FKKT

Advanced Organic Synthesis and Catalysis

P1-0179

Duration: 1.1.2020 - 31.12.2027

Asymmetric organocatalysis is the use of small chiral organic molecules (organocatalysts) that stereoselectively catalyze the formation of C-C and C-X bonds. The breakthrough of asymmetric organocatalysis and its exponential development did not occur until 2000 with the pioneering work of Benjamin List and David W. C. MacMillan, for which they were awarded the 2021 Nobel Prize in Chemistry. A key advantage of organocatalysts is the absence of potentially toxic metals, their stability in the presence of oxygen and moisture, and their easy availability in the synthesis of natural compounds from the chiral pool. In our group we are engaged in the development of new, especially non-covalent bifunctional organocatalysts based on hydrogen bonding. Known bifunctional organocatalysts are based on a handful of privileged chiral frameworks such as quinine alkaloids and amino acid derivatives, cyclohexane-1,2-diamine, 1,2-diphenyl-1,2-diamine, and 1,1'-binaphthyl. We have developed effective non-covalent organocatalysts based on 1,3-diamine derivatives of camphor for the addition of 1,3-dicarbonyl compounds and heterocyclic pyrrolone nucleophiles to trans-β-nitrostyrene derivatives. We are also engaged in the development of potential new hydrogen bond donors, alternatives to the established (thio)urea and (thio)squaramide donors. Another part of the research deals with organocatalyzed asymmetric derivatizations of heterocycles to 3D-rich products. Both established and new organocatalysts are evaluated. Both parts of the research are accompanied by the investigation of the mechanism of action of the organocatalysts in specific conversions.

Photocatalysis with visible light has become a widely used method in organic synthesis in the last decade. Light enables various photocatalytic conversions for many important transformations, such as cross-coupling reactions, α-amino functionalizations, cycloadditions, ATRA, or fluorination reactions. Photocatalytic reactions proceed under milder reaction conditions, usually at room temperature, and the stoichiometric reagents are replaced by simple oxidants or reducing agents such as air, oxygen or amines. Does visible light photocatalysis have implications for organic synthesis? The ability to transfer electrons back and forth to substrates and intermediates, or to selectively transfer energy using a photocatalyst that absorbs visible light, promises to improve current processes in radical chemistry and open new avenues with access to previously unknown reactive species, especially by combining photocatalysis with organic or metal catalysis. In our program group, we are currently focusing on photochemical and photoredox transformations of 3-pyrazolidinones, 3-pyrazolidinone-1-azomethine imines, and fluorescent cycloadducts of copper-catalyzed azomethine-imine-alkyne cycloadditions (CuAIAC), and we are expanding our research into the area of ATRA reactions, photocyclizations, and photochemical cycloadditions.

The synthesis of chemically degradable and renewable organic materials is based on the use of previously acquired knowledge and many years of experience in the study of the chemistry of enaminones (vinylogous amides), which are widely used difunctional reagents in organic synthesis. In contrast, their polymeric analogues (polyenaminones) are still poorly studied. We have recently shown in our research group that polyenaminones can also be synthesised by acid-catalysed transamination of bis-enaminones. In this way, we have produced optically active polyenaminones with interesting absorption properties that can also be easily chemically degraded or even recovered. Chemically renewable polymers are also compatible with the circular economy, which is critical to the pursuit of sustainable development worldwide. Continuing our research on polyenaminones, we are also focusing our attention on redox-active polyenaminones that would be useful in energy storage and conversion systems, which would also help reduce dependence on fossil energy sources.

The biochemistry and bioorganic chemistry of the program group focuses on the development of enzyme inhibitors based mainly on the structures of small organic molecules that we synthesize in our synthetic studies in the field of organic chemistry. Based on the results of testing the biological activity of the aforementioned small molecules for inhibitory activity and simultaneous in silico assays, we attempt to predict the appropriate interactions of the small molecules with macromolecules (mainly enzymes) for the rational design of inhibitors. In our group, we have so far succeeded in synthesizing inhibitors of proteases from the cysteine cathepsin family and inhibitors of dihydroorotate dehydrogenase from Plasmodium falciparum (the causative agent of malaria). Among the target enzymes we are studying as part of the program group are proteases - enzymes that catalyze the cleavage of peptide bonds. We are focusing mostly on cysteine proteases from the caspase (mostly metacaspase) and papain-like families (cysteine cathepsins). For these enzymes, we use a variety of biochemical methods to investigate the mechanisms and roles of these proteins in various physiological and pathophysiological processes. At the same time, we use recombinant DNA methods to generate proteases that do not yet exist in nature, thus creating new enzymes with the desired properties.

More detailed information is available on the website of the programme group.