Superacid-Synthesized Fluorinated Diamines Act as Selective hCA IV Inhibitors.

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.

Leveraging long-lived arenium ions in superacid for meta-selective methylation.

Electrophilic aromatic substitution is one of the most mechanistically studied reactions in organic chemistry. However, precluded by innate substituent effects, the access to certain substitution patterns remains elusive. While selective C-H alkylation of biorelevant molecules is eagerly awaited, especially for the insertion of a methyl group whose magic effect can boost lead molecules potency, one of the most obvious strategies would rely on electrophilic aromatic substitution.

Determination of the Hammett Acidity of HF/Base Reagents.

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 F NMR spectroscopy which allows highly sensitive measures and short-time analyses.

Exploring Superacid-Promoted Skeletal Reorganization of Aliphatic Nitrogen-Containing Compounds.

Here we report a method to reorganize the core structure of aliphatic unsaturated nitrogen-containing substrates exploiting polyprotonation in superacid solutions. The superelectrophilic activation of N-isopropyl systems allows for the selective formal C -H activation/cyclization or homologation / functionalization of nitrogen-containing substrates. This study also reveals that this skeletal reorganization can be controlled through protonation interplay.

Direct Superacid-Promoted Difluoroethylation of Aromatics.

Under superacid conditions, aromatic amines are directly and regioselectively 1,1-difluoroethylated. Low temperature in situ NMR studies confirmed the presence of benzylic α-fluoronium and α-chloronium ions as key intermediates in the reaction. This method has a wide substrate scope and can be applied to the late-stage functionalization of natural alkaloids and active pharmaceutical ingredients.

Access to Optically Pure Benzosultams by Superelectrophilic Activation.

Through superacid activation, -(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.