Ester hydrolysis chemoselectivity

An unusual case of intramolecular competition (chemoselectivity, see Chapt. 1 in [la]) between ester and oxirane occurs in the detoxification of (oxiran-2-yl)methyl 2-ethyl-2,5-dimethylhexanoate (10.49), one of the most abundant isomers of an epoxy resin. The compound is chemically very stable, i.e., resistant to aqueous hydrolysis, but is rapidly hydrolyzed in cytosolic and microsomal preparations by epoxide hydrolase and carboxylesterase, which attack the epoxide and ester groups, respectively [129], The rate of overall enzymatic hydrolysis was species dependent, decreasing in the order mouse > rat > human, but was relatively fast in all tissues examined (lung and skin as portals of entry, and liver as a further barrier). In mouse and rat lung microsomes, ester hydrolysis was 3-4 times faster than epoxide hydration, whereas the opposite was true in human lung microsomes. 

The hydrolysis of phosphonic acid esters in Brij-35 micelles by cerium(IV) was investigated by Moss and Ragunathan (1999). The phosphonic esters differ from the phosphodiesters by the presence of only one ester bond and by a direct bond between phosphorus and the carbon atom of an alkyl or aryl group. Cerium(IV) ions also accelerate the hydrolysis of these diesters (Moss and Morales-Rojas, 2001 Moss et al., 2004). The phosphonoformate diesters show structural similarities with the phosphodiesters. Whereas zirconium(IV) and hafnium(IV) hydrolyze mainly the P-OR bond, cerium(IV) and thorium(IV) hydrolyze principally the C-OR bond in the phosphonoformate diesters. This chemoselective ester hydrolysis was not observed for the phosphodiester compounds. 

A synthetically useful virtue of enol triflates is that they are amenable to palladium-catalyzed carbon-carbon bond-forming reactions under mild conditions. When a solution of enol triflate 21 and tetrakis(triphenylphosphine)palladium(o) in benzene is treated with a mixture of terminal alkyne 17, n-propylamine, and cuprous iodide,17 intermediate 22 is formed in 76-84% yield. Although a partial hydrogenation of the alkyne in 22 could conceivably secure the formation of the cis C1-C2 olefin, a chemoselective hydrobora-tion/protonation sequence was found to be a much more reliable and suitable alternative. Thus, sequential hydroboration of the alkyne 22 with dicyclohexylborane, protonolysis, oxidative workup, and hydrolysis of the oxabicyclo[2.2.2]octyl ester protecting group gives dienic carboxylic acid 15 in a yield of 86% from 22. 

Hydrolysis of both ester groups and chemoselective re-esterification of the more reactive alkyl acid... 

Searching for a method of synthesis of enantiopure lamivudine 1, the compound having a monothioacetal stereogenic centre, Rayner et al. investigated a lipase-catalysed hydrolysis of various racemic a-acetoxysulfides 2. They found out that the reaction was both chemoselective (only the acetate group was hydrolysed with no detectable hydrolysis of the other ester moieties) and stereoselective. As a result of the kinetic resolution, enantiomerically enriched unreacted starting compounds were obtained. However, the hydrolysis products 3 were lost due to decomposition." In this way, the product yields could not exceed 50% (Equation 1). The product 2 (R = CH2CH(OEt)2) was finally transformed into lamivudine 1 and its 4-epimer. ... 

Elaboration of triol 88b to bryostatin 7 requires chemoselective hydrolysis of the Cl methyl ester in the presence of the C7 and C20 acetates, macrolide formation, installation of the C13 and C21 methyl enoates, and, finally, global deprotection. The sequencing of these transformations is critical, as attempts to introduce the C21 methyl enoate to form the fully functionalized C-ring pyran in advance of macrolide formation resulted in lactonization onto the C23 hydroxyl. In the event, trimethyltin hydroxide promoted hydrolysis [73] of the Cl carboxylate of triol 88b, and subsequent trie thy lsilylation of the C3 and C26 hydroxyls each occurs in a selective fashion, thus providing the seco-acid 89. Yamaguchi macrolacto-nization [39] proceeds uneventfully to provide the macrolide 67 in 66 % yield (Scheme 5.14). 

Acid- and base-sensitive lipidated peptides can be selectively deprotected by enzymatic hydrolysis of choline esters.[13al Choline esters of simple peptides, but also of sensitive peptide conjugates like phos-phorylated and glycosylated peptides,1141 nucleopep-tides1151 and lipidated peptides,113,1631 can be cleaved with acetyl choline esterase (AChE) and butyryl choline esterase (BChE) under virtually neutral conditions with complete chemoselectivity. Acid-labile farnesyl groups and base-sensitive thioesters are not attacked. 

Displacement of the C7-F of 106 (Scheme 4.20) proceeded via chemoselective attack by the more nucleophilic pyrrolidine nitrogen rather than the piperidine nitrogen to afford the intermediate C7-octahydropyrrolopyridine. Hydrolysis of the ethyl ester with hydrochloric acid ultimately furnished moxifloxacin (2). 

Fig. 13.17. Alkenylation of a dienylboronic acid with an iodinated triene stereoselective synthesis of vitamin A. The enyne (top left) is added to catecholborane to prepare the tra/rs-configured boronic ester in a chemoselective fashion. The latter affords trans-dienylboronic acid A upon acid-catalyzed hydrolysis.

The synthesis starts with the coupling of two more amino acids aspartic acid and phenylalanine. As you would expect, the carboxylic acid group of phenylalanine is protected, this time as a methyl ester, and the NH2 group of aspartic acid is protected as a Cbz-derivative. Since aspartic acid has two carboxylic acid groups, one of these also has to be protected. Here is the method—first the Cbz-group is put on then both acids are protected as benzyl esters. Then just one of the benzyl esters is hydrolysed. It may seem surprising to you that this chemoselective hydrolysis is possible, and you could not have predicted that it would work, without trying it out in the lab. 

Enantioselective Addition of Dialkylzincs to Aldehydes with Functional Groups. Enantioselective and chemoselective addition of dialkylzincs to formyl esters using (15,2R)-DBNE as a catalyst affords optically active hydroxy esters. The subsequent hydrolysis of the esters affords the corresponding optically active alkyl substituted lactones with up to 95% ee (eq 13). ... 

The considerations in the previous section need to be addressed and customized for every screening project. As an example, when we set out to develop a new library of esterases for synthetic chemistry use, we first needed to determine the criteria that would be used in the screening project. Esterases and lipases catalyze the hydrolysis of ester bonds as shown in Scheme 1 and are useful for reactions requiring different regioselectivities, chemoselectivities, and stereoselectivities depending on the enzyme s substrate specificities. 

The hydrolysis of hydroxy, amino or unsaturated esters is usually accompanied by side reactions, loss of chirality or isomerization. Various esters have been selectively hydrolysed at room temperature and in high yields under high pressure in the presence of V-methylmorpholine or Pr2NEt. For example, the hydrolysis of the p,Y-unsaturated diester 105 into p-hydroxyester 106 occurred chemoselectively in 100% yield at high pressure in methanol solution subsequent high-pressure induced hydrolysis of 106, in CH3CN/H2O (60 1) as medium, afforded the desired hydroxy acid 107 as a single product (Scheme 7.27). The usual aqueous procedures produced a mixture of products. 

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