Modified natural substances—fluorinated and fluoroalkylated monosaccharides and inositols

In the completion of our fluorine scan of tricyclic inhibitors to map the fluorophilicity/fluorophobicity of the thrombin active site, a series of 11 new ligands featuring alkyl, alkenyl, and fluoroalkyl groups was prepared to explore fluorine effects on binding into the hydrophobic proximal (P) pocket, lined by Tyr 60A and Trp 60D, His 57, and Leu 99. The synthesis of the tricyclic scaffolds was based on the 1,3-dipolar cycloaddition of azomethine ylides, derived from L-proline and 4-bromobenzaldehyde, with N-(4-fluorobenzyl)maleimide. Introduction of alkyl, alkenyl, and partially fluorinated alkyl residues was achieved upon substitution of a sulfonyl group by mixed Mg/Zn organometallics followed by oxidation/deoxyfluorination, as well as oxidation/reduction/deoxyfluorination sequences. In contrast, the incorporation of perfluoroalkyl groups required a stereoselective nucleophilic addition reaction at the "upper" carbonyl group of the tricycles, thereby yielding scaffolds with an additional OH, F, or OMe group, respectively. All newly prepared inhibitors showed potent biological activity, with inhibitory constants (K(i) values) in the range of 0.008-0.163 microM. The X-ray crystal structure of a protein-ligand complex revealed the exact positioning of a difluoromethyl substituent in the tight P pocket. Fluorophilic characteristics are attributed to this hydrophobic pocket, although the potency of the inhibitors was found to be modulated by steric rather than electronic factors.

Mapping the fluorophilicity of a hydrophobic pocket: synthesis and biological evaluation of tricyclic thrombin inhibitors directing fluorinated alkyl groups into the p pocket.

The trifluoromethyl and perfluoroalkyl functional groups possess significant thermal, chemical, and metabolic stability, as well as high lipophilicity and electronegativity. These physicochemical properties render fluorinated carbon residues indispensable in diverse applications, such as agrochemistry, drug design, and material chemistry. The generation and properties of nucleophilic perfluoroalkyl reagents as well as the scope and limitations of their additions to various electrophilic partners is described in this chapter.


Keywords:

fluorine;
trifluoromethyl;
perfluoroalkyl;
nucleophilic addition

Cecile Boyer

Papers

Synthesis of homochiral 2-C-perfluoroalkyl substituted d- and l-riboses