Conformational Control of Macrocycles by Remote Structural Modification

The conformational analysis of macrocycles is a complex and challenging problem. There are many factors that contribute to this complexity. These include a large number of degrees of freedom, transannular interactions such as hydrogen bonds and hydrophobic interactions, and a range of steric interactions, along with ring strain effects. To a greater extent than within acyclic molecules, these interactions within macrocycles are coupled such that changing one dihedral angle can significantly affect other dihedral angles, further complicating the situation. However, this coupling of bond rotations and transannular interactions enables the transmission of three-dimensional information from one side of a macrocycle to the other. Making relatively small structural modifications to a macrocycle can result in local conformational changes that propagate along the ring to affect distal structural features. The factors that control how such changes can propagate are poorly understood, and it is difficult to predict which modifications will result in significant conformational reorganizations of remote regions of a macrocycle. This review discusses examples where small structural modifications to macrocyclic scaffolds change the conformational preferences of structurally remote regions of the ring. We will highlight evidence provided for conformational changes triggered by remote substituents and explanations of how these changes might occur in an effort to further understand the factors that control such phenomena.