Angew. Chem. Int. Ed. http://dx.doi.org/10.1002/anie.201008042 (2011)

Enantioselective organocatalysis is now a well established synthetic tool. A potential criticism is that many organocatalytic processes require large catalyst loadings (in comparison with metal-catalysed processes) for reactions to proceed at a useful rate. Now, Albrecht Berkessel, Harald Gröger and co-workers from the Universities of Cologne, Erlangen-Nuremberg and Düsseldorf have reported that in some cases a smaller catalyst loading could actually lead to a much improved enantioselectivity.

Gröger, Berkessel and co-workers were investigating an enantio- and diastereoselective route to chiral diols. They planned to combine an organocatalysed aldol reaction with an enzymatic reduction. The first step was to investigate the organocatalytic reaction in a medium that would be enzyme-compatible: aqueous sodium chloride. The first attempt, however, did not seem promising. The organocatalytic aldol reaction using 5 mol% catalyst gave the aldol product with only 47% e.e. compared with 70% e.e. in an organic solvent. On doubling the catalyst loading, the team were surprised to observe no enantioselectivity. Cutting the catalyst loading to just 0.5 mol% gave a dramatic improvement, with aldol product in 93% e.e.

The team attribute this initially surprising negative influence of increased catalyst loading to a change from kinetic to thermodynamic control. With a high catalyst loading, the reaction reached equilibrium quickly, and the reversibility of the reaction means that the enantioselectivity is eroded to produce a racemic product. At low catalyst loading, the reaction does not reach equilibrium and remains under kinetic control with high enantioselectivity. Gröger, Berkessel and co-workers were ultimately able to combine the reaction with the planned enzymatic reduction — which also neatly traps the kinetic product — to produce a chiral diol with high diastereo- and enantioselectivity.