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Molybdenum dependent enzymes are involved in essential metabolic transformations in bacteria, plants, and human beings. The extreme instability of the molybdenum cofactor (Moco) prevents its use as an effective treatment for patients with a Moco deficiency. Therefore, the design, develop and execute the artificial molybdenum cofactor models are essential.
In the present thesis, the asymmetric molybdopterin (mpt) model precursors with oxygen functionality and various electronic structures and their Moco model complexes mimicking the natural cofactor have been synthesized and comprehensively investigated through multi-nuclear NMR, MS, IR, resonance Raman, X-ray crystallography, UV-Vis, and electrochemical methods. Notably, the asymmetrically substituted dithiolenes in this thesis are confirmed through a significant push-pull effect, which is tuning its electronic structure. The redox behavior of Moco model complexes was investigated by temperature-dependent cyclic voltammetry. Electronic and vibrational spectral studies were investigated in detail to understand substituents effect on the electronic structure of model complexes and to elucidate roles of mpt in catalysis. Since the model complexes can be considered as structural models for the Moco dependent oxidoreductases, catalytic oxygen atom transfer (OAT) reactions in DMSO/PPh3 were investigated.
The main focus of the present thesis was achieved through the development of various synthetic routes that address phosphonate bearing dithiolene ligands, inspiring the natural mpt. Simultaneously the Minisci protocol was applied for the synthesis of new pterin ketophosphonates, taking into consideration the essential aspects of the natural molybdopterin, including the phosphate anchor group. Even though some aspects of this protocol require further optimizations, but the mentioned synthetic route has exceptional potential and flexibility.
The synthesis of pterin-dithiolene ligands was achieved by employing the radical nucleophilic substitution, i.e. the so-called “Minisci- Reaction”1. This protocol was used for the first time by Professor W. Pfleiderer on pterin substrates2 and proved a powerful method for the preparation of 6 acyl-pterins in course of this work. Subsequent construction of the dithiolene ring facilitates the synthesis of pterin-dithiolene ligands with completely unprotected pterin moieti.
The molybdenum cofactor is probably one of the most relevant discoveries in the recent history of pterin chemistry and biochemistry. Many efforts have been made for the preparation of compounds able to mimic the features of the Moco ligand system called "Molybdopterin". In fact, the study of MPT models enables a deeper understanding of the “mechanism of function” of this cofactor and most importantly, lays the foundation for a potential treatment for the Moco related diseases MoCOD and iSOD.
Because heavy metal ions prefer to bind sulfur, inspired by molybdopterin the main goal of this work was combining dithiolene binding moieties with optically active substituents with the aim to detect/capture metal ions, which could preferably bind to the dithiolene moiety of for instance MPT. Therefore a number of dithiolene based molecules mimicking the natural immediate coordination sphere composition of Mo and W dependent oxidoreductase enzymes were synthesized and characterized by NMR, MS, IR, X-ray crystallography, UV-Vis, EPR and electrochemical methods. In order to work at the lowest possible base concentration due to potentially base sensitive substituents and reaction partners, the procedure for the de-protection of the ligand precursors and the in situ complexation reaction was first optimized in course of the work and interim we explored the surprising fact that the ring opening reaction of the 1,3- dithiol-2-one system is fully reversible and can be controlled simply by adjusting the pH-value of the solution. Then, the coordination behavior of the de-protected ligands towards different metal ions, including biologically relevant ions like Cu+, Cu2+, Fe3+ was tested. As the optically active substituents necessarily possess interesting electronic properties, a second focus of this work was to utilize the developed ligand systems for MoCo and WCo models and to investigate their potential catalytic activity in the model oxotransfer reaction between DMSO and PPh3 in order to evaluate the substituent’s effect on the dithiolene binding moiety.