Wolfgang H. Kramer

Research Interests

Oxidative Processes in DNA and other Organic Biomolecules

            Oxidation of DNA has been shown to result in localization of the positive charge by formation of guanine radical cations, particularly at GG steps.  It is now accepted that reactions of these radical cations result in nicking of the DNA backbone, and thus to permanent damage.  The efficiency of these oxidations is limited due to back electron transfer.  To minimize this energy wasting step we use compounds with fragmenting bonds as oxidizing agents. Upon irradiation these compounds form a radical and a radical cation species. The radical cation species can oxidize DNA bases and becomes a stable uncharged molecule. The design and synthesis of compounds with fragmenting bonds is an integral part of our research.

            We are now trying to establish quantitative relationships between one-electron oxidation and DNA damage, i.e. the number of one-electron oxidations that result in irreversible breaking of the DNA backbone.  Knowledge of the efficiency of formation of backbone breakages is important since it would allow an assessment of the other important processes that result from one-electron oxidation, and would provide information about the relative efficiencies of damage and "self-repair" mechanisms available to the DNA. 

            Cleavage of single-stand DNA is known to follow two main mechanisms.  One is the abstraction of a hydrogen atom from the backbone and the other is oxidation of DNA bases. By varying the oxidation potential of the radical cation we can switch the oxidative mechanism on and off.  We are planning on using photochemical steady state and time-resolved methods to quantify these different processes and their mechanisms.

Fink, H. W.; Schonenberger, C. "Electrical Conduction Through DNA Molecules" Nature 1999, 398, 407.

Murphy, C. J.; Arkin, M. R.; Jenkins, Y.; Ghatlia, N. D.; Bossman, S. H.; Turro, N. J.; Barton, J. K. "Long-Range Photoinduced Electron Transfer Through a DNA Helix" Science 1993, 262, 1025.

 Edward D. Lorance, Wolfgang H. Kramer, Ian R. Gould "Kinetics of Reductive N-O Bond Fragmentations. The Role of Conical Intersections"  J. Am. Chem. Soc. 2002, 124, 15225-15238.

Decarboxylative Photocyclization

The decarboxylative photocyclization of w-phthalimido carboxylic acids is a useful tool in the synthesis of macrocyclic ring systems.

The efficiency of this triplet reaction is probably caused by ground-state chelation effects. A large variety of heterocyclic ring system can be synthesized with the decarboxylative photocyclization. These include lactams, benzopyrrolizidines, lactones, cyclic peptides, pyrrolizidines, indolizidines and crown ethers.

Of particular interest are the [1,4]-benzodiazepines and the pyrrolo-[1,4]-benzodiazepines. This class of compounds is widely used as tranquillizers ([1,4]-benzodiazepines) as well as potential groove binder in DNA (pyrrolo-[1,4]-benzodiazepines). The photocyclization occurs with a remarkable memory of chirality effect. The configuration of the chiral center is inversed via a 1,7-triplet biradical. The reason for the this effect is probably the rigid conformation of the anthranilic acid which prevents rotation along the phthalimide-anthranilic acid axis. Control experiments with b-alanine instead of anthranilic acid show no effect of chirality transfer.

Representative Publications:

"Synthesis of 1,4-Benzodiazepines via Photoinduced Decarboxylation of N-Phthaloyl-anthranilic acid amides" Axel G. Griesbeck, Wolfgang Kramer, Johann Lex, Synthesis: Special Issue 2001, 1159-1166.

"Photocyclization of 2-Azabicyclo[3.3.0]octane-3-carboxylate Derivatives: Induced and Non-Induced Diastereoselectivity", A. G. Griesbeck, W. Kramer, A. Bartoschek, H. Schmickler, Org. Lett. 2001, 3, 537-539.

"Chiralitaetserinnerung bei Triplett-1,7-biradikalen: Diastereo- und enantioselektive Synthese von Pyrrolo[1,4]-benzodiazepinen durch decarboxylierende Photocyclisierung von Anthranilsaeurebausteinen" A. G. Griesbeck, W. Kramer, J. Lex, Angew. Chem. 2001, 113, 585-589. Angew. Chem. Int. Ed. 2001, 40, 577-579.

"Synthesis of Medium- and Large-Ring Compounds Initiated by Photochemical Decarboxylation of w-Phthalimido Alkycarboxylates", A. G. Griesbeck, A. Henz, W. Kramer, J. Lex, F. Nerowski, M. Oelgemöller, K. Peters, E.-M. Peters, Helvetica Chim. Acta 1997, 80, 912-933.