Strengthening an Intramolecular Non‐Classical Hydrogen Bond to Get in Shape for Binding

Abstract In this research article, we report on the strengthening of a non‐classical hydrogen bond (C−H⋅⋅⋅O) by introducing electron withdrawing groups at the carbon atom. The approach is demonstrated on the example of derivatives of the physiological E‐selectin ligand sialyl Lewis x ( 1 , sLe x ). Its affinity is mainly due to a beneficial entropy term, which is predominantly caused by the pre‐organization of sLe x in its binding conformation. We have shown, that among the elements responsible for the pre‐organization, the stabilization by a non‐classical hydrogen bond between the H−C5 of l ‐fucose and the ring oxygen O5 of the neighboring d ‐galactose moiety is essential and yields 7.4 kJ mol −1 . This effect could be further strengthened by replacing l ‐fucose by 6,6,6‐trifluoro‐ l ‐fucose leading to an improved non‐classical H‐bond of 14.9 kJ mol −1 , i.e., an improved pre‐organization in the bioactive conformation. For a series of glycomimetics of sLe x ( 1 ), this outcome could be confirmed by high field NMR‐shifts of the H−C5 Fuc , by X‐ray diffraction analysis of glycomimetics co‐crystallized with E‐selectin as well as by isothermal titration calorimetry. Furthermore, the electron‐withdrawing character of the CF 3 ‐group beneficially influences the pharmacokinetic properties of sLe x mimetics. Thus, acid‐stability, a prerequisite for gastrointestinal stability, could be substantially improved.