Ester hydrolysis Lewis acid catalysis

Thus, many metal ions catalyze the hydrolysis of esters [7,8], amides [9], and nitriles [10] via electrophilic activation of the C=0 or C=N group. This type of catalysis is characteristic of coordination complexes and is very common in metalloenzyme-mediated processes. Zinc(II), for example, is a key structural component of more than 300 enzymes, in which its primary function is to act as a Lewis acid (see Chapter 4). The mechanism of action of zinc proteases, e.g., thermolysin, involves electrophilic activation of an amide carbonyl group by coordination to zinc(II) in the active site (Figure 4). 

Artificial enzymes with metal ions can also hydrolyze phosphate esters (alkaline phosphatase is such a natural zinc enzyme). We examined the hydrolysis of p-nitro-phenyfdiphenylphosphate (29) by zinc complex 30, and also saw that in a micelle the related complex 31 was an even more effective catalyst [118]. Again the most likely mechanism is the bifunctional Zn-OH acting as both a Lewis acid and a hydroxide nucleophile, as in many zinc enzymes. By attaching the zinc complex 30 to one or two cyclodextrins, we saw even better catalysis with these full enzyme mimics [119]. A catalyst based on 25 - in which a bound La3+ cooperates with H202, not water - accelerates the cleavage of bis-p-nitrophenyl phosphate by over 108-fold relative to uncatalyzed hydrolysis [120]. This is an enormous acceleration. 

There have been a few reports of first generation coordination complex structural models for the phosphatase enzyme active sites (81,82), whereas there are some examples of ester hydrolysis reactions involving dinuclear metal complexes (83-85). Kim and Wycoff (74) as well as Beese and Steitz (80) have both published somewhat detailed discussions of two-metal ion mechanisms, in connection with enzymes involved in phosphate ester hydrolysis. Compared to fairly simple chemical model systems, the protein active site mechanistic situation is rather more complex, because side-chain residues near the active site are undoubtedly involved in the catalysis, i.e, via acid-base or hydrogenbonding interactions that either facilitate substrate binding, hydroxide nucleophilic attack, or stabilization of transition state(s). Nevertheless, a simple and very likely role of the Lewis-acidic metal ion center is to... 

Another important research direction is the mimieking of enzymes and the construction of selective catalysts. For these purposes, the polymer is imprinted with the desired reaetion-product or better, a molecule which resembles the transition state of the reaction adducts. If the educts bind specifically to the recognition site, they become confined into these micro-reactors and are supposed to react faster and more defined than outside the cavities [445]. Examples for reactions in the presence of such synthetic enzymes can be found in [452,453,454,455,456,457] (cf Figure 40c). First positive results have been reported, e.g. an synthetic esterase , increasing the rate of alkaline hydrolysis of substituted phenyl-(2-(4-carboxy-phenyl)-acetic esters for 80 times [488] and Diels-Alder catalysis fiuic-tional holes containing titanium lewis-acids [489]... 

For designing enzyme-mimicking catalysts exploiting metal ions as catalytic centers, it is necessary to understand catalytic repertories (32, 33) of metal ions acting as Lewis acid catalysts in the hydrolysis of peptide bonds and related carboxyl derivatives (e.g., esters). Although esters are much easier to hydrolyze than peptides, important mechanistic information for catalysis in peptide hydrolysis can be obtained from that in ester hydrolysis. 

Most transition states involve charged intermediates, which are stabilized within the active site of an enzyme via ionic bonds in pockets or holes bearing a matching opposite charge. Such charges are derived from acidic or basic amino acid side chains (such as Lys, Arg, Asp, or Glu) ° or are provided by (Lewis acid-type) metal ions, typically Zn +. Computer simulations studies suggested that in enzymes electrostatic effects provide the largest contribution to catalysis [107]. As a prominent example, the tetrahedral intermediate of carboxyl ester hydrolysis is stabilized in serine hydrolases by the so-called oxyanion hole (Scheme 2.1). 

A recent example has been described by Brown et al. who have studied the KR of p-nitrophenyl esters of the d- and i-N-tert-butoxycarbonyl derivatives of glutamine and phenylalanine with ethanol or methanol promoted by chiral lanthanide complexes, providing enantioselectivities of up to 99% ee [302]. On the other hand, an enantioselective hydrolysis of phenylalanine derivatives was reported in 1986, providing a perfect enantiomer discrimination (s> 1000), as a result of catalysis with a tripeptide [303]. In 2007, Maruoka et al. reported the KR of differently a,a-disubstituted a-siloxy aldehydes based on an asymmetric rearrangement into the corresponding chiral acyloins using axially chiral organoaluminium Lewis acids, which provided selectivity factors of up to 39.5... 

Mentz, M., Modro, A.M., Modro, T.A. Solvation and metal ion effects on the structure and reactivity of phosphoryl compounds. Part 3. Alkali metal ion catalysis in the alkylation by phosphate esters. J. ChettL Res. (S) 1994, 46-47. Hendry, P, Sargeson, A.M. Base hydrolysis of the pentaamine (trimethylphos-phate)iridium(in) ion. J. Chem. Soc., Chem. Commun. 1984, 164—165. Wadsworth, W.S., Jr. Lewis acid catalyzed methanolysis of a phosphate triester. J. Org. Chem. 1981, 46(20), 4080-4082. 

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