Principles and Applications of CF₂X Moieties as Unconventional Halogen Bond Donors in Medicinal Chemistry, Chemical Biology, and Drug Discovery

Abstract

As an orthogonal principle to the established (hetero)aryl halides, we herein highlight the usefulness of CF 2 X (X = Cl, Br, or I) moieties. Using tool compounds bearing CF 2 X moieties, we study their chemical/metabolic stability and their logP/solubility, as well as the role of XB in their small molecular crystal structures. Employing QM techniques, we analyze the observed interactions, provide insights into the conformational flexibilities and preferences in the potential interaction space. For their application in molecular design, we characterize their XB donor capacities and its interaction strength dependent on geometric parameters. Implementation of CF 2 X acetamides into our HEFLibs and biophysical evaluation (STD-NMR/ITC), followed by X-ray analysis, reveals a highly interesting binding mode for fragment 23 in JNK3, featuring an XB of CF 2 Br toward the P-loop, as well as chalcogen bonds. We suggest that underexplored chemical space combined with unconventional binding modes provides excellent opportunities for patentable chemotypes for therapeutic intervention. ■ SIGNIFICANCEStarting from asciminib, we thoroughly characterize the great potential of CF 2 X moieties as strong halogen bond donors with a multitude of experimental and computational methods. While traditionally halogens in drug-like molecules are only attached to (hetero)aryl systems, these new moieties facilitate the escape from planarity into the third dimension. Hence, they provide completely new opportunities to harness the highly directional XB interactions in drug design and discovery.

Ligand-enabled ruthenium-catalyzed meta-C−H alkylation of (hetero)aromatic carboxylic acids

“…Expectedly, competing esterification could not fully be suppressed for sterically less hindered secondary alkyl bromides ( 3ay ), and esters were found as the main products for primary alkyl halides ( 3az ). The selectivity for C–C coupling over esterification was found to be particularly high for difluoro alkyl electrophiles ( 3bb–mb ), which substantially enhances the preparative utility of the transformation 48 . After all, α-CF 2 carbonyl groups are desirable functionalities in drug discovery, as they are stable towards metabolic degradation via enolate mechanisms 49 , 50 .…”

Chemoselective Synthesis of α-Halo-α,α-difluoromethyl Ketones from Trimethyl(phenylethynyl)silane

“…The trifluoromethyl (CF 3 ) group, in particular, has proven to be a valuable moiety for fine-tuning the lipophilicity and bioavailability of druglike molecules, thereby leading to its high prevalence in agrochemicals and active pharmaceutical ingredients (APIs). Additionally, it also serves as a fundamental element for further development of valuable organic transformations for producing bioactive molecules, drugs, and agrochemicals, etc . Given the increasing demand for abundant molecular libraries and the pursuit of highly complex structures with attractive biomedical activities, the quest for new approaches enabling the selective synthesis of structurally diverse trifluoromethyl ketones (−COCF 3 motif) is of paramount importance as useful synthons in both the scientific and industrial realms.…”

Copper-Mediated Oxidative Chloro- and Bromodifluoromethylation of Phenols

“…Fluoroalkyl ethers are valuable structural motifs in the development of new pharmaceuticals, agrochemicals, and materials because the incorporation of fluoroalkoxy groups into organic compounds often alters their physical, chemical, and pharmacokinetic properties . Among these fluoroalkyl ethers, recently chloro- and bromodifluoromethyl aryl ethers (ArOCF 2 X, X: Cl, Br) are increasingly found as important moieties in biologically active compounds (Figure ) , because of the strength of their halogen bond interactions and their unconventional interaction geometries . For example, asciminib was approved by the FDA in 2021 as a BCR-ABL1 allosteric inhibitor .…”