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The insertion of fluorine atoms and/or fluoroalkyl groups can lead to many beneficial effects in biologically active molecules, such as enhanced metabolic stability, bioavailability, lipophilicity, and membrane permeability, as well as a strengthening of protein-ligand binding interactions. However, this "magic effect" of fluorine atom(s) insertion can often be meaningless. Taking advantage of the wide range of data coming from the quest for carbonic anhydrase (CA) fluorinated inhibitors, this Minireview attempts to give "general guidelines" on how to wisely insert fluorine atom(s) within an inhibitor moiety to precisely enhance or disrupt ligand-protein interactions, depending on the target location of the fluorine substitution in the ligand. Multiple approaches such as ITC, kinetic and inhibition studies, X-ray crystallography, and NMR spectroscopy are useful in dissecting single binding contributions to the overall observed effect. The exploitation of innovative directions made in the field of protein and ligand-based fluorine NMR screening is also discussed to avoid misconduct and finely tune the exploitation of selective fluorine atom insertion in the future., (© 2021 Wiley-VCH GmbH.)

The accumulation of chiral ammonium‐oxocarbenium dications in superacid is evidenced by low‐temperature NMR spectroscopy, X‐ray diffraction analysis and confirmed by DFT calculations. Its potential for the diastereoselective remote hydrofunctionalization of non‐activated alkene is also explored. [ABSTRACT FROM AUTHOR]

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 Csp3−H activation/cyclization or homologation / functionalization of nitrogen‐containing substrates. This study also reveals that this skeletal reorganization can be controlled through protonation interplay. The mechanism of this process involves an original sequence of C−N bond cleavage, isopropyl cation generation and subsequent C−N bond and C−C bond formation. This was demonstrated through in situ NMR analysis and labelling experiments, also confirmed by DFT calculations. [ABSTRACT FROM AUTHOR]

Understanding the influence of emerging fluorinated motifs is of a crucial importance in the context of the exponentially growing exploitation of fluorine in many fields. Herein, we report on the dramatic effect of a local partial charge inversion by replacing a CHCH3 group by a CFCF3. This strategy allows the diastereoselective reduction of 5-membered ring oxocarbenium ions to access highly substituted tetrahydrofurans. [ABSTRACT FROM AUTHOR]

The insertion of fluorine atoms and/or fluoroalkyl groups can lead to many beneficial effects in biologically active molecules, such as enhanced metabolic stability, bioavailability, lipophilicity, and membrane permeability, as well as a strengthening of protein–ligand binding interactions. However, this "magic effect" of fluorine atom(s) insertion can often be meaningless. Taking advantage of the wide range of data coming from the quest for carbonic anhydrase (CA) fluorinated inhibitors, this Minireview attempts to give "general guidelines" on how to wisely insert fluorine atom(s) within an inhibitor moiety to precisely enhance or disrupt ligand–protein interactions, depending on the target location of the fluorine substitution in the ligand. Multiple approaches such as ITC, kinetic and inhibition studies, X‐ray crystallography, and NMR spectroscopy are useful in dissecting single binding contributions to the overall observed effect. The exploitation of innovative directions made in the field of protein and ligand‐based fluorine NMR screening is also discussed to avoid misconduct and finely tune the exploitation of selective fluorine atom insertion in the future. [ABSTRACT FROM AUTHOR]

An expansive NMR‐based structural analysis of elusive glycosyl cations derived from natural and non‐natural monosaccharides in superacids is disclosed. For the first time, it has been possible to explore the consequence of deoxygenation and halogen substitution at the C2 position in a series of 2‐halogenoglucosyl, galactosyl, and mannosyl donors in the condensed phase. These cationic intermediates were characterized using low‐temperature in situ NMR experiments supported by DFT calculations. The 2‐bromo derivatives display intramolecular stabilization of the glycosyl cations. Introducing a strongly electron‐withdrawing fluorine atom at C2 exerts considerable influence on the oxocarbenium ion reactivity. In a superacid, these oxocarbenium ions are quenched by weakly coordinating SbF6− anions, thereby demonstrating their highly electrophilic character and their propensity to interact with poor nucleophiles. [ABSTRACT FROM AUTHOR]

Upon activation under superacid conditions, functionalized tailor-made N-SCF3 sulfenamides served as reagents for the trifluoromethylthiolation of aromatic amines. This method has a broad substrate scope and can be used for the late-stage functionalization of complex molecules such as alkaloids or steroids. Mechanistic studies based on in situ low-temperature NMR spectroscopy revealed the involvement of dicationic superelectrophilic intermediates. [ABSTRACT FROM AUTHOR]

A series of substituted pyrrolidines and piperidines were synthesized using superacid HF/SbF5chemistry. Investigated as inhibitors of several human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, i.e. the cytosolic hCA I and II as well as the tumor-associated transmembrane isoforms hCA IX and XII, these compounds showed a never yet reported selectivity toward the human carbonic anhydrase hCA II. In the tertiary benzenesulfonamide family, this class of inhibitors points out a new mechanism of action for human carbonic anhydrase II inhibition. [ABSTRACT FROM AUTHOR]

Superacid activation of N‐SCF3 sulfenamide reagents generates diprotonated superelectrophilic species for the trifluoromethylthiolation of aromatic amines, as shown by T. Billard, S. Thibaudeau, and co‐workers in their Communication on page 173 ff. This method can be used for the late‐stage functionalization of complex biomolecules such as alkaloids and steroids. [ABSTRACT FROM AUTHOR]

Abstract: A novel series of 4-aminobenzofused sultams was prepared using an efficient synthetic procedure based on superacid mediated reactions followed either by copper-catalyzed coupling or SNAr reactions. The synthetic potential of the method toward the divergent synthesis of novel potent bioactive (fluorinated) aminobenzofused sultams and fluorinated 4-aminobenzene sulfonamides was shown, making it a new valuable process to synthesize a large diversity of compounds in bioactive 4-aminobenzene sulfonamide family. [ABSTRACT FROM AUTHOR]