NAD+ dependent catalyzed reductions and oxidations are of particular interest due to formation of ternary enzyme/co-enzyme/substrate complexes (Figure 3). Studying transformations of natural substrates, artificial substrate analogues, and not accepted compounds allow conclusions how these enzymes use non covalent interactions to bind and transform its substrates. The gained results can be correlated with macroscopic features like substrate specificity and catalytic activity (kcat) and used for synthetic applications.[4c,d] In further progress a NMR based directed design of mutants for selected biocatalysed transformations is aspired.

Figure 1: Analysis of binding situations during biocatalyzed reactions using STD NMR.[2c,d]

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Figure 2: Molecular docking of α-Xylp and β-Xylp to CtXR/NADH complex.[2e]

 

Figure 3: Schematic progress of in situ STD NMR measurements considering binding of substrates and products.[2d,2e]

[1]    a) H.-J. Weber, L. Brecker, Curr. Opinions Biotechnol. 2000, 11, 572-578; b) L. Brecker, D. W. Ribbons, Trends Biotechnol. 2000, 18, 197-202; c) T. Pacher, A. Ranninger, E. Lorbeer, L. Brecker, P. But, H. Greger, J. Nat. Prod. 2010, 73, 1389-1393. [2]    a) B. Meyer, T. Peters, Angew. Chem. Int. Ed. 2003, 42, 864-890; b) L. Brecker, G. D. Straganz, C. E. Tyl, W. Steiner, B. Nidetzky. J. Mol. Catal. B.: Enzymatic 2006, 42, 85-89.  c) L. Brecker, A. Schwarz, C. Gödl, R. Kratzer, C.E. Tyl, B. Nidetzky, Carbohydr. Res. 2008, 343, 2153-2161; d) L. Brecker, M. Husa, Nachr. Chem. 2013, 61, 153-155; e) M. Vogl, L. Brecker, RSC Adv. 2013, 3, 25997-26004. [3]    L. Brecker, M. F. Kögl, C. E. Tyl, R. Kratzer, B. Nidetzky, Tetrahedron Lett. 2006, 47, 4045-4049. [4]    a) A. Schwarz, L. Brecker, B. Nidetzky, FEBS J. 2007, 274, 5105-5115; b) L. Brecker, M. Mahut, A. Schwarz, B. Nidetzky, Magn. Reson. Chem. 2009, 47, 328-332; c) L. Brecker, M. Vogl, R. Kratzer, B. Nidetzky, Eur. Pat. Appl. 2011, 28 pp., EP 2348120; d) M. Vogl, R. Kratzer, B. Nidetzky, L. Brecker, Chirality 2012, 24, 847-853. e) T. Eixelsberger, L. Brecker, B. Nidetzky, Carbohydr. Res. 2012, 356, 209-214; f) T. Eixelsberger, S. Sykora, S. Egger, M. Brunsteiner, K. L. Kavanagh, U. Oppermann, L. Brecker, B. Nidetzky, J. Biol. Chem. 2012, 287, 31349-31358; g) P. Wildberger, L. Brecker, B. Nidetzky, Chem. Commun. 2014, 50, 436-438.

Computer-Assisted Structure Elucidation (W. Robien)

* Algorithm Development for Prediction of NMR-spectra
* Algorithm Development for peaklist-oriented searches
* Algorithm Development for Automatic Assignment of NMR-Spectra
* Quality-Management of Spectral Data
* Automatic Structure Verification
* Extension of the existing Database of NMR-Spectra named "CSEARCH"     
For more informations, cf: nmrpredict.orc.univie.ac.at - On this page there are many links showing more details and also links to Webservices available to the community for free using technologies and/or data developed within the CSEARCH-Project.


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Letzte Änderung: 19.05.2014 - 11:36