Hydrolysis of a methyl ester

Base-catalysed hydrolysis using alkali metal hydroxides or carbonates in aqueous methanol or THF remains the commonest method for cleaving simple esters limited mainly by the stability of the substrate to the basic conditions. In more complex substrates, lithium hydroxide in a mixture of THF-methanol-P O (2 2 1) is the base of choice.1-3 In a synthesis of Lepicidin A, Evans and Black4 accomplished the hydrolysis of a methyl ester with lithium hydroxide in aqueous /err-butyl alcohol at 35 °C [Scheme 6.1). Destannylation that accompanied hydrolysis with other solvents was not observed nor was harm inflicted on the TIPS and TES ethers. In a synthesis of cydoisodityrosine derivatives, Boger and co-workers attempted to hydrolyse methyl ester 2 1 [Scheme 6.2] with 1-3 equivalents of lithium hydroxide in a mixture of THF-methanol-HaO (3 1 1) at room temperature, but the desired hydrolysis was accompanied by scission of the tripeptide side chain from the ring system. However, when the reaction was conducted in the presence of the more nucleophilic lithium hydroperoxide, the desired hydrolysis was achieved in 97% yield without racemisation. 

Chlorotetaine is an irreversible inhibitor of glucosamine-6-phosphate synthetase and thereby interferes with ceil wall biosynthesis. The terminal steps of a synthesis of Chlorotetaine are shown in Scheme 6.15 in which deprotection of an iV-terminal amino group is a prelude to the final enzymatic hydrolysis of a methyl ester function.43 Critical to the success of the synthesis was the suppression of easy racemisation at the ring juncture in the ester hydrolysis step by using porcine pancreatic lipase. 

Poly(acrylic acid) and Poly(methacrylic acid). Poly(acryHc acid) (8) (PAA) may be prepared by polymerization of the monomer with conventional free-radical initiators using the monomer either undiluted (36) (with cross-linker for superadsorber appHcations) or in aqueous solution. Photochemical polymerization (sensitized by benzoin) of methyl acrylate in ethanol solution at —78° C provides a syndiotactic form (37) that can be hydrolyzed to syndiotactic PAA. From academic studies, alkaline hydrolysis of the methyl ester requires a lower time than acid hydrolysis of the polymeric ester, and can lead to oxidative degradation of the polymer (38). Po1y(meth acrylic acid) (PMAA) (9) is prepared only by the direct polymerization of the acid monomer it is not readily obtained by the hydrolysis of methyl methacrylate. 

Treatment of (89) with lead tetraacetate generates the unstable open-ring aldehyde (90) which is quickly converted to a dimethylacetal (91). Following basic hydrolysis of the methyl ester and acetates, the acetal is cleaved with aqueous acid to produce TxB2. A number of other approaches, including one starting from the Corey aldehyde, have been described (58). 

K2CO3 or Na2C03, MeOH, H2O, rt, 55-95% yield." Note that the trifluoroacetamide has been cleaved in the presence of a methyl ester, which illustrates the ease of hydrolysis of the trifluoroacetamide group. ... 

The formation of ethyl cyano(pentafluorophenyl)acetate illustrates the intermolecular nucleophilic displacement of fluoride ion from an aromatic ring by a stabilized carbanion. The reaction proceeds readily as a result of the activation imparted by the electron-withdrawing fluorine atoms. The selective hydrolysis of a cyano ester to a nitrile has been described. (Pentafluorophenyl)acetonitrile has also been prepared by cyanide displacement on (pentafluorophenyl)methyl halides. However, this direct displacement is always aecompanied by an undesirable side reaetion to yield 15-20% of 2,3-bis(pentafluoro-phenyl)propionitrile. 

To set the stage for the crucial aza-Robinson annulation, a reaction in which the nucleophilic character of the newly introduced thiolactam function is expected to play an important role, it is necessary to manipulate the methyl propionate side chain in 19. To this end, alkaline hydrolysis of the methyl ester in 19, followed by treatment of the resulting carboxylic acid with isobutyl chlorofor-mate, provides a mixed anhydride. The latter substance is a reactive acylating agent that combines smoothly with diazomethane to give diazo ketone 12 (77 % overall yield from 19). 

Pectin methylesterase (PM) is the enzyme which catalyzes the hydrolysis of the methyl ester groups in pectinic acids. In contrast to PG and protopectinase, a great deal of progress has been made during the past decade in our knowledge of PM. The older term pectase, 8 invented before the chemical action of the enzyme was understood, is now used by a decreasing number of workers while the name pectin-... 

In 30% dioxan (Glenn and Kirby, unpublished). The reference intermolecular reaction is the hydrolysis of the methyl ester catalysed by a general acid (RC02H) of pKt 4.72... 

Buffet and Lamaty, 1976. The pA. -values quoted are for the corresponding methoxymethoxy-benzoic acids. The reference intramolecular reaction is the acetic acid catalysed hydrolysis of the methyl ester in each case corrected for differences in pKt using a= 0.5 (Capon and Nimmo, 1975)... 

NSAIDs) has been reported [36]. As shown in Table 8.3, the hydrolysis of the methyl esters in human plasma proceeds far too slowly to be of therapeutic interest, with tm values ranging from ca. 5 to 150 h. In contrast, the carbamoylmethyl benzoates are hydrolyzed very rapidly (perhaps too rapidly ) with tm values in the order of minutes. But Table 8.3 also illustrates another important point, namely the marked influence of the acyl moiety on the rate of hydrolysis, with a more than 500-fold difference between the smallest and the largest acid (salicylic acid and sulindac, respectively). 

Hydrolysis of the methyl ester and decarboxylation at C-18 occur only under forcing conditions. Alkaline hydrolysis of the C-18 ester of vinblastine requires refluxing m 5 N sodium hydroxide for several hours to give the diacid (18), and ammonialysis of this position in anhydrous methanol is accomplished in a sealed vessel at 100°C for 60 hr to yield the 18 -decarbomethoxy-4-deacetylvinblastine amide (19) (55). Bisindole derivatives lacking the C-22 carboxyl have also been prepared by coupling the vindoline portion with an appropriately chosen ibogane precursor (Section V,G) (54). 

These enzymes [EC 3.1.1.1] (also referred to as ali-ester-ase, B-esterase, monobutyrase, cocaine esterase, methyl-butyrase, and procaine esterase) catalyze the hydrolysis of a carboxylic ester to yield a carboxylate anion and an alcohol. They exhibit a broad specificity, even acting on vitamin A esters. 

For more remote substitution p is expected to be smaller. Thus Hay and Porter-28 found p = 0.6 for the alkaline hydrolysis of the methyl esters of a-amino acids, RCH(NH2)COOCH.3 in water at 25°C. However, higher sensitivities are possible if the geometry of the system is such that the direct transmission of polar effects becomes more important. For example, Roberts and Moreland245 found that the effects of substituents in the 4 position of ethyl bicyclo-[2.2.2]octane-l-carboxylates (28) on the hydrolysis in 88% ethanol at 30°C are comparable to those observed for meta- anti para-substituted benzoates (p = 2.24), and a similar, though smaller, effect, is observed for methyl rrarts-4-substituted cyclohexanecarboxylates (29). 

More detailed studies of reactions of this type have been reported.96,97 Nickel(II) complexes of histidine and tryptophan provide stereoselectivity in the hydrolysis of histidine methyl ester, but stereoselectivity is not observed with nickel(Il) complexes of aspartic acid or methionine. Only tridentate ligands with a minimum steric bulk appear to be capable of exhibiting stereoselectivity in reactions of this type. 

Evidence for intramolecular hydrolysis of the methyl ester (62) by metal hydroxide has been provided.329 Molecular models of the metal complex (63) indicate that when complexation with the imidazole nitrogen and the phenolic hydroxyl group occurs, it is not possible for coordination of the ester carbonyl group to occur. This point, taken in conjunction with the observed pH rate profile which shows that ionization of the M—OH2 group is associated with catalysis, eliminates metal ion activation of the carbonyl bond to intermolecular attack by OH- as a contributing factor. For base hydrolysis of (62) kOH = 2.7 x 10-2 M-1 s-1 at 25 °C. The specific rate constants for intramolecular hydrolysis by the M—OH species are 0.245 s-1 and 2 x 10-2 s-1 for the Co11 and Ni11 complexes respectively. 

Hydrolysis of a methyl ether.1 Treatment of either 1 or 2 with BF3 etherate yields exclusively 3 (aklavinone). One explanation for the result is formation of a cyclic borate ester intermediate involving the C7- and C9-hydroxyl groups. Under similar conditions, trifluoroacetic acid converts either 1 or 2 into an 8 1 mixture of 3 and 7-epi-3. BF3 etherate was also used to convert the C,0-epimer of 2 into 3. 

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