Synthesis, separation, and structural analysis of planar chiral carboxy-substituted [2.2]metacyclophanes

A two-step synthesis of carboxy-functionalized planar chiral [2.2]metacyclophanes from m-xylenes is described. Both transformative steps utilize LiNK metalation conditions (BuLi, KOt-Bu, TMP(H)) for m-xylene benzylic deprotonation with subsequent in situ oxidative C–C coupling. Inclusion of the carboxy substituents at either C4, or C4 and C14, renders the [2.2]metacyclophanes planar chiral and the structural analysis of both substitution patterns has been achieved with X-ray crystallography and NMR spectroscopy. The C4 mono- and C4/14 di-substituted carboxylic acid methyl ester racemates were readily separated by analytical and preparative chiral HPLC and their inversion barriers measured in heptanes at 373 K at 125.3 kJ/mol and 130.9 kJ/mol, respectively. The facile synthesis, separation, and high inversion barriers of planar chiral [2.2]metacyclophanes present an opportunity for their investigation as chiral catalysts and ligands, which to date has yet to be explored.