Protection of carboxyl groups

See also E. Haslam, Recent Developments in Methods for the Esterification and Protection of the Carboxyl Group, Tetrahedron, 36, 2409-2433 (1980) E. Haslam, Activation and Protection of the Carboxyl Group, Chem. Ind. (London), 610-617 (1979) E. Haslam, Protection of Carboxyl Groups, in Protective Groups in Organic Chemistry, J. F. W. McOmie, Ed., Plenum Press, New York and London, 1973, pp. 183-215. 

Benzyl esters of carboxylic acids are frequently used in organic synthesis for the protection of carboxyl groups. The C-O bond in benzyl esters can be cleaved more easily than the corresponding benzyl ether bond. The hydrogenolysis of an ester leads to carboxylic acid and toluene. Examples of debenzylation of benzyl esters of carboxylic acids on Pd/C catalysts are summarized in Table 4.4. 

FIGURE 3.18 Protection of carboxyl groups by esterification of amino acids (A) by acid-catalyzed reaction with alcohol. [Curtius 1888, Fisher 1906] with X = Cl for H-Xaa-OMe, X-Xaa-OEt, and H-Pro-OCH2Ph ... 

FIGURE 3.20 Protection of carboxyl groups by esterification of V-protected amino acids (A) by reaction of the anion with an alkyl halide or haloalkyl resin (R = resin) in dimethylformamide51 and (B) by tertiary amine-catalyzed reaction of a symmetrical anhydride with hydroxymethylphenyl-resin (R = resin).53 The intermediate is probably that depicted in Figure 3.19. Reaction (A) is applicable also to the carboxyl groups of peptides. 

Protection of carboxyl groups. Phenacyl esters can be cleaved in 90% yield with Zn-HOAc/DMI. For peptides that are poorly soluble in DMF, cleavage can be effected with Zn-anthranilic acid-pyridine in a mixture of N-methylpyrrolidone and DM.SO (86-92% yield). 

Protection of carboxyl groups. The deblocking reaction discussed above with 2 is also applicable to a halogenated protected derivative of the terminal carboxyl group of peptides. The N-protected amino acid is converted by the Passerini reaction with an o-halo aldehyde into a protected derivative such as 4. The derivative is cleaved by reiietion with 2 at 20° in acetonitrile or methanol (equation III). 

Protection of carboxyl groups (8, 94). Two new methods for deprotection of methylthiomethyl esters have been reported one involves oxidation to the sulfone followed by alkaline hydrolysis, and the other involves methylation to a sulfonium iodide and hydrolysis. ... 

Carboxylic acid derivatives, like esters or acid chlorides, behave as reactive electrophiles, acylating species. This activity is greatly reduced for acid amides. Thus the latter derivatives can be utilized for the protection of carboxyl groups in a number of reactions.In general, it is not considered to be a convenient protecting group because its removal may require rather drastic conditions. 

The reaction was applied to model dipeptides exemplified by the y-phenyl-hydrazide of N-carbobenzoxy-a-L-glutamyl-L-methionine methyl ester (4) and found to afford the carboxylic acid (S) in good yield without disturbance of the carbo-benzoxy and ester protective groups. The results suggest use of the phenylhydrazide group for protection of carboxyl groups in peptide chemistry. 

Protection of —COOH (3, 14-15). Full experimental details have been published for the protection of carboxyl groups as the 4,4-dimethyl-A -oxazoline derivatives. The derivatives are stable to Grignard and hydride reagents. This mode of protection was used in the synthesis of various substituted benzoic acids from the corresponding bromo acids. ... 

Protection of carboxyl groups. The carboxyl group of N-acyl amino esters can be protected by conversion to the hydrazide by reaction with hydrazine hydrate. Deprotection can be accomplished in quantitative yield by perchloric acid with no evidence of racemization. The method has not been applied as yet to higher peptides. ... 

Hydrolysis of 2-haloethyl esters. 2,2,2-Trichloroethyl esters have been used for protection of carboxyl groups because they are readily cleaved by zinc-acetic acid at 0° (3, 295-296). Ho has reported that 2-haloethyl esters can be cleaved by sodium trithiocarbonate in refluxing acetonitrUe in 75-85% yield. The suggested mechanism is formulated. ... 

Protection of carboxyl groups. This reagent forms esters by reaction with a carboxylic acid in the presence of DCC and hydroxybenzotriazole. These esters have been used in syntheses of small peptides they are cleaved by catalytic hydrogenation. A more unusual and very selective deblocking is achieved quantitatively by reduction to the hydroquinone by sodium hydrosulfite. ... 

Protection of carboxylic acids. The p-nitrobenzyl group is not useful for protection of carboxyl groups of penicillins and cephalosporins because hydro-genolysis can present a problem with sulfur-containing substrates. Lilly chemists have found that the esters can be reduced with sodium sulfide (NaaS-OHaO) in aqueous THF, DMF, or acetone at 0° (25-35 minutes). In the case of 3-cephem esters, the reduction is accompanied by isomerization of the double bond to the A -position (last example). 

Protection of carboxyl groups. Trimethylsilylethyl esters, —COOCH2-CHaSiCCHala, can be prepared from N-benzyloxycarbonylamino acids and this reagent with DCC in the presence of pyridine (65 95% yield). The esters are stable under usual conditions of peptide synthesis, but are readily cleaved by fluoride ion, preferably by fetra-n-butylammonium fluoride in DMF. ... 

Protection of carboxyl groups. 2-Bromoethyl and 2-chloroethyl esters of carboxylic acids are cleaved in 90-99% yield by NaHSe in C2H5OH (20°, 1 hour). ... 

Protection of carboxyl groups, Methoxymethyl esters oE carboxylic acids can also be prepared from methylal as formulated for the preparration of methoxymethyl benzoate. The method is applicable to phenols and tl iols° as well. 

Protection of carboxyl groups, p-Chlorobenzyl esters are about twice as Stable as benzyl esters to hydrolysis by trifluoroacetic acid in methylene chloride at 45°. They can be removed by liquid HF at 0°. These esters are recommended for protection of the P- and y-carboxyl group of aspartic acid and glutamic acid in the synthesis of moderate-sized peptides. 

Protection of carboxyl groups as 2,2,2-trichloroethyl esters Reductive removal of the protective group... 

Saponification with alkali generally used for the removal of methyl and ethyl esters is avoided if instead of simple alkyl esters rather benzyl esters or tert.butyl esters are applied for the protection of carboxyl groups. In addition to acid catalyzed esterification benzyl esters can also be secured by the reaction of cesium salts of (blocked) amino acids with benzyl chloride ... 

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