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 1 981 to catalyze the enantioselective formation of cyanohydrins from al dehydes and HCN. Although 1 has proved to be very effective in the pro duction of optically active cyanohydrins, the precise structure of its catalytically active form remains unresolved. The reaction of 3-pheno xybenzaldehyde and HCN in the presence of 1 has also been shown to exh ibit enantioselective autocatalysis: the product (S)-3-phenoxymandelon itrile reacts with 1 to form a new, more enantioselective catalytic sp ecies. It is now demonstrated that this autocatalytic phenomenon is ge neral and that, furthermore, it can be used to improve the enantiosele ctivity of cyanohydrin formation for several problematic substrates. U pon addition of a small (8 mol %) quantity of (S)-mandelonitrile or (S )-3-phenoxymandelonitrile to these reactions, the enantioselectivity o f 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, eit her alone or complexed to the cyanohydrins of problematic substrates. A mathematical model has been developed, on the basis of a two-state e quilibrium between 1 and a complex of 1 and cyanohydrin and used to ex plain the enantioselective autoinduction phenomenon in terms of five p arameters: rate constants for the production of (R)- and (S)-cyanohydr in by both 1 and its cyanohydrin complex and an association constant f or the formation of a cyanohydrin complex by 1. Two versions of this m odel, based on monomeric and dimeric 1, have been evaluated in light o f the available data. Examination of the results reveals that the comp lexes of 1 and many of the cyanohydrins studied are highly enantiosele ctive catalysts but that the complexes of 1 and cyanohydrins are only weakly associated; moreover, the complexation of 1 with most cyanohydr ins leaves the rate of cyanohydrin formation unchanged, though both au tocatalysis and enantioselective poisoning have been observed as well.