Anion-π Enzymes

In this report, we introduce artificial enzymes that operate with anion-pi interactions, an interaction that is essentially new to nature. The possibility to stabilize anionic intermediates and transition states on an pi-acidic surface has been recently demonstrated, using the addition of malonate half thioesters to enolate acceptors as a biologically relevant example. The best chiral anion-pi catalysts operate with an addition/decarboxylation ratio of 4:1, but without any stereoselectivity. To catalyze this important but intrinsically disfavored reaction stereoselectively, a series of anion-pi catalysts was equipped with biotin and screened against a collection of streptavidin mutants. With the best hit, the S112Y mutant, the reaction occurred with 95% ee and complete suppression of the intrinsically favored side product from decarboxylation. This performance of anion-pi enzymes rivals, if not exceeds, that of the best conventional organocatalysts. Inhibition of the S112Y mutant by nitrate but not by bulky anions supports that contributions from anion-pi interactions exist and matter, also within proteins. In agreement with docking results, K121 is shown to be essential, presumably to lower the pK(a) of the tertiary amine catalyst to operate at the optimum pH around 3, that is below the pK(a) of the substrate. Most importantly, increasing enantioselectivity with different mutants always coincides with increasing rates and conversion, i.e., selective transitionstate stabilization.