Choreoisosteres:Pseudoatom Variation in MacrocyclicHinges Conserves Structure and Dynamics

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, Δ<i>G</i>^‡, are identical within experimental error: Δ<i>G</i>^‡ = 14.2–15.2 kcal/mol as judged by variable-temperature ¹³C NMR spectroscopy. Consistent with conserved dynamic behavior and isosterism, other physical properties including hydrophobicity and solution/membrane diffusion constants are amenable to prediction.