Lehrstuhl für Organische Chemie I
Am Hubland, D-97074 Würzburg
Other participating persons and organisations:
Research foci (and basic equipment-based research projects):
Coumpounds with chiral biaryl axes are gaining increasing relevance as pharmacologically active compounds and as useful tools in asymmetric synthesis. The atroposelective total synthesis of biaryl target molecules is an important device for the elucidation of the full absolute stereostructure of axially chiral biaryls and it provides reliable access to bioactive natural compounds or simplified analogs (e.g., for bio-testing) and to biarylic ligands and catalysts. Yet, compared with the numerous sophisticated techniques for the asymmetric synthesis of stereogenic centers, truly practicable methods for the regio- and stereoselective construction of chiral axes are still rare. We have developed a conceptionally novel and preparatively efficient concept for the directed synthesis of even highly hindered axially chiral biaryls. Key step is the atroposelective cleavage of lactone-bridged biaryl precursors by various metal activated chiral O-, N-, and H-nucleophiles. The required lactones are easily available by intramolecular coupling of appropriately substituted bromo esters, they can be cleaved atropo-enantio- or atropodiastereo-divergently to the one or the other stereoisomeric form, e.g., to the M-configured biaryl, or, optionally, to the P-configured product. Mechanistically, this reaction constitutes a dynamic kinetic resolution at the level of the rapidly interconverting lactone enantiomers: Only one of them is ring cleaved, to give the axially chiral, configurationally stable biaryl product, whereas the other, non-reactive lactone enantiomer will, by the rapid atropo-enantiomeric interconversion, provide more of the reactive species and thus permit a high-yield conversion of virtually all of the racemic starting material into one particular atropisomeric biaryl. Besides the mechanistic exploration of this novel reaction principle - both, experimentally and computationally - we are in particular interested in the practical application of this novel procedure, which succeeded already in successful syntheses of a broad series of axially chiral biaryl natural products of most different structures, among them the nerve growth stimulating dimeric sesquiterpene mastigophorene A from liverworts, the antiplasmodial phenylanthraquinone knipholone from African torchlilies, and a whole series of highly bioactive naphthylisoquinoline alkaloids, like the antimalarial agents dioncopeltine A (from Triphyophyllum peltatum) and korupensamine B (from Ancistrocladus korupensis), dimeric carbazole alkaloids like bismurrayachinone A form the Asian shrub Murraya koenigii, and the antifeedent bicoumarin isokotanin A from the fungus Aspergillus alliaceus. Furthermore, the lactone methodology gives rise to novel non C2-symmetric mono- and bidentate ligands and to C3-symmetric catalysts for asymmetric synthesis.
For the results in this research area, please consult the above-mentioned publications.
Rewards and prizes:
Prof. Dr. G. Bringmann: Prize for Excellent Teaching awarded by the Freistaat Bayern, 1999. - JSPS Invitation Fellowship for Research in Japan, 2000. - Eli Lilly Research Laboratories Lecturer, 2000. -- Dipl.-Chem. A. Hamm: VCI Graduate Research Fellowship. -- Dipl.-Chem. R.-M. Pfeifer: Graduate Research Fellowship according to the Graduiertenförderungsgesetz des Freistaates Bayern. - International Students Summer Course of the BASF Company, 2002. -- Dr. C. Günther: VCI Graduate Research Fellowship. - Faculty Award (Dissertation) of the Faculty of Chemistry and Pharmacy, 2000. -- Dr. W. Saeb: International Students Summer Course of the BASF Company, 1999. -- Dr. S. Tasler: Dissertation Award of the Unterfränkische Gedenkjahrsstiftung, 2002.
NMR spectrometer: Bruker Avance (400 MHz), Bruker DMX 600 (600 MHz), Bruker 250 (250 MHz). - Mass spectrometer: Finnigan MAT 90, Finnigan MAT 8200. - J-715 spectropolarimeter (Jasco Deutschland). - Various apparatus for gas chromatography, HPLC and MPLC analysis. - LC-CD Coupling (using the J-715 spectrometer). - LC-MS/MS Coupling (using the Finnigan TSQ 7000 mass spectrometer equipped with an ESI and APCI interface). - LC-NMR Coupling (using the NMR 600 spectrometer).