Bridging Heterocycle-Mediated Hydrogen Bonding Facilitates Permeability of Polar Macrobicycles

Octafluorocyclopentene engages linear, unprotected peptides in relative-rate-controlled polysubstitution cascades. In one flask at ambient temperature, the reactions generate stable, fluoro-crowned macrobicyclic structures that display dual-loop surfaces. A subset of these molecules was found to have unusually high membrane permeability, as measured by PAMPA. Structures with a bridging imidazole unit were overrepresented in this group. To probe this finding, a larger set of compounds was synthesized wherein peripheral functionality and the bridging residue were incrementally varied. Crystallographic data, NMR studies, and MD simulations indicate the imidazole-bridged structures adopt conformations stabilized by internal H-bonding. The heterocycle further serves to occlude cavity water and allows macrobicycles harboring polar residues, such as serine and aspartate, to retain passive permeability. Calculations reveal a quantity termed 'desolvation cost efficiency' that is predictive of PAMPA performance. This parameter may be leveraged for the de novo design of polar peptidomimetics that can enter cells passively.