THE EFFECTS OF N-METHYLATION ON THE ENANTIOSELECTIVITY OF CATALYSIS BY CYCLO[(R)-HIS-(R)-PHE]

The cyclic dipeptide cyclo[(R)-His-(R)-Phe] 1 has been known since 198 1 to catalyze the enantioselective formation of cyanohydrins from alde hydes and HCN. Although 1 has proved to be very effective in the produ ction of optically active cyanohydrins, the precise structure of its c atalytically active form remains unresolved. Two derivatives, in which the two amides in 1 were independently N-methylated, were synthesized as probes of the structural and functional requirements for catalysis by 1. Both derivatives were far more soluble in organic solvents and were found to catalyze the formation of racemic cyanohydrin, but diffe red greatly in their turnover rates. Mixtures of the two derivatives w ith each other and with 1 were also examined as hydrocyanation catalys ts. Only the mixtures containing 1 demonstrated any enantioselectivity , but did not appear any more competent as catalysts than reduced quan tities of 1. From these data, it is concluded that both amide bonds ar e essential for effective catalysis by 1, but that the amide containin g the His N-alpha appears to be involved in interactions with the subs trate while the other amide plays a structural role, possibly for self -associative hydrogen bonding. (C) 1997 Published by Elsevier Science Ltd. All rights reserved.