Two-Dimensional Barriers for Probing Conformational Shifts in Macrocycles.

We describe the development and use of composite two-dimensional barriers in macrocyclic backbones. These tunable constructs derive their mode of action from heterocyclic rearrangements. The Boulton-Katritzky reaction has been identified as a particularly versatile means to effect a composite barrier, allowing the examination of the influence of heterocycle translocation on conformation. Kinetic studies using 1H NMR have revealed that the in-plane atom movement is fast in 17, 18, 19-membered rings but slows down in 16-membered rings. The analysis by NMR and MD simulation experiments is consistent with the maintenance of rare cis-amide motifs during conformational interconversion. Taken together, our investigation demonstrates that heterocyclic rearrangement reactions can be used to control macrocyclic backbones and provides fundamental insights that may be applicable to the development of a wide range of other conformational control elements.