Computational Chemistry, Computational Drug Design, Reaction Mechanism Investigation
26
Scopus Publications
Scopus Publications
Enantioselective Pd-Catalyzed Electrochemical Dearomative Allylation of Tropones: Construction of All-C Quaternary Stereocenters Giulia Monda, Sofia Kiriakidi, Olalla Nieto Faza, Andrea Mazzanti, Giulio Bertuzzi, Marco Bandini Organic Letters, 2026 A Pd-catalyzed electroreductive enantioselective dearomatization of tropones is documented. High levels of chemoselectivity toward the formation of seven-membered ring ketones featuring a stereochemically controlled all-carbon α-stereocenter are successfully accomplished by means of a Tsuji–Trost-like process (24 examples, regioselectivity >25:1, enantiomeric ratio of up to 96:4). Computational and electrochemical analyses allowed elucidation of the reaction manifold that involves initial reduction of the tropone motif and a subsequent chemo- and enantioselective allylation via an outer-sphere approach. In this way, a novel concept for the dearomatization of electron-poor scaffolds is disclosed by means of electrochemical reductive umpolung.
Dual Au(I) Catalysis in Regioselective Cycloaddition of Bicyclo[1.1.0]butanes with Allenes Riccardo Giovanelli, Giulio Gallorini, Yuhao Huang, Andrea Brunetti, Kyriakos D. Nikopoulos, Magda Monari, Carlos Silva López, Sofia Kiriakidi, Giulio Bertuzzi, Marco Bandini ACS Catalysis, 2025 A formal [2π+2σ] cycloaddition between electron-rich allenes and bicyclobutanes (BCBs), under a gold-catalyzed regime, is reported. A dual gold activation mechanism was revealed through kinetic studies and further supported by detailed DFT analysis, introducing intriguing paradigms into the dual activation strategy of homogeneous Au catalysis. This protocol enables the synthesis of a broad array of densely functionalized bicyclohexanes (32 examples) in high yields (up to 93%) with complete regioselectivity and stereoselectivity.
Three-Way Chemodivergent Derivatization of Non-Activated 2-Arylphenyl Benzyl Ethers Marta Solas, Carlos Sedano, Samuel Suárez-Pantiga, Sofia Kiriakidi, Carlos Silva-López, Roberto Sanz Journal of Organic Chemistry, 2025 High Resolution Image Download MS PowerPoint Slide A thermally controlled rare chemodivergent mechanistic trifurcation has been found through experimental and computational efforts. Notably, one of the available paths in this three-way mechanism allows for an unprecedented dearomatization reactivity of non-activated 2-arylphenyl benzyl ethers under very mild thermal conditions after Csp 3 –H bond functionalization through α-lithiation, bringing easy access to regioselectively functionalized dearomatized benzochromene scaffolds via anionic dearomatization enabled by carbolithiation of a non-activated aromatic ring. A [1,2]-Wittig rearrangement and a benzyl migration reaction complete the available product alternatives. Moreover, a delicate but useable balance within this reaction path manifold permits steering the reactivity toward each of the three possible products. A kinetically-, thermodynamically- and quantum tunneling-controlled path can be selected to afford one of its three possible products by only tuning reaction time and temperature.
Electrochemical Chemo- and Regioselective Heterofunctionalization of Tropones via C(sp2)H Derivatization Mauro Garbini, Samuele Moncullo, Sofia Kiriakidi, Manuela Melucci, Sara Bellini, Chiara Zanardi, Carlos Silva López, Giulio Bertuzzi, Marco Bandini Advanced Synthesis and Catalysis, 2025 A general electrochemical synthetic procedure for the site‐selective heterofunctionalization of activated tropones is documented. Detailed voltametric analysis and quantum chemistry calculations enabled the development of a predictive model for the process efficiency, accounting for both reactivity and regioselectivity. Mono‐ and poly‐halogenation, nitration, sulfonation, and thiocyanation protocols are successfully executed starting from inexpensive sodium salts under oxidative electrolytic conditions (35 examples, isolated yields up to 95%, faradaic efficiencies up to 95%). The implementation of an iterative electrochemical/metal‐catalyzed cross‐coupling synthetic strategy, along with the adaptation of the protocol for the preparation of biologically relevant tropolone derivatives, underscores the generality and robustness of the methodology.
Electrochemical Nickel-Catalyzed C(sp2)-H Functionalization of Tropones with Aldehydes Andrea Brunetti, Sofia Kiriakidi, Mauro Garbini, Giulia Monda, Chiara Zanardi, Carlos Silva López, Giulio Bertuzzi, Marco Bandini ACS Catalysis, 2025 A direct electroreductive functionalization of tropones employing aldehydes as alkylating agents is reported. This C(sp2)-H functionalization process leverages the mediation of electroactive nickel complexes, enabling a wide range of both native and substituted tropones (44 examples) to be alkylated selectively at the α-position in high yields (up to 90%). Combined elec-trochemical, spectroelectrochemical and computational analyses disclosed the whole mechanistic pathway and revealed the key role played by reduced Ni complexes in activating the tropone core toward condensation with the aldehydes
Exploring Hypertension: The Role of AT1 Receptors, Sartans, and Lipid Bilayers Nikitas Georgiou, Eleni Chontzopoulou, Efthymios Alexandros Routsi, Irene Georgia Stavrakaki, Errikos Petsas, Nikoletta Zoupanou, Margarita Georgia Kakava, Demeter Tzeli, Thomas Mavromoustakos, Sofia Kiriakidi ACS Omega, 2024 The rational design of AT1 receptor antagonists represents a pivotal approach in the development of therapeutic agents targeting cardiovascular pathophysiology. Sartans, a class of compounds engineered to inhibit the binding and activation of Angiotensin II on the AT1 receptor, have demonstrated significant clinical efficacy. This review explores the multifaceted role of sartans in mitigating hypertension and related complications. We highlight the integration of crystallography, computational simulations, and NMR spectroscopy to elucidate sartan-AT1 receptor interactions, providing a foundation for the next-generation antagonist design. The review also delves into the challenges posed by the high lipophilicity and suboptimal bioavailability of sartans, emphasizing advancements in nanotechnology and novel drug delivery systems. Additionally, we discuss the impact of lipid bilayers on the AT1 receptor conformation and drug binding, underscoring the importance of the lipidic environment in receptor-drug interactions. We suggest that optimizing drug design to account for these factors could enhance the therapeutic potential of AT1 receptor antagonists, paving the way for improved cardiovascular health outcomes.
Site-Selective Gold-Catalyzed Alkylation of α‑Aminotropones with Allenes Giulio Gallorini, Sofia Kiriakidi, Sara Bellini, Carlos Silva López, Giulio Bertuzzi, Marco Bandini Organic Letters, 2024 The site-selective alkylation of α-aminotropones is effectively realized via gold(I)-catalyzed electrophilic activation of allenamides and allenyl ethers, yielding up to 85% in 30 examples. A dedicated and combined spectroscopic and computational investigation accounts for both chemo- and regioselective profiles of the protocol. New opportunities in the chemical space of tropone/tropolone derivatives are identified.
Direct Access to Benzolactams and Benzolactones via Nickel Catalyzed Carbonylation with CO2 Riccardo Giovanelli, Giulia Monda, Sofia Kiriakidi, Carlos Silva López, Giulio Bertuzzi, Marco Bandini Chemistry A European Journal, 2024 A new nickel catalyzed cross‐electrophile coupling for accessing γ‐lactams (isoindolinones) as well as γ‐lactones (isobenzofuranones) via carbonylation with CO2 is documented. The protocol exploits the synergistic role of redox‐active Ni(II) complexes and AlCl3 as a CO2 activator/oxygen scavenger, leading to the formation of a wide range of cyclic amides and esters (28 examples) in good to high yields (up to 87 %). A dedicated computational investigation revealed the multiple roles played by AlCl3. In particular, the simultaneous transient protection of the pendant amino group of the starting reagents and the formation of the electrophilically activated CO2‐AlCl3 adduct are shown to concur in paving the way for an energetically favorable mechanistic pathway.
Deciphering Nitroaromatics Reduction: Theoretical Insights into Dioxomolybdenum Catalysis with Biomass-Derived Pinacol Sofia Kiriakidi, Carlos Silva López, Roberto Sanz, Olalla Nieto Faza Chemcatchem, 2024 Density Functional Theory is used to unravel the mechanism of the nitrobenzene to aniline reduction, catalyzed by dioxomolybdenum (VI) dichloride. The use of pinacol as an oxoaccepting reagent and the production of only acetone and water as byproducts, signals a novel and environmentally friendly way to add value to the oxygen‐rich biomass‐derived polyols. The reaction proceeds through three consecutive cycles, each one responsible for one of the three reductive steps needed to yield aniline from nitrobenzene, with nitrosobenzene and hydroxylamine as intermediates. Each cycle regenerates the catalyst and releases one water and two acetone molecules. The mechanism involves singlet/triplet state crossings, a crucial feature in polyoxomolibdate catalyzed processes. The role of the Mo‐coordinated water as the provider of the mysterious protons needed to reduce the nitro group, was revealed. The disclosure of this challenging mechanism and its rate limiting step can contribute to the design of more effective Mo(VI) catalysts.
Fluorinated Biphenyl Phosphine Ligands for Accelerated [Au(I)]-Catalysis Riccardo Pedrazzani, Sofia Kiriakidi, Magda Monari, Irene Lazzarini, Giulio Bertuzzi, Carlos Silva López, Marco Bandini ACS Catalysis, 2024 Fluorinated JohnPhos-type ligands are proposed as accelerating tools in homogeneous gold(I) catalysis, with PedroPhosAuC l ( Cat1 ) as the most efficient one. The ligands as well as the corresponding gold complexes were synthesized in high yields and fully characterized also via single-crystal X-ray diffraction. A secondary interaction between the distal phenyl ring of the phosphane ligand and the metal center is identified as key for the fine-tuning of the overall catalytic performance of the complexes. In particular, kinetic as well as computational analysis revealed that by accommodating F atoms on the biphenyl pendant of the ligand, more reactive organo-gold intermediates are realized toward subsequent nucleophilic condensations. The gold-catalyzed indole-hydroarylation of 1,6-enynes and the intramolecular hydroindolynation of alkynes have been adopted as benchmark reactions to exemplify these accelerating effects.
Quercetin: A Potential Polydynamic Drug Nikitas Georgiou, Margarita Georgia Kakava, Efthymios Alexandros Routsi, Errikos Petsas, Nikolaos Stavridis, Christoforos Freris, Nikoletta Zoupanou, Kalliopi Moschovou, Sofia Kiriakidi, Thomas Mavromoustakos Molecules, 2023
Molecular investigation of artificial and natural sweeteners as potential anti-inflammatory agents Eleni Chontzopoulou, Christina D. Papaemmanouil, Maria V. Chatziathanasiadou, Dimitrios Kolokouris, Sofia Kiriakidi, Athina Konstantinidi, Ioanna Gerogianni, Theodore Tselios, Ioannis K. Kostakis, Evangelia D. Chrysina, Dimitra Hadjipavlou-Litina, Demeter Tzeli, Andreas G. Tzakos, Thomas Mavromoustakos Journal of Biomolecular Structure and Dynamics, 2022
Enhancement of glioblastoma multiforme therapy through a novel Quercetin-Losartan hybrid Antonis D. Tsiailanis, Alexander Renziehausen, Sofia Kiriakidi, Eirinaios I. Vrettos, Georgios S. Markopoulos, Nisar Sayyad, Baydaa Hirmiz, Marie-Isabel Aguilar, Mark P. Del Borgo, Evangelos Kolettas, Robert E. Widdop, Thomas Mavromoustakos, Tim Crook, Nelofer Syed, Andreas G. Tzakos Free Radical Biology and Medicine, 2020
