Cyclodextrins ester hydrolysis

Molecular dynamics free-energy perturbation simulations utilizing the empirical valence bond model have been used to study the catalytic action of -cyclodextrin in ester hydrolysis. Reaction routes for nucleophilic attack on m-f-butylphenyl acetate (225) by the secondary alkoxide ions 0(2) and 0(3) of cyclodextrin giving the R and S stereoisomers of ester tetrahedral intermediate were examined. Only the reaction path leading to the S isomer at 0(2) shows an activation barrier that is lower (by about 3kcal mol ) than the barrier for the corresponding reference reaction in water. The calculated rate acceleration was in excellent agreement with experimental data. ... 

Numerous examples of modiflcations to the fundamental cyclodextrin structure have appeared in the literature.The aim of much of this work has been to improve the catalytic properties of the cyclodextrins, and thus to develop so-called artificial enzymes. Cyclodextrins themselves have long been known to be capable of catalyzing such reactions as ester hydrolysis by interaction of the guest with the secondary hydroxyl groups around the rim of the cyclodextrin cavity. The replacement, by synthetic methods, of the hydroxyl groups with other functional groups has been shown, however, to improve remarkably the number of reactions capable of catalysis by the cyclodextrins. For example, Breslow and CO workersreported the attachment of the pyridoxamine-pyridoxal coenzyme group to beta cyclodextrin, and thus found a two hundred-fold acceleration of the conversion of indolepyruvic acid into tryptophan. 

We now can prepare, in principle, enzyme models by use of the concept of host design, where artificial enzymes are so designed as multiple recognition hosts schematically shown in Fig. 20. Although unsubstituted cyclodextrins are well known to catalyze some organic reactions such as ester hydrolysis, their catalytic activities are relatively small. Recent progress in cyclodextrin chemistry has shown that it is possible to enhance the catalytic... 

We have made several artificial enzymes that use cyclodextrin to bind a substrate and then react with it by acylating a cyclodextrin hydroxyl group. This builds on earlier work by Myron Bender, who first studied such acylations [83]. We added groups to the cyclodextrin that produced a flexible floor, capping the ring [84]. The result was to increase the relative rate of cyclodextrin acylation by m-t-butylphenyl acetate from 365 relative to its hydrolysis rate in the buffer to a Complex/ buffer of 3300. We changed the substrate to achieve better geometry for the intracomplex acylation reaction, and with a p-nitrophenyl ester of ferroceneacrylic acid 10 we achieved a relative rate for intracomplex acylation of ordinary [3-cyclodextrin vs. hydrolysis of over 50 000 and a Vmax comparable to that for hydrolysis of p-nitrophenyl acetate by chymotrypsin... 

We have pursued such ester hydrolysis by artificial enzymes further. With a cyclodextrin dimer related to 25 we have hydrolyzed an ordinary doubly bound ester, not just the more reactive nitrophenyl esters [116], with catalytic turnovers. Also, with a catalyst consisting of a cyclodextrin linked to a metal ligand carrying a Zn2+ and its bound oxime anion, we saw good catalyzed hydrolysis of bound phenyl esters with what is called burst kinetics (fast acylation, slower deacylation), as is seen with many enzymes [117]. 

In nucleophilic catalysis, an anion of a secondary hydroxyl group of the cyclodextrin (CD-OH) attacks at the electrophilic center of the ester substrate included in the cavity of the cyclodextrin, resulting in the formation of acyl-cyclodextrin (2) together with the release of the leaving group (see Scheme 1 for ester hydrolysis). The catalysis is completed by the regeneration of the cyclodextrin through the hydrolysis of 2. 

This is the only example of the cyclodextrin-catalyzed hydrolysis of an amide. The rate-determining step in this process is acylation whereas the rate-determining step in the cyclodextrin-catalyzed hydrolysis of phenyl esters is deacylation. This dichotomy completely parallels the situation in chymotr3rpsin-catalyzed hydrolysis as shown in Table 3. 

By contrast, Table VII shows that nickel and zinc will catalyze the deacetylation of pyridine carboxaldoxime acetate, but the cyclodextrin ester does not add anything to the rate. The ester will not increase the metal-catalyzed hydrolysis rate of materials which if bound into the cavity would have the group held in the wrong place. This fits a geometric picture—that is, that the substrate must both bind into the cavity and in addition have the proper orientation with respect to the attacking group within that cavity. But still the cooperativity is rather modest. 

R. Breslow, B. Zhang, Very fast ester hydrolysis by a cyclodextrin dimer with a catalytic linking group, J. Am, Chem. Soc., 1992, 114, 5882-5883. 

Figure 3.3 Complementary diastereoselectivity in the acylation of ft-cyclodextrin with the acid chloride of Ibuprofen and in the hydrolysis of the corresponding cyclodextrin ester ...

A. Ueno, F. Moriwaki, Y. Hino, T. Osa, Ester hydrolysis by a 2-naphthylacetyl-substituted /-cyclodextrin, J. Chem. Soc., Perkin Trans. 2, 1985, 921-923. 

A site-selective C-C bond formation is important for syntheses of valuable chemicals. Bond cleavage reactions, such as ester hydrolysis and amide hydrolysis, using cyclodextrin (CyD) have been extensively studied. However, there has been only a few reports on C-C bond formation using CyD catalyst [1]. 

Table I. Kinetic parameters for ester hydrolysis by native and modified cyclodextrins ...

We have previously seen that calix[4]arenes and cyclodextrins have been used as host molecules for the recognition of various guest molecules (Sections 2.3-2.6) As a consequence of their hydrophobic cavity in conjunction with reactive functional groups, both calix[4]arenes and cyclodextrins, in particular, (3-cyclodextrin, have been used in many catalytic applications, for example, ester hydrolysis, oxidation reactions, hydroformylation, hydrogenation and cross-coupling reactions. 

The 3, 5 -cyclic monophosphate of adenosine (cAMP) (2.148) is an important secondary messenger for intercellular communication in biochemistry. When the cell is stimulated by the first messenger, compound 2.148 is formed from adenosine triphosphate (ATP) (Scheme 2.25). This reaction is catalysed by an adenosine cyclase enzyme. The cAMP then goes on to activate other intracellular enzymes, so producing a cell response. The response is terminated by the hydrolysis of cAMP by phosphodiesterase (a phosphate-ester-hydrolysis enzyme). The action of adenylate cyclase has been mimicked successfully with a p-cyclodextrin complex of Pr(iii) and other lanthanide(iii) metals, under physiological conditions. The... 

Scheme 2.26 Catalytic cycle of ester hydrolysis by P-cyclodextrin.

Figure 24 (a) Schematic illustration and amino acid sequences of -cyclodextrin peptide catalysts (b) Illustration of ester hydrolysis... 

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