Enantiomer-selective solvolysis catalysed by a histidine-containing cyclic dipeptide carrying chiral side chain

Tripeptides with cyclic dipeptide backbones, cyclo[l-Glu(l-Leu-O Bzl)-t-His] and cyclo[l-Glu(l-Leu-OH)-Ir His, and the corresponding tripeptides with linear backbones, Me₃COCO-l-Glu(l-Leu-OBzl)-l-His-OMe and Me₃COCO-l-Glu(l-Leu-OH)-l-His-OMe, were synthesized and used as catalysts for the hydrolysis of carboxylic acid active esters of various types. The experimental results are summarized as follows. (I) In the hydrolysis of a neutral and hydrophobic substate, p-nitrophenyl laurate, in 20% dioxane/H₂O mixture of pH 7.8, a hydrophobic and flexible peptide, Me₃COCO-l-Glu(l-Leu-OH)-l-His-OMe, was more reactive than imidazole. On the other hand, cyclo[l-Glu(l-Leu-OBzl)-l-His] and cyclo[l-Leu-OH)-l-His], which have rigid backbone chain and fixed sidechain conformation, were not particularly reactive. (2) in the solcolysis of a positively charged substrate, p-nitrophenyl glycinate hydrochloride, in 42% i-PrOH/H₂O mixture at pH 6.95, a positively charged substrate, p-nitrophenyl glycinate hydrochloride, in 42% i-PrOH/H₂O mixture at pH 6.95, a negatively charged and flexible peptide, Me₃COCO-l-Glu(l-Leu-OH)-l-His-OMe, was more reactive than imidazole. However, cyclo [l-Glu(l-Leu-OH)-l-His] was not particularly reactive in the same reaction. In the hydrolysis of p-nitrophenyl glycinate hydrochloride in aqueous solution at pH 7.8 a hydrophobic and rigid peptide, cyclo[(l-Glu(l-Leu-OBzl)-l-His], was more reactive than imidazole. However, in the hydrolysis of p-nitrophenyl CO-AMINODODECANOATE hydrochloride, which has a positive charge and a rective site separated by a long hydrophobic chain, peptide catalysts did not show efficient catalysis. (3) In the hydrolysis of a positively charged, hydrophobic and chiral substrate, p-nitrophenyl leucinate hydrochloride, in aqueous solution at pH 6.95, the d-enantiomer was hydrolysed more quickly that the t-enantiomer with cyclo[l-Glu(l-Leu-OBzl)l-His] or cyclo[t-Glu(l-Leu-OH)-l-His] as catalyst. On the other hand, the tripeptides with linear backbone did not effect an enantiomer-selective catalysis. The solvolytic reaction catalysed by the tripeptides with cyclic dipeptide backbone in 42% i-PrOH/water mixture was also enantiomer-selective.     

Conformational properties of tripeptides having cyclic dipeptide backbone and their catalytic properties for enantiomer-selective hydrolysis

Conformation in aqueous solution at pH 6.95 of tripeptides having cyclic dipeptide backbones, cyclo[l-Glu(l-Leu-OBzl)-l-His] and cyclo[l-Glu(l-Leu-OH)-l-His], was investigated by u.v., c.d. and n.m.r. spectroscopy and by the lanthanide probe method. In the major conformation of cyclo[l-Glu(l-Leu-OBzl)-l-His], the cyclic dipeptide backbone takes a flagpole-boat conformation in which the sidechain of the l-His residue is nearly parallel with the backbone plane and the sidechain of the l-Glu residue protrudes outside the backbone plane. In the major conformation of cyclo[l-Glu(l-Leu-OH)-l-His], the cyclic dipeptide backbone takes a flagpole-boat conformation in which the sidechains of the l-His and l-Glu residues are accommodated in the same side of the backbone plane so that the imidazolyl sidechain of l-His residue is twisted slightly. Tripeptides were not found to change the conformation when metal salts or ammonium salts such as Cl^?H₃N^?(CH₂)₁₁ COOEt, Gly-OEt-HCl, dl-Val-OEt-HCl and l-Leu-OEt-HCl were added, but a significant conformation change occurred upon adding d-Leu-OEt·HCl. If the same situation holds with the addition of α-amino acid p-nitrophenyl ester hydrochlorides, the previously reported enantiomer-selective catalysis by the tripeptides which hydrolysed d-Leu-OPh(NO₂·HCl faster than l-Leu-OPh(NO₂)·HCl can be explained; that is, the tripeptides change the conformation only when d-Leu-OPh(NO₂)·HCl is bound and consequently the intramolecular reaction is facilitated. This phenomenon may be compared with that of ‘induced fit’ in enzyme catalysis.