Thesis projecten 2018-2019 onderzoeksgroep LOSA professor Wim Dehaen Project I. Heterocyclic and medicinal chemistry - Novel products with interesting biological properties In this line of research, novel compounds are synthesized starting from either natural products or via functionalization of known biologically active compounds. The biological activity is then improved by making these natural products more drug-like ; for instance by fusing with heterocycles or appending polar groups. A recent research topic is based on the biological activity of certain (hetero)aryl substituted 1,4-naphthoquinones which can be obtained via radical reactions. A second line of research is based on the functionalization of betulin, a terpenoid molecule studied for its cytotixic (anticancer) and antiviral properties. Resulting libraries of compounds are tested for their biological activity by the REGA institute of KU Leuven. Lead compounds resulting from this screening are subsequently developed further in order to optimize the activity. - New multicomponent reactions : synthetic methodology and target-driven synthesis Multicomponent reactions (MCR) are one-pot processes that combine three or more substrates either simultaneously or through a sequential-addition procedure that does not involve any change of solvent. We work on devising processes where there is orthogonal reactivity of the functions A,B,C,D. Existing classical heterocyclic reactions such as the Gewald reaction or 1,3-dipolar cycloaddition are modified to a MCR version; the challenge is to find orthogonal conditions for the reactions involved. Chief among the MCR developed in our lab is the synthesis of 1,2,3-triazoles, starting from enolizable ketones, primary amines and p-nitrophenyl azide. Compounds generated via these MCR are once again screened for their biological activity.
- Synthesis of nitrogen-containing polycyclic compounds with potential biological activities Recently, our group reported a metal-free route towards the synthesis of 1,2,3-triazoles via an organocascade process. This has been applied widely, and was named the triazolization reaction. This method opens up new opportunities to get polycyclic 1,2,3-triazoles after cyclization reactions of appropriately functionalized monocyclic triazoles. For instance, in ongoing work, we have combined our triazolization reaction with a Pomeranz-Fritsch type cyclization and acid-catalyzed ring opening to result in a short synthesis of the alkaloid papaverine. In future work, the same chemistry will be applied for the synthesis of various nitrogen-containing polycyclic compounds with potential biological activities. DNA is one of the more promising biological targets of anti-tumor drugs. Therefore, in a first project, new polyaza structures, triazole- and triazolium-based mono- and dicationic species will be prepared as possible DNA intercallators, via our triazolization reaction on cyclic ketones and and diketones, in combination with cyclization, aromatization, or alkylation reactions. In a second project, we want to devise several methods towards fused indoles, again involving our triazolization reaction and several cyclization strategies. Indole derivatives occur widely in nature in alkaloid structures and diverse bioactivities were reported for these compounds. Below, a few indole containing structures relevant to the project, and their bioactivities, are mentioned.
Project II. Supramolecular chemistry - Homoheteracalixarenes : synthesis and supramolecular binding Homoheteracalixarenes are the larger derivatives of the well-known calix[n]arenes, containing a heteroatom (O,N, S) as a bridging atom. In this project, we want to study post functionalization of these macrocycles (X = O, NR, S) by protection/deprotection strategy of the phenolic functions. After appending functionalities that can be causing for instance anion binding, the binding properties will be measured by spectroscopic techniques. This is a generic strategy that also can be used to append ligands for metal ions of interest in order to get effective chelation. - Heterocyclic analogs of pillararenes Pillar[n]arenes, as the name suggests, are macrocyclic molecules with a pillar like structure when viewed sideways. After crown ethers, cyclodextrins, and calixarenes they are the newest in line of macrocycles. Pillar[n]arenes have received wide recognition in a short period of time due to their superiority over existing traditional host molecules, they. Their interesting structural features and their rigid electron-rich cavity make them good candidates as host molecules. The project aims at the introduction of heteroatoms as the bridging atom X. Diverse synthetic strategies will be used and optimized, starting from substituted hydro- and benzoquinones. Both the synthesis and the supramolecular properties and assemblies of the novel hosts will be investigated. Extensive use will be made of different spectroscopic and physical organic techniques.
Project III Dyes - Selective functionalization of BODIPY dyes The use of fluorescent molecules in new materials is receiving increasing attention in the scientific literature. They are currently used in several organic materials such as LED s, lasing materials and photonic devices. 4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (commercialized as BODIPY ) is currently one of the most studied fluorescent molecules. In recent years our group found and reported several methods of substituting the BODIPY core. We are currently trying to expand these methods towards applications in the field of new molecular materials, sensors and long wavelength emitting dyes. In this project, we will use an aldehyde, amine, azide or other substituted derivatives of BODIPY, that are readily available from our previous studies, to connect 1,2,3-triazoles in a new three-component 1,2,3-triazole synthesis developed recently in our laboratory. The triazoles can then be deprotected to very polar diacids that have good water solubility at neutral ph. The more promising BODIPY-triazole conjugates (from the properties viewpoint) will be converted to activated esters or similar compounds that make conjugation to biomolecules, such as DNA or peptides, possible. - Synthesis of new class HQ-BODIPY chemosensors 8-Hydroxyquinoline (HQ) is a powerful fluorescent metal ion chelator motif which turn-on after metal recognition. Although its exceptional properties, It presents some problems that reduce their chemosensory applications e.g. modest fluorescence changes after metal ion binding, low quantum yields, among others. Boron-Dipyrromethenes (BODIPY s), are robust organic fluorescence molecules with high fluorescence sensor photostability ph independent, large extinction coefficients and high quantum yields. In this project we are synthesizing hybrid HQ-BODIPYs to create a synergism between both molecules improving the photophysical properties required for the application in chemical or biological systems.
Project IV materials - Synthesis of axially chiral compounds Atropoisomerism is a stereochemical phenomenon that arises from hindered rotation around the bond joining the aromatic units in nonplanar molecules which leads to axial chirality. The molecules that display axial chirality often have bulky substituents at the ortho-position of the aryl rings such that there is restricted rotation around the biaryl axis. Atropoisomerism is the key element essential for chirality transfer in enantioselective synthesis. In this project we aim to synthesize novel naphthyltriazoles via multicomponent reactions that were developed in our laboratory. The prepared naphthyltriazoles will be used in enantioselective synthesis. V. Ionic liquids - Novel synthetical pathways towards biosustainable Ionic Liquids Ionic liquids (ILs) are salts devised to be liquid about and below ~100 C (arbitrary temperature). The reduced melting point is a consequence of the steric hindrance and asymmetry of the voluminous cation, which is the main cause in the disruption of a regular crystalline lattice, thus impeding the formation of an organized solid phase. Remarkable physical features are reported for these solvents as negligible vapour pressure, wide liquid-phase window and commonly also high electrochemical, thermal and chemical stability. Additional features can be integrated by modification of the ion-pair couple. This project aims at the synthesis of novel ionic cores by following green chemistry principles, which is a top priority of this research field.