Development of Bioorthogonal Iridium Catalysts for Transfer Hydrogenation and Intramolecular Tishchenko-type Reactions

Bioorthogonal chemistry refers to chemical reactions that can occur in living systems without disrupting normal biological processes. These reactions are highly selective and can be used to label or modify specific biomolecules in cells or organisms. This has the potential to be useful in solving biological problems, such as identifying the location and function of specific proteins, studying cell signaling pathways, and developing new diagnostic and therapeutic tools for diseases. The main theme of this dissertation is the development of bioorthogonal metal catalysts for potential therapeutic applications. The oxidation and reduction of substrates in biological systems are catalyzed by dehydrogenase and reductase enzymes, respectively. Many oxidative stress-related diseases, including diabetes, cardiovascular diseases, neurodegenerative disorders (e.g., Alzheimer's and Parkinson's), and cancer have been associated with deficiencies in these enzymes. In the first project, our research goal is to develop a detoxification method utilizing small molecule intracellular metal catalysts (SIMCats) as reductase enzyme mimics to catalytically convert toxic aldehydes to non-toxic alcohols. We have previously shown that pentamethylcyclopentadienyl (Cp*) iridium complexes are able to convert aldehyde to alcohol inside living cells. To expand on this work, we have prepared multinuclear iridium transfer hydrogenation catalysts that show higher activity per iridium in comparison to that of their parent mononuclear iridium analogues, even at nanomolar iridium concentrations. These findings suggest that the use of multi-metallic centers is a useful strategy to enhance catalytic activity. These new transfer hydrogenation catalysts could have potential applications in the remediation of toxic aldehydes that are formed as a result of oxidative stress or exposure to environmental pollutants.

In the second project, we demonstrated that Cp* iridium complexes can selectively produce lactones from dialdehydes under physiologically relevant conditions. Lactones such as phthalides have antimicrobial, anti-platelet, analgesic, antifungal, and antioxidant properties. A classical method to synthesize phthalides is using an intramolecular Tishchenko reaction, which is a disproportionation reaction that converts dialdehydes to lactones. Here we show the first example of iridium catalyzed Tishchenko reactions under physiologically relevant conditions. This bioorthogonal reaction can have useful applications in biology and medicine. For example, it could be used to convert non-toxic precursor dialdehyde molecules to biologically active phthalide compounds.