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ASYMMETRIC CATALYSIS WITH CHIRAL-AT-METAL COMPLEXES

This is our new main research direction pursued actively in our groups at Xiamen and Marburg. Aim is to exploit the metal as a powerful structural center and beyond!

For metal-templated "organocatalysis, see: JACS 2013 (for cover picture, click here) and ACIE 2013. For chiral Lewis Acid catalysis, see: JACS2014. For asymmetric photoredox catalysis, see for example: Nature 2014.

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ASYMMETRIC SYNTHESIS OF OCTAHEDRAL METAL COMPLEXES

Most of our metal-containing enzyme inhibitors are chiral-at-metal and, as expected, typically only one enantiomer has the desired properties, whereas the optical antipode often displays undesired different target selectivities. Furthermore, our studies on chiral-at-metal complexes as asymmetric catalysts require the economical access to enantiopure metal complexes. We therefore developed a number of bidentate ligands that serve as chiral auxiliaries and in one case even as a catalyst for controlling the metal-centered configuration in octahedral ruthenium complexes.

Our earliest publication on this topic: G. Lei, S. P. Mulcahy, K. Harms, E. Meggers, J. Am. Chem. Soc. 2009,  131,  9602-9603.

For a recent account article on auxiliary-mediated asymmetric coordination chemistry, see: L. Gong, M. Wenzel, E. Meggers, Acc. Chem. Res. 2013, 46, 2635-2644.

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CHEMICAL BIOLOGY AND MEDICINAL CHEMISTRY WITH INERT METAL COMPLEXES

"Natural product-like" complicatedness of octahedral metal complexes: Whereas the initial years (2003-2007) were dedicated to use half-sandwich complexes as scaffolds, our focus later (2008-2013) shifted to truly octahedral coordination geometries. Note that this research is based on the hypothesis that octahedral coordination geometries are superior structural centers for the design small molecules with globular and defined shapes. Strikingly, the octahedron permits a much larger structural complicatedness than the tetrahedron which can be illustrated by the number of possible stereoisomers; a tetrahedron is capable of building a maximum of two enantiomers, in comparison to an octahedron which can form up to 30 stereoisomers, 15 diastereomers as pairs of enantiomers. Since unfortunately Nature did not provide us with stable octahedral carbon coordination spheres, we are instead using substitutionally inert transition metal centers, currently especially ruthenium and iridium.

For our most sophisticated metal-based inhibitors, see: JACS 2011.

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BIOORTHOGONAL CATALYSIS WITH ORGANOMETALLICS

The catalysis of bioorthogonal transformations inside living organisms is a formidable challenge, yet bears great potential for future applications in chemical biology and medicinal chemistry. We developed a highly active organometallic ruthenium complexes for bioorthogonal catalysis under biologically relevant conditions as well as inside living mammalian cells. The reported catalysts uncage allyl carbamate protected amines with unprecedented high turnover numbers of up to 270 cycles in the presence of water, air and millimolar concentrations of thiols. Live-cell imaging of cervical cancer cells (HeLa cell line) supports the bioorthogonality of the catalysts and reveals a rapid development of intense fluorescence (130-fold increase) within the cellular cytoplasm when a caged fluorescent probe is used. In addition, to introduce the manifold applications of bioorthogonal organometallic catalysis, we developed a method for catalytic in-cell activation of a caged anticancer drug which efficiently induced apoptosis in HeLa cells.

Our latest research article on this topic: Angew. Chem. Int. Ed. 2014, 53, 10536.

Reviews from our group: T. Völker and E. Meggers, Curr. Opin. Chem. Biol. 2015, 25, 48-54.

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PREVIOUS RESEARCH IN BIOMIMETIC NUCLEIC ACID CHEMISTRY

THE MINIMAL NUCLEIC ACID GNA:

We recently discovered a minimal nucleic acid backbone (GNA, glycol nucleic acid). Due to its unique combination of high duplex stability, base pairing fidelity, and easy synthetic access of its nucleotides, GNA comprises a promising scaffold for future nucleic-acid-based nanotechnology. Furthermore, GNA is structurally the most simplified solution for a phosphodiester-containing nucleic acid backbone and thus constitutes a candidate for initial genetic molecules of life. See: L. Zhang, A. Peritz, E. Meggers, J. Am. Chem. Soc. 2005, 127, 4174-4175. For the crystal structure of a GNA duplex, see: M. K. Schlegel, L.-O. Essen, E. Meggers, J. Am. Chem. Soc. 2008, 130, 8158-8159.

METAL-MEDIATED BASE PAIRING:

In 2000, Meggers, Romesberg, and Schultz demonstrated for the first time that interbase metal coordination can replace the hydrogen bonding schemes found in the natural base Watson-Crick base pairs by reporting an artificial copper(II)-mediated base pair between pyridine and pyridine-2,6-dicarboxylate nucleotides. Metal-mediated base pairing (metallo-base pairing) will find potential applications in nucleic-acid-derived nanoelectronics or molecular motors and for the design of metal ion sensors and switches. See: E. Meggers, P. L. Holland, W. B. Tolman, F. E. Romesberg, P. G. Schultz, J. Am. Chem. Soc. 2000, 122, 10714-10715. For the first crystal structure of metal-mediated base pairs in a DNA duplex, see: S. Atwell, E. Meggers, G. Spraggon, P. G. Schultz, J. Am. Chem. Soc. 2001, 123, 12364-12367.

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Zuletzt aktualisiert: 03.11.2016 · Michael Marsch

 
 
 
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