Ester lability

Ester functions present in molecules tend to be considered labile although steric effects etc. may be utilized to produce drugs without inherent chemical or metabolic problems due to ester lability. For instance a series of antimuscarinic compounds which had selectivity for the M3 receptor (Figure 7.18) were stabilized by the incorporation of a hydroxy ethyl side chain or a cyclic ring system at positions surrounding the ester function. Presumably the proximity of these groups to the ester function (carbonyl) prevents close approach of the attacking nucleophile, in this case probably a serine hydroxyl. 

Common ester labile bonds are formed between an alcohol and a carboxylic acid. The ester bond is hydrolyzed by hydrogen and hydroxyl ions as shown ... 

By addition of thiols to isonitriles thioformimidates (274 equation 147) are accessible. 2-Methyl-propaneisonitrile inserts into the thietane system to give triiminothiolanes (275 Scheme 42). A related insertion of isonitriles into a C—S bond was observed in the reaction of alkylmercaptocyanoacetic acid esters, labile thioimidates (276) are the products. - The addition of thiocarboxylic acids to isonitriles, giving mixed anhydrides of thioformimidic acids and carboxylic acids has been studied. ... 

Cryst. -f- HjO from HjO. M.p. 200° decomp. Sublimes in needles. Decomp, on prolongs heating, Sol. hot HjO, EtOH, Et 0, Me CO, CHClg. Spar. sol. cold HjO, CSji ligroin. k — 5-815 X 10". Forms three esters, labile, normal, and enolic, the latter being readily soluble in cold dilute alkali. 

In peptide syntheses, where partial racemization of the chiral a-carbon centers is a serious problem, the application of 1-hydroxy-1 H-benzotriazole ( HBT") and DCC has been very successful in increasing yields and decreasing racemization (W. Kdnig, 1970 G.C. Windridge, 1971 H.R. Bosshard, 1973), l-(Acyloxy)-lif-benzotriazoles or l-acyl-17f-benzo-triazole 3-oxides are formed as reactive intermediates. If carboxylic or phosphoric esters are to be formed from the acids and alcohols using DCC, 4-(pyrrolidin-l -yl)pyridine ( PPY A. Hassner, 1978 K.M. Patel, 1979) and HBT are efficient catalysts even with tert-alkyl, choles-teryl, aryl, and other unreactive alcohols as well as with highly bulky or labile acids. 

More successful are solid-phase methods in which the linear precursor is attached through a labile ester bond (e.g. o-nitrophenyl) to a polymer. 

Pos twe-Tone Photoresists. The ester, carbonate, and ketal acidolysis reactions which form the basis of most positive tone CA resists are thought to proceed under specific acid catalysis (62). In this mechanism, illustrated in Figure 22 for the hydrolysis of tert-huty acetate (type A l) (63), the first step involves a rapid equihbrium where the proton is transferred between the photogenerated acid and the acid-labile protecting group ... 

Diphenylmethyl esters are similar in acid lability to r-butyl esters and can be cleaved by acidic hydrolysis from 5-containing peptides that poison hydrogenolysis catalysts. 

DNA is not susceptible to alkaline hydrolysis. On the other hand, RNA is alkali labile and is readily hydrolyzed by dilute sodium hydroxide. Cleavage is random in RNA, and the ultimate products are a mixture of nucleoside 2 - and 3 -monophosphates. These products provide a clue to the reaction mechanism (Figure 11.29). Abstraction of the 2 -OH hydrogen by hydroxyl anion leaves a 2 -0 that carries out a nucleophilic attack on the phosphorus atom of the phosphate moiety, resulting in cleavage of the 5 -phosphodiester bond and formation of a cyclic 2, 3 -phosphate. This cyclic 2, 3 -phosphodiester is unstable and decomposes randomly to either a 2 - or 3 -phosphate ester. DNA has no 2 -OH therefore DNA is alkali stable. 

NH2NHC(S)SH, lutidine, AcOH, 2-20 min, rt, 88-99% yield. This method is superior to the use of thiourea in that it proceeds at lower temperatures and affords much higher yields. The reagent also serves to remove the related bromoacetyl esters that are 5-10 times more labile under these conditions. Cleavage occurs cleanly in the presence of an acetate. 

H2O2, (NH4)6Mo7024 NaOH, pH 11, 97% yield. The MTM ester is converted to the much-more-base labile methylsulfonylmethyl ester. It is possible to hydrolyze the methylsulfonylmethyl ester in the presence of the MTM ester. 

This ester was designed as a base-labile protective group. Monoprotection of aspartic acid was achieved using the DCC/DMAP protocol. Cleavage is... 

Few methods exist for the protection of sulfonic acids. Imidazolides and phenolic esters are too base labile to be useful in most cases. Simple sulfonate esters often cannot be used because these are obviously quite susceptible to nucleophilic reagents. 

Of interest is a recent report of a rapid synthesis of efaroxin (51), a potent, selective O2 adrenoceptor antagonist, using Darzens Reaction. Accordingly, a-bromoester 48 was condensed with aldehyde 47. The glycidic ester (49) was then hydrogenated to reduce the more labile epoxide bond to give alcohol 50. Subsequent standard transformations subsequently lead to a completed 4-step synthesis of efaroxin. o... 

The Wenker aziridine synthesis entails the treatment of a P-amino alcohol 1 with sulfuric acid to give P-aminoethyl sulfate ester 2 which is subsequently treated with base to afford aziridine 3. Before the discovery of the Mitsunobu reaction, wbicb transforms an amino alcohol into an aziridine in one step under very mild conditions, the Wenker reaction was one of the most convenient methods for aziridine synthesis. However, due to the involvement of strong acid and then strong base, its utility has been limited to substrates without labile functionalities. 

As described in Section 1.7.1, the utility of the Wenker reaction is limited to substrates without labile functionalities because of the involvement of strong acid and then strong base. The Fanta group prepared a variety of aziridines by taking advantage of the Wenker reaction.For example, 6-aza-bicyclo[3.1.0]hexane (14) was produced from the ring-closure of ( )-rra s-2-aminocyclopentanol hydrochloride (13). In a similar fashion, sulfate ester 16 was prepared from A-methyl dl-trans- >-ssmnoA-hydroxytetrahydrofuran (15). Subsequent treatment of sulfate ester 16 with NaOH then delivered aziridine I . " Additional examples of Wenker aziridine synthesis may also be found in references 15-17. 

Pyridine, and its monomethyl and 3,5-dimethyl derivatives " combine exothermically with dimethyl acetylenedicarboxylate in ether yielding some ether soluble materials, including trimethyl pyrrocoline-1,2,3-tricarboxylate (Section III,F,3) and deep red ether-insoluble gums. A number of crystalline compounds have been isolated from these gums by fractional crystallizations and will now be considered in detail. In the case of pyridine, Diels et al. ° isolated a red labile 1 2 molar adduct, which they formulated as (75), which isomerized rapidly on standing to a yellow stable adduct (76). These formulations are no longer accepted. Diels and Alder also suggested that the acetylenic ester first dimerized to the diradical (74) which then combined with the pyridine. 

Quinoline,like pyridine, and the ester give a 1 2 molar labile adduct (117) which is not basic and isomerizes on heating or with acids to a stable isomer (118) as in the pyridine series. It has been... 

In methanol, isoquinoline and the ester gave the benzo[fif]indolizine [(121), cf. Section II,D,3] while in ether the labile adduct, tetra-methyl llbH-benzo[a]quinolizine-l,2,3,4-tetracarboxylate (122) was obtained. The labile adduct is much less easily isoraerized than the 9-methyl-9aH-quinolizines derived from pyridines (Section III,F,1) but with boiling xylene or, better, with sulfuric-acetic acids the cor-... 

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