In WP1, non-nucleophilic superacid environment was used to generate, accumulate and fully characterize by low-temperature NMR spectroscopy non-protected glycosyl cations. A panel of natural and non-natural carbohydrates were synthetised and submitted to in situ NMR studies. The results were supported by DFT calculations, performed by our collaborators in Bilbao (Pr. J. Jiménez Barbero (CICbioGUNE, Spain)). Estimation of their electrophilic character/reactivity through stability (t°, time) studies and trapping experiments was also performed.
In WP2 we wanted to explore the possibility that some glycosyl cations generated in superacid environment could mimic the cationic TS core of the related glycosyl processing enzymes. At this aim, we turned to QM/MM MD simulations, modelling a superacidic ionic environment. A conformational energy landscape (CEL) map of this cation in superacid was produced and compared to the same glycosyl cations modelled in the relevant enzymes. This work, which necessitates a strong expertise in quantum calculations and access to calculation facilities, was supervised by Dr. C. Rovira at University of Barcelona. This step of the project was also very successful, confirming that structural and electronic properties of the observed glycosyl cations in superacid solution can parallel those observed in the active site of relevant enzymes. This finding led to the conclusion that the strong confinement effect played by superacid can mimic the enzymatic cavity of carbohydrate-active enzyme. Moreover, the persistence of the cations in a preferential conformation in superacid medium led to the stereoselective formation of deuterated and/or fluorinated products after aqueous quenching. This phenomenon confirmed again the analogy between superacid and enzymatic media, opening the way for the use of superacid chemistry to catalyse stereoselective reactions in an enzymatic fashion (Armand M, Nin-Hill A, Ardá A, Berrino E, Désiré J, Martin-Mingot A, Michelet B, Jiménez-Barbero J, Blériot Y, Rovira C, Thibaudeau S, Glycosylium ions in superacid mimic the transition state of enzyme reactions. JACS, just accepted, doi.org/10.1021/jacs.4c11677).
Therefore, in WP3 we aimed gathering more information about conformation and reactivity of glycosyl cations. A first objective was to apply the novel methodology developed herein, combining superacid-DFT-QM/MM dynamic simulations, to stereoselective glycosylation (manuscript in preparation). The second objective was to explore the possibility to exploit the stereoselective generation of cyclic ammonium oxocarbenim dications in superacid to access diastereoenriched amines. In superacid, reactions involving polycationic superelectrophiles have been exploited to generate innovative molecules in bioactive series. However, these reactions are limited by the absence of stereoselective versions (Berrino E. et al, Journal of Medicinal Chemistry Article ASAP, DOI: 10.1021/acs.jmedchem.4c01795). This approach aimed to overcome this limitation, opening the way for the diastereoselective hydrofunctionalization of non-activated alkenes in superacid exploiting in situ generation of chiral cyclic oxocarbenium ions. The study was supported by DFT calculations applied to the determination of reaction mechanisms (Berrino E, Cantin T, Artault M, Beck S, Jessen C, Marrot J, Guégan F, Mingot A, Kornath A, Thibaudeau S. Accumulation, Characterization and Reactivity of Chiral Ammonium-Carboxonium Dications in Superacid. Angew Chem Int Ed Engl. 2024 Jun 3;63(23):e202404066. doi: 10.1002/anie.202404066).
