Methoxymethyl acetate , hydrolysis

A synthesis of 2-fluoroshikimic acid 91.2 [Scheme 3.91]169 exposes the robust nature of the methylene acetal Hydrolysis of the methoxymethyl ether and methylene acetal in 91.1 required concentrated hydrochloric add at reflux for 17,5 h to give a 60% yield of the target. 

The most efficient system of this sort - and the only one to show intramolecular general acid catalysis of the hydrolysis of a methoxymethyl acetal derived from an aliphatic alcohol - is compound 3.13, based on the most reactive aromatic system... 

Compound 3.13 (Scheme 2.22) is hydrolyzed with a half-life of 3.5 h in water at 39 °C, some 10 times faster than expected for the spontaneous hydrolysis of a methoxymethyl acetal of a tertiary alcohol, corresponding to a transition state stabilization of 14 kcal (58 kj) mol [47], and at the rate expected for the methoxymethyl derivative of an alcohol of pKa about 4. Perhaps significantly, this is almost equal to the pKa (4-18) of the catalytic COOH group of 3.13. (Which also confirms that there is no significant intramolecular hydrogen bonding in the reactant.)... 

As discussed above (Section 2.2.2) the hydrolysis reactions of glycosides and methoxymethyl acetals involve nucleophilic participation by water. If water can act as a nucleophile in these systems then reactions with other, better nucleophiles are to be expected. (The model, and the inspiration for most work in this area is the enzyme lysozyme which - like retaining glycosidases in general - uses two carboxyl groups, one acting as a nucleophile, the other as a general acid, to accomplish (exo-... 

The argument is based on the explicit assumption that for each mechanism, the activation parameters are uninfluenced by temperature. The authors feel this assumption to be permissible in view of the constancy of these parameters in the case of the acid hydrolysis of methoxymethyl acetate and ethoxymethyl acetate. The plausibility of this assumption will be discussed in the next section. 

The acid-catalyzed hydrolysis of simple partial acylals has been studied in condensed phase, " " and a study of the behavior of methoxymethyl formate and methoxymethyl acetate in chemical ionization mass spectrometry was undertaken " to provide a comparison of the gaseous and solution phase chemistry of these simple partial acylals. Methoxymethyl formate and methoxymethyl acetate undergo hydrolysis in aqueous acid by an A lI mechanism,... 

The relationship, between magnitudes of these sensitivity parameters and the reactivity of the system concerned, was explored quantitatively for three sets of acetal structures, and a further linear relationship was found (Kirby and Jones, 1986). Figure 25 shows a plot of the sensitivity parameter against relative reactivity for series of compounds, tetrahydropyranyl-, methoxymethyl- and a-glucosyl-OX, known to react with C-OX cleavage at very different rates (relative rates of hydrolysis approximately 1, 103 5 and 106 5, respectively). The correlation is good for both the intercepts (i.e. the... 

The next step was the introduction of the methylene acetal residue in 6 and 7 (Scheme 5). The initial plan was to effect this transformation in a single step, by exposure of the methoxymethyl derivatives 6 and 7 to dimethylboron bromide, following the conditions developed by Roush and co-workers (38). However, this reaction was not successful for either substrate, presumably due to competing cleavage of the acetonide residue. More promising results were obtained with triol 29 (obtainable from controlled hydrolysis of 7). Thus,... 

Related oxidants that have been exploited to similar ends include l-(tert-butoxy)-l,2-benzoiodoxol-3(l//)-one292 and sodium bromate.293 Oxidation of benzyl ethers by l-(/erf-butoxy)-l,2-benzoiodoxol-3(l/f)-one followed by easy basic hydrolysis of the resultant benzoate ester provides a convenient alternative to the usual reductive deprotection. The reaction is carried out in the presence of alkali metal carbonates and the conditions are mild enough to be compatible with other hydroxyl protecting groups such as methoxymethyl, tetrahydropyranyl, TBS and acetate. 

Such exploded transition states, in which the reaction centre carries a pronounced positive charge, are the commonest type of nucleophilic displacements at acetal centres. The reactions are unambiguously bimolecular, but in quantitative measures of transition state structure they differ only slightly from those of true 5 nI reactions. Thus, the value of for the hydrolysis of aryloxytetrahydropyrans, in which the solvent-equilibrated tetrahydropyranyl cation is a true intermediate, is —1.18, modestly but significantly more negative than the value of —0.82 obtained for hydrolysis of methoxymethyl esters of the type CH30CH20C0R. ... 

Ether cleavage. The polymer-bound reagent catalyzes hydrolysis of TBS ether and acetals in aqueous acetonitrile. Methoxymethyl and tetrahydropyranyl ethers are stable under such conditions. 

The methoxymethyl group is an acetal, easily removed by acid hydrolysis. What are the products of the following hydrolysis ... 

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