Electrochemical Generation of N-Heterocyclic Carbenes for Use in Synthesis and Catalysis

The electrochemical generation of N-heterocyclic carbenes (NHCs) offers a mild and selective alternative to traditional synthetic methods that usually rely on strong bases and air-sensitive materials. The use of electrons as reagents results in an efficient and clean synthesis that enables the direct use of NHCs in various applications. Herein, the use of electrogenerated NHCs in organocatalysis, synthesis and organometallic chemistry is explored

Organocatalytic Asymmetric Synthesis of Isochromanones, Tetranortriterpenoids and Pyrazolone Derivatives

This thesis explores the applications of organocatalysis and its combination with metal catalysis for the enantioselective synthesis of novel oxygen- and nitrogen-containing heterocycles. The developed procedures rely on both covalent- and hydrogen-bounding organocatalysis and metal coordination catalysis. The first project focused on the development of an efficient asymmetric synthesis of new 4-amino-isochromanones starting from anilines and 2-formylbenzoates. The imine-formation followed by a cis-selective 6-enolexo-exo-trig Mannich reaction catalysed by a tetrazole analogue of proline provided the potentially bioactive title heterocycles with good yields (up to 85%) and excellent stereoselectivities (dr up to 99:1, up to 99% ee). The second developed procedure involved a quadruple domino oxa-Michael/Michael/Michael/aldol reaction followed by a lanthanide catalysed IEDHDA reaction in a one-pot fashion for the synthesis of novel polyfunctionalised tetranortriterpenoids with high yields and excellent stereocontrol. The five reactions occurred smoothly to the formation of six bonds and six stereogenic centres starting from readily available and simple substrates. Furthemore, we investigated a novel desymmetrising cross-dehydrogenative coupling, which relies on an initial Michael addition followed by a combination of aromaticity and extensive conjugation driving to an oxidant- and metal-free hydride elimination. A series of new densely functionalised pyrazoles bearing a quaternary stereocenter were synthesised with high yield and good enantioselectivities. Lastly, the electrophilic reactivity of a series of novel pyrazole-4,5-dione derivatives in the organocatalytic Friedel-Crafts reaction with variously substituted indoles has been tested. The disclosed procedure catalyzed by a cinchona alkaloid derivative allows the conjugation of two very important aza-heterocyclic scaffolds to generate a new class of indolyl-pyrazolones bearing a quaternary stereocenter in excellent yields (up to 99%) and enantioselectivities (up to 88% ee)

Electrogenerated NHCs in organic synthesis: ionic liquids vs organic solvents effects

In the last twenty years, N-heterocyclic carbenes (NHCs) have been extensively studied for their application as organocatalysts in stereoselective synthesis as well as ligands for transition metals-promoted synthetic methodologies. Derived mainly from azolium salts, NHCs have demonstrated exceptional versatility in their generation usually performed by deprotonation or reduction (chemical or electrochemical). In particular, the generation of NHC under electrochemical conditions, starting from azolium-based ionic liquids, has proven to be a successful green approach and demonstrated wide applicability in organic synthesis. In this Personal Account, the application of electrogenerated NHCs in organic synthesis will be discussed, with a particular attention to the different reactivity in ionic liquids compared to classical organic solvents

Sustainable approaches for asymmetric synthesis – from domino reactions to Chiral Carbon Dots as nano-organocatalysts

Organocatalysis is considered the third pilar of asymmetric synthesis and, due to the green aspects of organocatalytic procedures, has paved the way to the extensions of organic stereoselective synthesis horizons towards efficient, practical and more sustainable methodologies. For instance, organocatalyzed cascade reactions and sequential catalysis have been shown to be excellent candidates because of the number of steps that can occur under the same reaction conditions, thereby leading directly to high molecular complexity, in a cost-effective protocol.[1] Additionally, the technological advancement contributed to the application of other techniques such as electroorganic chemistry and photocatalysis to organocatalytic protocols, especially in the transferring of organocatalysis to heterogeneous processes. Within this context, carbon dots (CDs) are an emerging class of carbon-based nanoparticles, characterized by low-toxicity, biocompatibility, excellent suspensibility, and remarkable photoluminescent properties. CDs have therefore found many applications, including heterogeneous catalysis and photocatalysis.[2] In this presentation, some sustainable approaches for asymmetric synthesis will be described: i) the sequential stereoselective synthesis of spiro-decalin oxindoles; ii) electroorganic synthesis of Chiral Carbon Dots and their application as nano-organocatalysts for an asymmetric aldol reaction

Free-radical-mediated formation of trans-cardiolipin isomers, analytical approaches for lipidomics and consequences of the structural organization of membranes

Free-radical-mediated processes, such as peroxidation, isomerization and hydrogenation affecting fatty acid integrity and biological functions, have a trans-disciplinary relevance. Cardiolipins (CL, (1,3-diphosphatidyl-sn-glycerol)) and tetra-linoleoyl-CL are complex phospholipids, exclusively present in the Inner Mitochondrial Membrane (IMM) lipids, where they maintain membrane integrity and regulate enzyme functionalities. Peroxidation pathways and fatty acid remodeling are known causes of mitochondrial disfunctions and pathologies, including cancer. Free-radical-mediated isomerization with the change of the cis CL into geometrical trans isomers is an unknown process with possible consequences on the supramolecular membrane lipid organization. Here, the formation of mono-trans CL (MT-CL) and other trans CL isomers (T-CL) is reported using CL from bovine heart mitochondria and thiyl radicals generated by UV-photolysis from 2-mercaptoethanol. Analytical approaches for CL isomer separation and identification via 1H/13C NMR are provided, together with the chemical study of CL derivatization to fatty acid methyl esters (FAME), useful for lipidomics and metabolomics research. Kinetics information of the radical chain isomerization process was obtained using \u3b3-irradiation conditions. The CL isomerization affected the structural organization of membranes, as tested by the reduction in unilamellar liposome diameter, and accompanied the well-known process of oxidative consumption induced by Fenton reagents. These results highlight a potential new molecular modification pathway of mitochondrial lipids with wide applications to membrane functions and biological consequences

Total synthesis of (-)-parthenolide through a stereoselective approach

(-)-Parthenolide (figure 1, compound 1), a sesquiterpene lactone of the germacranolide class originating from the plant Tanacetum parthenium (Asteraceae family, figure 1.A)1, has been studied as promising treatment against endometriosis2, a severe and highly diffuse feminine disease which causes chronic symptoms3. Moreover, it also shows strong antitumoral properties4, similar to those of the chemotherapic 5-azacytidine, and high selectivity towards target tissues2. Therefore, by proposing a highly stereoselective retrosynthetic pathway (figure 1), the first stereoselective total synthesis of (-)-parthenolide has been approached. The synthetic route will be characterized by the least number of steps, compared to the few already existent semisynthesis5, and enantio and diastereoselectivity will be possible through 4 key steps (figure 1, marked in red): an olefin metathesis (figure 1, B), a diastereoselective epoxidation (figure 1, C), a diastereoselective iodolactonization (figure 1, D), and an enantioselective conjugate addition (figure 1, E). Moreover, compound 4 will be used as common intermediate in two different steps, thus improving the synthesis reactants usage and resources waste for a greener perspective. [1] (EMA), E. M. A. Assessment report on Tanacetum parthenium (L.) Schultz Bip., herba. (HMPC), C. o. H. P., Ed.; 8 July 2020. [2] Freund, R. R. A.; Gobrecht, P.; Fischer, D.; Arndt, H. D. Advances in chemistry and bioactivity of parthenolide. Nat Prod Rep 2020, 37 (4), 541-565. DOI: 10.1039/c9np00049f. [3] Ministero della Salute, Endometriosi. 2021. https://www.salute.gov.it/portale/donna/dettaglioContenutiDonna.jsp?id=4487&area=Salute donna&menu=patologi e. [4] Ghantous, A.; Sinjab, A.; Herceg, Z.; Darwiche, N. Parthenolide: from plant shoots to cancer roots. Drug Discov Today 2013, 18 (17-18), 894-905. DOI: 10.1016/j.drudis.2013.05.005. [5] Li, L.; Pan, X.; Guan, B.; Liu, Z. Stereoselective total synthesis of (±)-parthenolide and (±)-7-epi-parthenolide. Tetrahedron 2016, 72 (29), 4346-4354. DOI: 10.1016/j.tet.2016.05.07

Converging Fate of the Oxidation and Reduction of 8-Thioguanosine

Thione-containing nucleobases have attracted the attention of the scientific community for their application in oncology, virology, and transplantology. The detailed understanding of the reactivity of the purine derivative 8-thioguanosine (8-TG) with reactive oxygen species (ROS) and free radicals is crucial for its biological relevance. An extensive investigation on the fate of 8-TG under both reductive and oxidative conditions is here reported, and it was tested by employing steady-state photooxidation, laser flash photolysis, as well as gamma-radiolysis in aqueous solutions. The characterization of the 8-TG T-1 excited state by laser flash photolysis and the photooxidation experiments confirmed that singlet oxygen is a crucial intermediate in the formation of the unexpected reduced product guanosine, without the formation of the usual oxygenated sulfinic or sulfonic acids. Furthermore, a thorough screening of different radiolytic conditions upon gamma-radiation afforded the reduced product. These results were rationalized by performing control experiments in the predominant presence of each reactive species formed by radiolysis of water, and the mechanistic pathway scenario was postulated on these bases

Free radical-mediated formation of trans-cardiolipin isomers, analytical approaches for lipidomics and consequences for the structural organization of membranes

Free radical-mediated processes, such as peroxidation, isomerization and hydrogenation affecting fatty acid integrity and biological functions have a trans-disciplinary relevance. Cardiolipins [CL, (1,3-diphosphatidyl-sn-glycerol)] and tetra-linoleoyl-CL are complex phospholipids, exclusively present in the Inner Mitochondrial Membrane (IMM) lipids where they maintain membrane integrity and regulate enzyme functionalities. Peroxidation pathways and fatty acid remodeling are known causes of mitochondrial disfunctions and pathologies, including cancer. Free radical-mediated isomerization with the change of the cis CL into geometrical trans isomers is an unknown process with possible consequences on the supramolecular membrane lipid organization. Here, the formation of mono-trans CL and all-trans CL is reported using CL from bovine heart mitochondria and thiyl radicals generated by UV-photolysis from 2-mercaptoethanol. Analytical approaches for CL isomer separation and identification via 1H/13C NMR are provided, together with chemical study of CL derivatization to fatty acid methyl esters (FAME), useful for lipidomics and metabolomics research. Kinetics information of the radical chain isomerization process was obtained using γ-irradiation conditions. The CL isomerization affected the structural organization of membranes, as tested by reduction of unilamellar liposome diameter, and accompanied the well-known process of oxidative consumption induced by Fenton reagents. These results highlight a new molecular modification pathway of mitochondrial lipids with wide applications to membrane functions and biological consequences