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Carbonic anhydrase (CA) IV is a membrane-bound enzyme involved in important physio-pathological processes, such as excitation-contraction coupling in heart muscle, central nervous system (CNS) extracellular buffering, and mediation of inflammatory response after stroke. Known since the mid-1980s, this isoform is still largely unexplored when compared to other isoforms, mostly for the current lack of inhibitors targeting selectively this isoform. The discovery of selective CA IV inhibitors is thus largely awaited. In this work, we report β-(di) fluoropropyl diamines as effective CA IV inhibitors, opening real perspectives for a new mode of selective inhibition of this isoform. Inhibition data reveal that the essential structure core to ensure a potent and selective inhibition of CA IV is the N-propyldiamine. Molecular modeling studies were employed to understand the binding mode of the synthesized amines. Conformational searches within the active site space carried out in an implicit solvent (water) model were also conducted.

Under superacidic conditions, aniline and indole derivatives are sulfonylated at low temperature with easy-to-access arenesulfonic acids or arenesulfonyl hydrazides. By modification of the functional-group directing effect through protonation, this method allows nonclassical site functionalization by overcoming the innate regioselectivity of electrophilic aromatic substitution. This superacid-mediated sulfonylation of arenes is complementary to existing methods and can be applied, through protection by protonation, to the late-stage site-selective functionalization of natural alkaloids and active pharmaceutical ingredients.

Carbohydrates (glycans, saccharides, and sugars) are essential molecules in all domains of life. Research on glycoscience spans from chemistry to biomedicine, including material science and biotechnology. Access to pure and well-defined complex glycans using synthetic methods depends on the success of the employed glycosylation reaction. In most cases, the mechanism of the glycosylation reaction is believed to involve the oxocarbenium ion. Understanding the structure, conformation, reactivity, and interactions of this glycosyl cation is essential to predict the outcome of the reaction. In this Account, building on our contributions on this topic, we discuss the theoretical and experimental approaches that have been employed to decipher the key features of glycosyl cations, from their structures to their interactions and reactivity.

Functionalized angular cycloalkane-fused naphthalenes were prepared using a two-step process involving a Pd-catalyzed Suzuki–Miyaura coupling of aryl pinacol boronates and vinyl triflates followed by a boron trifluoride etherate-catalyzed cycloaromatization.

Through superacid activation, N-(arenesulfonyl)-aminoalcohols derived from readily available ephedrines or amino acids undergo an intramolecular Friedel–Crafts reaction to afford enantiopure benzosultams bearing two adjacent stereocenters in high yields with fully controlled diastereoselectivity. Low-temperature NMR spectroscopy demonstrated the crucial role played by the conformationally restricted chiral dicationic intermediates.

The hydrolysis of glycosides is a biochemical transformation that occurs in all living organisms, catalyzed by a broad group of enzymes, including glycoside hydrolases. These enzymes cleave the glycosidic bond via a transition state with substantial oxocarbenium ion character, resulting in short-lived oxocarbenium ion-like species. While such transient species have been inferred through theoretical studies and kinetic isotope effect measurements, their direct spectroscopic characterization remains challenging. In this study, we exploit a superacid environment to generate, accumulate, and fully characterize nonprotected 2-deoxy glycosyl cations in the d-glucopyranose, d-galactopyranose, and l-arabinofuranose series using low-temperature NMR spectroscopy, supported by DFT calculations. Additionally, QM/MM MD simulations reveal that the properties of these glycosyl cations in superacid closely resemble those within the active sites of glycosidase enzymes, particularly in terms of conformation and anomeric charge distribution. These findings highlight a parallel between the stabilizing effect of counterions in superacid media and the network of multidentate noncovalent interactions within glycosidase active sites, which stabilize transition states with pronounced oxocarbenium ion character.

Harnessing the acidity of HF/base reagents is of paramount importance to improve the efficiency and selectivity of fluorination reactions. Yet, no general method has been reported to evaluate their acidic properties, and experimental designs are still relying on a trial-and-error approach. We report a new method based on 19F NMR spectroscopy which allows highly sensitive measures and short-time analyses. Advantageously, the basic properties of the indicators can be determined upstream by DFT calculations, affording a simple yet robust semiempirical approach. In particular, the indicators used in this study were rationally designed to fit on the conceptually appealing and commonly used Hammett scale. This method has been applied to commercially available and recently developed HF/base reagents.

Due to their combined stability and peculiar reactivity, ynamides have emerged as remarkably useful building blocks for chemical synthesis. The development of general and robust methods for their preparation has resulted in a massive interest in their chemistry. This notably gave rise to the development of incredibly efficient processes starting from these building blocks, which also recently found various applications in medicinal chemistry and natural product synthesis. Our efforts and contributions to the chemistry of ynamides, for which we have developed several reactions both for their preparation and for their use in synthesis, are overviewed in this highlight review.