Sara Damiani
| Synthesis and Investigation of Fluorinated Scaffolds Exhibiting Through-Space Scalar 19F –19F NMR Coupling |
| Damiani Sara1, Oštrek Andraž 1, Lozinšek Matic 2, Zupančič Špela 1, Peršolja Peter 1, Satta Giuseppe 3, Plavec Janez 3 and Cotman Andrej Emanuel 1 1 University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia; 2 Jožef Stefan Institute, Jamova cesta 39, 1000 Ljubljana, Slovenia; 3 Kemijski inštitut, Hajdrihova 19,1000 Ljubljana, Slovenia |
| Abstract Fluorinated functional groups play a central role in modern medicinal and chemical research due to their strong influence on molecular conformation, physicochemical properties, and intermolecular interactions [1]. Among them, the trifluoromethyl (CF3) group is particularly important [2]. In this work we report design, synthesis and characterization of α-phthalimido-trifluoromethyl carbinols as precursors of homochiral JFF-detected H-bond sensors. Following a modified literature procedure on phenylalaninol [3], preliminary studies on the corresponding α-phthalimido-aldehydes revealed a selective mono-trifluoromethylation only at -78 °C, while double addition with Rupert–Prakash reagent occurs only at higher temperature. The obtained hit compound was prepared on a gram scale with a diastereomeric ratio of 44:39:7:10. One of the diastereomers displayed a peculiar pattern in the 19F NMR spectrum, characterized by a pentet and a quartet corresponding to the tertiary and quaternary carbon-bound CF3 group. Single-crystal X-Ray diffraction analysis confirmed close proximity of the two CF3 groups and the relative (R*,R*,S*) configuration revealing a hydrogen-bond-gated 19F–19F through-space scalar coupling [4]. Understanding the structural origin of this phenomenon could enable the rational design of fluorinated molecular systems acting as NMR-responsive probes. Therefore, motived by the use of CF3 as promising probe for 19F NMR [4], we started to explore β-carboxamido trifluoromethyl carbinols as potential systems in which hydrogen-bond modulation controls the presence or absence of through-space 19F –19F scalar coupling. Namely, solvent-dependent 19F NMR experiments were performed, revealing a disruption of this hydrogen bond in DMSO-d6/buffer mixtures and the consequent disappearance of the scalar coupling pattern, confirming the dynamic and solvent-sensitive nature of the system. Moreover, to explore potential pharmaceutical application, the hit compound was incorporated into lipid-based delivery systems to evaluate whether the characteristic 19F –19F coupling could still be observed in a biomimetic lipophilic environment through 19F 2D NMR experiments. The results are expected to contribute to the broader understanding of fluorine-based molecular reporters and to support the development of responsive fluorinated systems for chemical and biochemical applications. |
| References [1] Müller, K.; Faeh, C.; Diederich, F., Fluorine in Pharmaceuticals: Looking Beyond Intuition, Science, 2007, 317, 1881 1886. https://doi.org/10.1126/science.1131943. [2] Novás, M.; Matos, M.J. The Role of Trifluoromethyl and Trifluoromethoxy Groups in Medicinal Chemistry: Implications for Drug Design. Molecules 2025, 30, 3009. https://doi.org/10.3390/molecules30143009 [3] Eeda, V.; Selvaraju, M.; Altman, R. A., Synthesis of Leu-enkephalin peptidomimetics containing trifluoromethylalkenes as amide isopolar mimics, J. Fluor. Chem. 2019, 218, 90–98. https://doi.org/10.1016/j.jfluchem.2018.12.005. [4] Orton, H. W.; Qianzhu, H.; Abdelkader, E. H.; Habel, E. I.; Tan, Y. J.; Frkic, R. L.; Jackson, C. J.; Huber, T.; Otting, G., Through-Space Scalar 19F-19F Couplings between Fluorinated Noncanonical Amino Acids for the Detection of Specific Contacts in Proteins, J. Am. Chem. Soc. 2021, 143 (46), 19587–19598. https://doi.org/10.1021/jacs.1c10104. |