Cyclopentadienyl

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Background

Cyclopentadienyl (Cp) is not what one would call a typical ligand for water. In bioorganometallic chemistry however, it is probably the most important ligand, mostly in form of ferrocene. Since Cp resembles phenyls, it can principally replace this structural feature in pharmaceutical lead structures thereby introducing a metal and sometimes even exhibiting superior activities as compared to its model as shown e.g. by Jaouen or Meggers and coworkers. It is a great challenge of finding conditions, under which 99mTc complexes can be synthesized. We had a breakthrough when we found that the Diels-Alder dimerized Cp-monomers cleave by metal-mediation in water. This approach enabled us to introduce functionalized Cp-compounds in radiopharmaceutical chemistry.  
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Figure 1. ORTEP of a bifunctionalized Cyclopentadienyl complex of rhenium. The 99(m)Tc homolog can be prepared in one step from [99(m)TcO4]-.

Current research

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Figure 2. ORTEP of ruthenocene derivatized with four methyl-acetyl ester functions which can easily be hydrolyzed, synthesized directly in water.  

To make Cp truly versatile for molecular imaging, the ring must be functionalized with one or more groups for combination with lead structures or targeting portions. This demands a good part of organic chemistry as is currently done along multiple lines. Besides the coupling of biomolecules to Thiel’s acid, which leads to mono-functionalized molecular imaging agents, we have introduced two groups for coupling in a not-dimerized Cp precursor. Since some of these precursors are well water soluble, their coordination chemistry in water with other d-elements is studied as well.

 

Challenges

integration of Cp in pharmaceutical lead structures – mechanism of coordination in water – Cp systems

Coworkers

Angelo Frei, in collaboration with Prof. Andreas Roodt, University of the Free State, South Africa

Publications

  • Metal-mediated retro Diels-Alder of dicyclopentadiene derivatives: A convenient synthesis of [(Cp-R)M(CO)3] (M=99mTc, Re) complexes.Liu, Y., Spingler, B., Schmultz, P. and Alberto, R. (2008): J. Am. Chem. Soc. 130, 1554-1556.
  • [(Cp-R)M(CO)3] (M=Re or 99mTc) Arylsulfonamide, Arylsulfamide, and Arylsulfamate Conjugates for Selective Targeting of Human Carbonic Anhydrase IX. Can, D., Spingler, B., Schmutz, P., Mendes, F., Raposinho, P., Fernandes, C., Carta, F., Innocenti, A., Santos, I., Supuran, C. T. and Alberto, R. (2012): Angew. Chem. Int. Ed. 51, 3354-3357.
  • Organometallic Rhenium Complexes Divert Doxorubicin to the Mitochondria. Imstepf, S., Pierroz, V., Rubbiani, R., Felber, M., Fox, T., Gasser, G. and Alberto, R. (2016): Angew. Chem. Int. Ed. 55, 2792-2795.