Carboxylic esters, hydrolysis enzymatic

Buchwald P. Structure-metabolism relationships steric effects and the enzymatic hydrolysis of carboxylic esters. Mini Rev Med Chem 2001 1 101-11. 

P. Buchwald, N. Bodor, Quantitative Structure-Metabolism Relationships Steric and Nonsteric Effects in the Enzymatic Hydrolysis of Noncongeneric Carboxylic Esters , J. Med. Chem. 1999, 42, 5160-5168. 

Gee and Langstrom synthesized255 1 -labelled a-methyl l-tyrosine via alkylation of a malonate derivative, enzymatic ester hydrolysis, conversion of carboxylic moiety to isocyanate followed by hydrolysis of the ester and isocyanate groups. Labelling of the a-posi-tion of the a-methyl L-tyrosine with 14C and UC, has been achieved also according to the pathway shown in equation 125256. 

Buchwald P, Bodor N. Quantitative structure-metabolism relationships Steric and non steric effects in the enzymatic hydrolysis of noncongener carboxylic esters. J Med Chem 1999 42 5160-8. 

The most prominent cellulose ester produced on the industrial scale is cellulose acetate. The reaction is usually performed with acetic anhydride and with sulfuric acid as a catalyst. To minimize heterogeneities, acetylation is allowed to run nearly to completion, and subsequently partial ester hydrolysis is initiated by the addition of water until a desirable solubility is achieved that corresponds to a DS of about 2.5. Such higher acyl homologues as propanoyl or butanoyl exhibit more thermoplastic properties. Many specialized esters such as chiral (-)-menthyloxyacetates, furan-2-carboxylates, or crown-ether-containing acylates have been prepared on the laboratory scale and characterized by NMR spectroscopy. Various procedures have been applied, using anhydrides and acyl chlorides as acylating agents in combination with such bases as pyridine, 4-dimethylaminopyridine (DMAP), or iV,iV -carbonyldi-imidazole. The substitution pattern of cellulose acetates has also been modified by postchemical enzymatic deacetylation. Cellulose 6-tosylates have been used as activated intermediates for nucleophihc substitution to afford 6-amino-6-deoxy, 6-deoxy, or 6-deoxy-6-halo-celluloses. ... 

Concerning the first approach, methyl or alkyl protection of the phosphinic group requires suitable masking of the carboxylic terminus of the main pseudodi-peptidic unit which could be selectively removed prior to C-elongation. Selective deprotection of carboxylic esters in the presence of alkyl phosphinates include enzymatic hydrolysis of methyl carboxylates [18, 58], controlled alkaline hydrolysis of ethyl carboxylates [59, 60], acidic cleavage of 3,4-dimethoxybenzyl... 

Carboxylic acids from their esters Preferential enzymatic hydrolysis... 

In contrast to y- and 8-lactams, highly strained p-lactams are more easily susceptible to enzymatic hydrolysis and thus can be (slowly) hydrolyzed by carboxyl ester hydrolyses, such as esterases [162] and lipases [163] (Scheme 2.20). 

Chiral hydroxyesters would be accessible via enzymatic hydrolysis of their acyloxy esters, but a disadvantage which is commonly encountered in such resolutions is an undesired side reaction involving the hydrolysis of the carboxyl ester moiety which leads to the formation of hydroxyacids as byproducts. Thus, low... 

The introduction of the hydrogen-bonded carboxylate does enhance catalysis by the neighboring imidazole and assesses the role of tandem general-base hydrolysis. However, the enhancement in rate of ester hydrolysis is still poor (only by a factor of three). So it is negligible from the stand point of enzymatic catalysis. 

Paal TA, Liljeblad A, Kanerva LT, Forro E, Eiilop E. Directed (R)- or (S)-selective dynamic kinetic enzymatic hydrolysis of 1,2,3,4-tetrahydroisoquinoline-l-carboxylic esters. Eur. J. Org. Chem. 2008 5269-5276. 

Aziridine carboxylates are chiral intermediates for the synthesis of -lactams and amino acids [200]. The use of enantioselective ester hydrolysis in the synthesis of optically active A -unsubstituted and A-substituted aziridine carboxylate by Candida cylindraceae lipase has been demonstrated by Bucciareli et al. [199]. Racemic methyl aziridine-2-car-boxylate and 2,3-dicarboxylate 110 were used as substrates both for enzymatic hydrolysis and for the synthesis of AAchloro, iV-acyl and A-sulfonyl derivatives (Fig. 38). The reaction yield of 35-45% (theoretical maximum yield is 50%) and the e.e. s of 90-98% were obtained depending on substrate used in the reaction mixture. 

Figure 38 Enantioselective enzymatic ester hydrolysis of TV-substituted aziridine carboxylates.

In contrast to the hydrolysis of prochiral esters performed in aqueous solutions, the enzymatic acylation of prochiral diols is usually carried out in an inert organic solvent such as hexane, ether, toluene, or ethyl acetate. In order to increase the reaction rate and the degree of conversion, activated esters such as vinyl carboxylates are often used as acylating agents. The vinyl alcohol formed as a result of transesterification tautomerizes to acetaldehyde, making the reaction practically irreversible. The presence of a bulky substituent in the 2-position helps the enzyme to discriminate between enantiotopic faces as a result the enzymatic acylation of prochiral 2-benzoxy-l,3-propanediol (34) proceeds with excellent selectivity (ee > 96%) (49). In the case of the 2-methyl substituted diol (33) the selectivity is only moderate (50). 

In comprehensive studies, the hydrolysis of some 30 naphthyl esters by human, rat, and mouse liver carboxylesterases was investigated [43], A general trend that was apparent was that the rate of hydrolysis of a- and /3-naphthyl carbonates (7.21, R = alkyl or arylalkyl) catalyzed by human microsomes or rat hydrolases showed a tendency to decrease with increasing lipophilic-ity (range ca. 2 to 5). A similar trend was not seen with naphthyl aryl carbonates nor with a-naphthyl carboxylates. These results tell us that, even with purified enzymes and large series of substrates, it is very difficult indeed to discern sound structure-hydrolysis relationships due to the complexity of the structural and enzymatic factors involved. 

The first inhaled glucocorticoid, beclomethasone dipropionate, revolutionized asthma therapy, when it was found that topical delivery to the lung resulted in reduced systemic side-effects (adrenal suppression, oseteoporosis and growth inhibition) typically seen with oral steroid treatments. Interestingly, a further reduction in systemic exposure was achieved with the introduction of fluticasone propionate (1). The evolution of this drug stemmed from observations with the steroid 17-carboxylates that showed that these esters were active topically when esterified, while the parent acids were inactive. Thus it was realized that enzymatic hydrolysis of the ester would lead to systemic deactivation. SAR studies led to a series of carbothioates, which were very active in vivo when topically applied to rodents, but were inactive after oral administration. It was shown that fluticasone propionate (1) underwent first pass metabolism in the liver to the corresponding inactive 173-carboxylic acid (la) (Scheme 1). This observation was... 

Furoic acid (furan-2-carboxylic acid, or pyromucic acid) is used as a bactericide, and the furoate esters are used as flavoring agents, as antibiotic and corticosteroid intermediates. It is obtained by the enzymatic or chemical/catalytic aerobial oxidation of furfural (2-furalaldehyde) the latter is the only unsaturated large-volume organic chemical prepared from carbohydrates today. D-Xylose and L-ara-binose, the pentoses contained in the xylan-rich portion of hemicelluloses from agricultural and forestry wastes, under the conditions used for hydrolysis undergo dehydration to furfural. 

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