Expanding the Repertoire of Large Scaffolds with Syn and Anti Macrocyclic Metacyclophanes

Understanding how changes in structure translate to changes in molecular shape is key to catalyst optimization and molecular design in medicinal chemistry and materials. One key contributor to the molecular shape is the relative orientation of substituents on a scaffold. Macrocyclic metacyclophanes display their two arenes in a parallel or antiparallel fashion, resulting in anti or syn conformations that lead to disparate relative orientations of the aryl substituents. This work reports the synthesis of new 14- and 16-membered metacyclophanes and the elucidation of their anti/syn preferences by 1H NMR and computational conformational analysis. Most metacyclophanes studied herein display a strong anti or syn preference and, thus, have well-defined substituent orientations. We propose that anti/syn conformational preferences arise from the minimization of torsional strain along the backbone of the macrocycle, which leads to the prediction that metacyclophanes with remote aryl substituents will adopt the same conformation as their unsubstituted counterparts. Exit vector analysis also reveals that anti-metacyclophanes project their substituents into regions in three-dimensional space that are not accessed by other common large scaffolds, e.g., [2.2]paracyclophanes and ferrocenes. This work also demonstrates how ring size and functional groups, two parameters commonly optimized in macrocycle design, can be used to tune molecular shape.