Expanding the Repertoire\nof Large Scaffolds with <i>Syn</i> and <i>Anti</i> Macrocyclic Metacyclophanes

Understanding how changes in structure\ntranslate to changes\nin\nmolecular shape is key to catalyst optimization and molecular design\nin medicinal chemistry and materials. One key contributor to the molecular\nshape is the relative orientation of substituents on a scaffold. Macrocyclic\nmetacyclophanes display their two arenes in a parallel or antiparallel\nfashion, resulting in <i>anti</i> or <i>syn</i> conformations that lead to disparate relative orientations of the\naryl substituents. This work reports the synthesis of new 14- and\n16-membered metacyclophanes and the elucidation of their <i>anti</i>/<i>syn</i> preferences by <sup>1</sup>H NMR and computational\nconformational analysis. Most metacyclophanes studied herein display\na strong <i>anti</i> or <i>syn</i> preference\nand, thus, have well-defined substituent orientations. We propose\nthat <i>anti</i>/<i>syn</i> conformational preferences\narise from the minimization of torsional strain along the backbone\nof the macrocycle, which leads to the prediction that metacyclophanes\nwith remote aryl substituents will adopt the same conformation as\ntheir unsubstituted counterparts. Exit vector analysis also reveals\nthat <i>anti</i>-metacyclophanes project their substituents\ninto regions in three-dimensional space that are not accessed by other\ncommon large scaffolds, e.g., [2.2]paracyclophanes and ferrocenes.\nThis work also demonstrates how ring size and functional groups, two\nparameters commonly optimized in macrocycle design, can be used to\ntune molecular shape.