Development of artificial transition metalloDNAzymes for highly efficient catalytic processes

Catalysts are becoming more and more important every day. A catalyst changes the pathway of a reaction such that formation of one product is favoured over other products. Consequently, the reaction becomes more selective and less waste is produced, also making purification easier. Another advantage is that catalysts accelerate reaction rates reducing energy consumption.Enzymes are nature's catalysts. They are in general more efficient both in speed and selectivity then man-made catalysts, but they cannot perform all the reaction we would like, such as hydroformylation. Man-made catalysts employing a transition metal are very efficient in these reactions.We aim to utilise the molecular recognition which oligonucleotides exhibit and combine that with the activity of transition metals to create artificial metallo DNAzymes. These metallo DNAzymes can then be used in industrial relevant catalytic reactions for which no enzyme exists such as hydroformylation, allylic substitution and hydrogenation to name a few. Two approaches can be envisioned: the supramolecular approach where the metal is non covalently bound to oligonucleotides[1] and the covalent approach where the transition metal is covalently attach to the DNA strand, often through a linker.In the first case a racemic or nonchiral ligand capable of both coordinating to a metal and binding to DNA is introduced to a DNA strand via self assembly. This approach has the clear advantage that catalyst can be optimised using commercially available DNA instead of synthesising each strand individually. Unfortunately it is unclear where the catalytic centre is located as the ligand has the potential to bind to numerous places in the DNA double helix. The covalent approach overcomes this problem by coordinating the transition metal directly to a linker bound to DNA. The disadvantage of this approach is that it is much more labour intensive, requiring complicated and troublesome synthetic methods.Both Jschke[2] and our group[3] have used this approach after which these DNA oligonucleotides were coordinated to iridium and palladium respectively and used in allylic amination. Although the enantioselectivities were moderate it indicates that this approach does work. By changing the base sequence and increasing the chain length the enantioselectivity might be increased.We plan to combine both approaches. Dervan et al.[4] have developed polyamide chains that bind to specific DNA sequences which we will modify by attaching a ligand capable of coordinating to a transition metal to it. After metal coordination the polyamide can be coupled selectively to a DNA double helix containing the correct sequence. These novel catalysts will then be tested in transition metal mediated conversions.Using the same approach different transition metal complexes will be immobilized on two-dimensional crystalline DNA arrays aiming at cascade catalytic conversions.This pilot study by the PhD student will be supervised by the PI and Prof. Dervan at Caltech and is aiming at long term collaboration between the two groups via follow-up joint grant proposals.1. Dijk, E. W.; Feringa, B. L.; Roelfes, G., Top Organomet. Chem. 2009, 25, 1.2. Fournier, P.; Fiammengo, R.; Jschke, A., Angew. Chem. Int. Ed. 2009, 48, 1.3. Ropartz, L.; Meeuwenoord, N. J.; Marel, G. A. v. d.; Leeuwen, P. W. N. M. v.; Slawin, A. M. Z.; Kamer, P. C. J., Chem. Commun. 2007, 1556.4. Hsu, C. F.; Phillips, J. W.; Trauger, J. W.; Farkas, M. E.; Belitsky, J. M.; Heckel, A.; Olenyuk, B. Z.; Puckett, J. W.; Wang, C. C. C.; Dervan, P. B., Tetrahedron 2007, 63, 6146.

The aim of the proposed research is to develop an international collaboration with the Dervan group at Caltech to execute a research program in the fields of biology, chemistry and catalysis with the potential of major scientific innovations toward a full control of molecular recognition in complex chemical transformations. By combining the concepts of biology for selective recognition with those of transition metal catalysis we will develop novel, highly selective catalysts for challenging reactions like important (asymmetric) catalytic C-C bond forming reactions. Smart catalyst systems will be developed for efficient and inexpensive chemical processes operating at optimal temperatures and pressures eventually leading to zero-waste emission by 100% selective hybrid bio- and chemo-catalysts. In the long run this unconventional research project has the potential to open new fields for UK science and technology. It could have great economic, environmental and societal impact by contributing to the development of fully catalytic production of important chemical products and materials. Present methods for the production of commodities and important fine-chemicals like pharmaceuticals lead to significant production of chemical waste, which can be reduced tremendously by changing to all-catalytic production methods. The required selectivity resulting in high atom economy will only be feasible by development of new scientific and technological tools. In spite of the advanced technology required, man-made catalysts are extremely simple entities compared to natural and modified enzymes. Still, many important fine chemicals are produced by homogeneous catalysis because efficient enzymes for important chemical transformations like CO and alkene insertions are lacking. The sustainable development and competitiveness of the UK will greatly benefit from scientific and technological breakthroughs resulting from this multidisciplinary project. Therefore, the potential benefits outweigh the risks of this ambitious project by far. Also, this project will offer a unique training environment for a young talented scientist who will learn to look over the borders of her own research discipline. Such new broadly educated scientists will be crucial for obtaining a leading role for the UK in competitive scientific, technological and economical developments. Moreover, this will offer a unique opportunity for the PhD student to work in a world leading group at one of the top-institutes in the US. Undoubtedly this will have a huge positive impact on the career perspectives of the student. The proposed long-term collaboration will be of great benefit to the PI, Dervan and their institutes as their research expertises are complementary and extremely well-fitted to launch such an interdisciplinary research project. All methods to connect the proposed ligands and metal complexes to peptides have been developed in St Andrews. Also the compatibility of transition metal complexes has already been established. The Dervan group is world leading in sequence specific DNA binding and the related structural analysis and characterization. Success of this proposed initial feasibility study will not only lead to first class publications, but also to high chances of the intended subsequent joint research proposals as well as real potential applications.