Piggyback your catalyst to get good ee and good conversion

17 September 2005

In a recent conference presentation Garett Hoge of Pfizer described a common conundrum facing development chemists when screening chiral ligands for an asymmetric reaction — Rh catalysed hydrogenation of the enamide, shown below, using Binapine as ligand gives higher
ee (98%), but lower conversion and higher catalyst loading than the alternative ligand trichickenfootphos (see J. Am. Chem. Soc., 2004, 126, 5966) which gives lower ee (94%), but full conversion.

One solution, suggested by a co-worker, was to run the hydrogenation of the enamide using Rh-Binapine until the reaction stopped at ~85% conversion (97% ee) and then to add trichickenfootphos to complete the reaction giving >99% conversion and 96% ee. The reaction was reproducible at production scale, although subsequent work has shown that the selectivity of the trichickenfootphos catalyst is affected by the water content of the reaction mixture or indeed the presence of other protic solvents. So, running the reaction in THF containing 5-10% methanol with trichickenfootphos catalyst alone gives product with the desired ee.

G. Hoge (Pfizer), Presentation at Modern Synthetic Methods Conference, Princeton NJ, July, 2005.