Examination and enhancement of enantioselective autoinduction in cyanohydrin formation by cyclo[(R)-His-(R)-Phe]

The cyclic dipeptide cyclo[(R)-His-(R)-Phe] (1) has been known since 1981 to catalyze the enantioselective formation of cyanohydrins from aldehydes and HCN. Although 1 has proved to be very effective in the production of optically active cyanohydrins, the precise structure of its catalytically active form remains unresolved. The reaction of 3-phenoxybenzaldehyde and HCN in the presence of 1 has also been shown to exhibit enantioselective autocatalysis: the product (S)-3-phenoxymandelonitrile reacts with 1 to form a new, more enantioselective catalytic species. It is now demonstrated that this autocatalytic phenomenon is general and that, furthermore, it can be used to improve the enantioselectivity of cyanohydrin formation for several problematic substrates. Upon addition of a small (8 mol %) quantity of (S)-mandelonitrile or (S)-3-phenoxymandelonitrile to these reactions, the enantioselectivity of cyanohydrin formation was improved by as much as 20% ee. This effect has been ascribed to the formation of a complex between the added (S)-cyanohydrin and 1 that exhibits superior enantioselectivity to 1, either alone or complexed to the cyanohydrins of problematic substrates. A mathematical model has been developed, on the basis of a two-state equilibrium between 1 and a complex of 1 and cyanohydrin and used to explain the enantioselective autoinduction phenomenon in terms of five parameters: rate constants for the production of (R)- and (S)-cyanohydrin by both 1 and its cyanohydrin complex and an association constant for the formation of a cyanohydrin complex by 1. Two versions of this model, based on monomeric and dimeric 1, have been evaluated in light of the available data. Examination of the results reveals that the complexes of 1 and many of the cyanohydrins studied are highly enantioselective catalysts but that the complexes of 1 and cyanohydrins are only weakly associated; moreover, the complexation of 1 with most cyanohydrins leaves the rate of cyanohydrin formation unchanged, though both autocatalysis and enantioselective poisoning have been observed as well.