J. Am. Chem. Soc. 135, 14548–14551 (2013)

Ever since the Nobel-prize-winning work of Noyori, synthetic chemists have taken advantage of the defined steric environment of axially chiral compounds, and their excellent chiral discrimination at metal centres, to create numerous highly efficient catalysts. Axial chirality is maintained by avoiding rotation around a central axis — typically between two biaryl units — and traditionally this has been prevented using steric interactions to destabilize the planar transition state. Now, Aaron Aponick and co-workers at the University of Florida have developed a different strategy — stopping rotation by stabilizing the ground-state conformation of the molecule.

To achieve this they designed a structure containing one biaryl unit linked to a substituted imidazole. The reduced steric demand of the five-membered imidazole ring means that rotation around the central axis would be expected to be facile; however, the presence of a pentafluorobenzyl group on N1 stabilized the chiral ground-state conformations. They obtained the enantiopure compound using a deracemization approach, which involved coordination of the racemate to a chiral palladium complex and subsequent heating in the presence of KPF6. This was then treated with 1,2-bis(diphenylphosphino)ethane, which regenerated the free ligand with an enantiomeric excess of 98%. This compound proved to be configurationally stable over a period of months, and this stability was attributed to π-stacking between the pentafluorophenyl ring and the biaryl unit. This claim was supported by X-ray crystallographic studies — showing π-stacking in the solid state — and by comparison with a sterically similar non-fluorinated analogue. This analogue showed a significantly decreased barrier to rotation and had a half-life of a mere 22 minutes at 75°C, as opposed to 8.7 hours for the original compound.

Aponick and co-workers used the ligand to asymmetrically catalyse an A3-coupling reaction. The results were highly impressive, with enantioselectivities up to 97% and yields up to 95% across a range of substrates. The reaction worked for both aromatic and aliphatic aldehydes, and the selectivity was reasonably insensitive to the presence of electron-donating or withdrawing groups.