Acylation of cyclodextrin

This argument is further supported by the very fast acylation of -cyclodextrin by bound p-nitrophenyl ferrocene acrylate (9) in dimethylsulfoxide-water. (60/40 v/v)... 

The 6 -monobutanoate of methyl p-lactoside was prepared by subtilisin-catalyzed ester transfer from 2,2,2-trichloroethyl butanoate. Mesitoylation gave the hexaester which was converted to the 6 -fluoride (see Chapter 8). 2,3,6,3, 4 -Penta-0-acetylsucrose, the precursor of sucralose, was available from the octaacetate by selective hydrolysis first with alcalase, then with AP-6 lipase. The main by-product, the 2,3,4,3, 4 -pentaacetate, was readily converted to the required isomer by acetyl migration on treatment with phosphate buffer. An enzymatic acylation of cyclodextrin is referred to in Chapter 3. 

Czamieki and Breslow (22) have studied the rate of acyl transfer from a substrate that is bound by the acyl part rather than by the leaving group. Having shown that ferrocene binds strongly to -cyclodextrin, Czamiecki and Breslow employed the p-nitrophenyl ester of ferrocinnamic acid in kinetic studies using DMSO-buffer mixtures. A rate acceleration of 51,000 times background was observed for acylation of /i-cyclodextrin. 

Other studies on the PFR in the presence of cyclodextrins include substrates with different acyl moieties (phenyl propionate and phenyl valerate) [261] 1-naphthyl acetate [262,263], 1-naphthyl benzoate [263], sulfonate esters, [264,265], benzenesulfonylanilides [266], acetanilide [259,267], and benzanilide [259,268]. 

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... 

Acylation of fl-cyclodextrin. The acylation of /5-cyclodextrin is modestly accelerated by bound m-nitrophenyl acetate, m-N02C6H40C0CH3. Recently acylation of /3-cyclodextrin at a rate comparable to acylation of chymotrypsin has been reported. The acylating reagent is the p-nitrophenyl ester (1) of ferrocinnamic acid. This reagent was chosen because ferrocene is strongly bound within the cavity of /3-cyclodextrin. The acylation is accelerated by > 50,000-fold compared to hydrolysis of 1 in DMSO-HjO alone buffered at pH 6.8. Thus cyclodextrins can behave as artificial enzymes. 

Hydroxy groups of cyclodextrins can be regioselectively alkylated in positions 2 and 6 of the glucose residues due to the high reactivity of these hydroxy groups. The 3-positions are much less reactive and can be alkylated or acylated under more drastic conditions. The preparation of pure per-O-alkylated cyclodextrin derivatives, which are mainly used for the separation of unpolar compounds (alkanes, alkenes, spiroacetals, alkyl halides, etc.) as well as a method for characterization of these phases have been described in detail (29). 

H.-G. Schmarr, A. Mosandl and A. Kaunzinger. Influence of Derivatization on the Chiral Selectivity of Cyclodextrins Alkylated/Acylated Cyclodextrins and y/5-Lactones as an Example. J. Micro-col. Sep. 3, 395-402(1991). 

Cyclodextrins were also threaded onto polymeric threads. Wenz and Keller used poly(methylene) chains [80]. Equilibration of a-CDX with poly(iminotrimethylene-iminodecamethylene) was reached in c. 9 days. The dethreading by dialysis was not even complete after two weeks. To analyse the degree of threading, the CDX rings were blocked on the chains by partial acylation of the amino groups of the polymer. Consequently, a material containing 23 -NH(CH2)io-N(H)-(CH2)3- subunits was shown to entrap 37 CDX rings. 

This question can be answered affirmatively by citing recent work of Breslow et al. (13), who were interested in the acylation of (5-cyclodextrins (CD) by bound esters. When, for example, m-nitrophenyl acetate binds to the -CD cavity, the ester transfers its acyl group 64 times faster than it hydrolyzes in water at the same pH ... 

In the )8-cyclodextrin-(9) complex the acyl group of the ester rather than the leaving group is bound to the cyclodextrin. The acylation of yS-cyclodextrin by this ester is accelerated by 750000-fold and the rate achieved is comparable with that for... 

Cyclodextrins, however, show no enantiomeric specificity in the deacylation step. The rate of hydrolysis of acyl-a-cyclodextrin derived from the (-I-) enantiomer of (14a) is equal to that derived from the ( —) enantiomer. This can be associated with the fact that the nitroxide function is not included in the cyclodextrin cavity, as shown by electron spin resonance. In the a-chymotrypsin-catalyzed hydrolysis of (14b), however, the acyl enzyme derived from the (-I-) enantiomer hydrolyzes 21 times faster than the acyl enzyme derived from the (—) enantiomer. 

Myron Bender had reported that a meta-f-butylphenyl acetate (4) acetylated 8-cyclodextrin in water with a rate 250 times as fast as that for hydrolysis of that same substrate at the same pH. We had shown that the same reaction was even faster in a mixed DMSO/ water solvent, but still the acceleration was not what one would have hoped for. Model-building suggested that in the acylation reaction the tetrahedral intermediate is partly pulled out of the cavity, so cyclodextrin binding is to some extent fighting against the reaction rate. Thus we made a new substrate, the p-nitrophenyl ester of ferrocene-acrylic acid (5), and saw that it acylated jS-cyclodextrin with a rate acceleration of 51,000 compared with the hydrolysis rate in free solution. With this substrate there... 

In a different experimental approach to the question of geometric changes during the acylation reaction of cyclodextrin bound substrates, we collaborated with Le Noble in a study of pressure effects on the reaction rates. The volume changes that this technique indicated - as starting materials proceeded to the transition state - were consistent with... 

In a previous study on simple cyclodextrin binding we examined the ability of cyclodextrin to bind various substrates in dimethyl sulfoxide solution rather than in water. We saw that indeed hydrophobic substances were bound into the cyclodextrin, and also that DMSO itself was a solvent in which the acylation of a cyclodextrin hydroxyl group by a bound ester could be observed. Cyclodextrin binding is not exclusively limited to water solutions, as had been suggested by others previously, but water is so far the best solvent to see such binding and catalytic processes. 

The first compound described as an artificial enzyme in the literature was the one we reported in which we attached a metal ion binding group to a-cyclodextrin. We found that this would bind p-nitrophenyl acetate into the cavity and a bound nickel ion then catalysed the hydrolysis of the substrate. This was a direct hydrolysis, not an acylation of a cyclodextrin hydroxyl (which is not in reach with the para esters). This type of catalyst then extends metal-catalysed reactions to substrates that do not intrinsically bind to metal ions, which was formerly required for such catalysis. 

M. F. Czarniecki, R. Breslow, Very fast acylation of j3-cyclodextrin by bound p-nitrophenyl ferrocinnamate, J. Am. Chem. Soc., 1978, 100, 7771-7772. 

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 ...

Hans-Jurgen, Thiem, Michael and R Breslow (1998). Molecular modeling calculations on the acylation of /3-Cyclodextrin by ferrocenylacrylate esters. Journal oftheAmerican Chemical Society, 110(26), 8612-8616. 

Several research groups tried to stabilize 3-chloro-4-phenyl-lH-pyrroles by varying the substituents on the phenyl ring [8], by acylation of the pyrrole-nitrogen [9] or by inclusion of 3-chloropyrroles into cyclodextrin [10]. No commercial crop protection compound resulted from such efforts. The use of biocontrol bacteria, which produce pyrrolnitrin as a metabolite, can protect plants from infection by soil-born fungal pathogens [11]. 

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