Phosphonate esters, hydrolysis

Tsubouchi and Bruice demonstrated remarkable rate enhancement (ca. 1013) in phosphonate ester hydrolysis catalyzed by two LaKI ions using a phosphonate attached with two 8-hydroxyquinoline moieties... 

The dependence of the activity of calcineurin on the redox state of the metal center highlights its importance for catalysis and provides clues to its function in that process. Site-directed mutagenesis studies of PPl, calcineurin, and bacteriophage X protein phosphatase have also provided insights regarding the roles of non-ligand active site residues. Furthermore, the contributions afforded by studies of synthetic model compounds which mimic features of metallophosphatase active sites provide important clues to possible catalytic mechanisms. Indeed many of these models exhibit impressive rate enhancements for phosphate and phosphonate ester hydrolysis [54-62]. In this section we discuss current models regarding the mechanism of phosphate ester hydrolysis by calcineurin and other metallophosphatases in consideration of these studies. 

Tsubouchi and Bruice demonstrated remarkable rate enhancement (ca. 10 ) in phosphonate ester hydrolysis catalyzed by two La ions using a phosphonate attached with two 8-hydroxyquinoline moieties (54). The complex with two La 46 showed double metal ion cooperativ-ity (i) facile formation of metal ligated hydroxide (piCg = 7.2 at 30°C) as an intramolecular nucleophile, (ii) stabilization of the transition... 

R. Kluger, P. Davis, and P. D. Adawadkar (1979), Mechanism of urea participation in phosphonate ester hydrolysis. Mechanistic and stereochemical criteria for enzymic formation and reaction of phosphorylated biotin. J. Amer. Chem. Soc. 101, 5995-6000. 

The cyclic phosphonate ester analog of the cyclic transition state. Antibodies raised against this phosphonate ester act as enzymes they are catalysts that markedly accelerate the rate of ester hydrolysis. 

Addition of the alcohol 42 to a solution of BF3 Et20/TMSCN in DCM provided the nitrile 43 in 83% yield. Hydrolysis of nitrile 43 then furnished amide 44 in 85% yield. Demethylation of the methoxyindole 44 with BBra in DCM provided the hydroxyindole 45 in 80% yield. This was followed by alkylation of 45 with the bromide 46 under phase transfer conditions to provide the phosphonate ester 47 and subsequent cleavage of the methyl ester by TMS-I furnished trimethylsilyl phosphonic acid 48, which upon alcoholic workup afforded LY311727. 

The rate of appearance of p-nitrophenolate ion from p-nitrophenyl methylphosphonate (7), an anionic substrate, is moderately accelerated in the presence of cycloheptaamylose (Brass and Bender, 1972). The kinetics and pH dependence of the reaction are consistent with nucleophilic displacement of p-nitrophenolate ion by an alkoxide ion derived from a cycloheptaamylose hydroxyl group to form, presumably, a phosphonylated cycloheptaamylose. At 60.9° and pH 10, the cycloheptaamylose-induced rate acceleration is approximately five. Interestingly, the rate of hydrolysis of m-nitrophenyl methylphosphonate is not affected by cycloheptaamylose. Hence, in contrast to carboxylate esters, the specificity of cycloheptaamylose toward these phosphonate esters is reversed. As noted by Brass and Bender (1972), the low reactivity of the meta-isomer may, in this case, be determined by a disadvantageous location of the center of negative charge of this substrate near the potentially anionic cycloheptaamylose secondary hydroxyl groups. 

An unusual reaction of electron-deficient acetylenes (usually DMAD is used) and triarylphosphines or -phosphites with Cjq leads to methanofullerenes that bear an a-ylidic ester (Scheme 3.11). Selective hydrolysis of the phosphite ylides yields phosphonate esters, phosphine oxides or phosphonic acids [49-51]. 

Surface-catalyzed dark and photoassisted phosphate ester hydrolysis (P—O bond rupture) in aqueous suspensions of TiO2 has been proposed [6,7,41]. A number of products indicative of radical cationic pathways have been reported in the TiO2 photocatalysis of benzyl phosphonic acid [44]. 

FIGURE 2 The expected transition states for ester or carbonate hydrolysis reactions. Phosphonate ester and phosphate ester compounds, respectively, make good transition-state analogs for these reactions. 

When ethyl phosphonates are used, the imine can be selectively deprotected after alkylation by treatment with dilute mineral acid (e.g., 10% HQ), 36"40 and the esters removed subsequently (see Section 10.10.3). When tert-butyl phosphonates are used, imine and ester hydrolysis is accomplished simultaneously under these conditions. These mild hydrolysis conditions are preferable when synthesizing amino acids with functionalized side chains 40 ... 

One of the most investigated type of reaction in the field of catalytic imprinted polymers, as indicated by the large number of publications available, is certainly ester hydrolysis. In particular, a great deal of work has been carried out on systems inspired by hydrolytic enzymes since 1987. In 2000, Shea et al. [37] reported the preparation of enantioselective imprinted polymers for the hydrolysis of N-tert-butoxycarbonyl phenylalanine-p-nitrophenyl ester (55), using a system already developed by the same group in 1994 [19]. The system was inspired by the natural hydrolytic enzyme chymotrypsin and polymerisable imidazole units (27) were used as functional monomers coupled via ester linkages to a chiral phosphonate (56), analogue of (d)- or (L)-phenyl-alanine. After template removal, the imprinted polymers showed selectivity towards the hydrolysis of the enantiomer with which they were imprinted. The ratio of the rate constants, k /k, was 1.9 for the polymer imprinted with the D-enantiomer and kjku was 1.2 for that imprinted with the L-enantiomer. Moreover, the imprinted polymer showed a 2.5-fold increase in the rate of the reaction when compared with the control polymer, imprinted with a... 

Phosphonates and phosphonamidates were selected as transition-state analogs for carbonate and ester hydrolysis they are relatively stable molecules, they are known inhibitors of acyl transfer enzymes and they imitate the initial negative charge of the tetrahedral oxyanion of acyl transfer enzymes (such as serine proteases) in the dipole of the P=0 bond. 

Five-membered cyclic phosphate and phosphonate esters have rates of hydrolysis orders of magnitude greater than those of the corresponding acyclic esters (6), therefore such five-membered cyclic esters are undesirable components if the oligomers are used as flame retardants. 

Thus the peculiar titration results were due to the heterogeneous catalysis, not of the original reaction, but of a new reaction that had arisen from the analytical procedure. Precipitates formed by the reagents themselves can also prove catalytically active. For instance, the catalysis by rare earth metal salts of the hydrolysis of acid phosphonate esters was actually due to the development of metal hydroxide gels [159], A quite different example concerns reactions of mercury salts where the disproportionation... 

Figure 4 (a) Phosphonate ester as a chemically stable mimic of ester hydrolysis, (b) Transition state analog hapten 1 elicited antibody 48G7 that catalyzes the hydrolysis of ester 2. (c) Key contacts of the 48G7 Fab-1 complex. 

It has already been reported that antibodies prepared against the transition state of a reaction show considerable catalytic activity [113]. For example, antibodies prepared against a phosphonic ester (as a transition state analogue for alkaline ester hydrolysis) enhanced the rate of ester hydrolysis by 10 -10" fold. Recently, similar systems based on imprinted polymers which display high catalytic activity have been successfully prepared. Initial attempts were performed by several groups [114-117] with imprinted polymers based on non-stoichiometric, non-covalent interactions, which, however, gave results far below those obtained with antibodies. Rate enhancements up to 6.7-fold were reached in one case. 

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