Abstract
Differing in pseudoatom, three macrocycles with isosteric substitutions (geminal dimethyl, cyclopropyl, cyclobutyl) can be described as choreoisosteres. Under ambient conditions, they share a dynamic hinge-like motion that can be described as fully revolute in solution. The barriers to hinging, ΔG (‡), are identical within experimental error: ΔG (‡) = 14.2-15.2 kcal/mol as judged by variable-temperature (13)C NMR spectroscopy. Consistent with conserved dynamic behavior and isosterism, other physical properties including hydrophobicity and solution/membrane diffusion constants are amenable to prediction.