Protection of the Carboxyl Group

The general approach for carboxyl protection is esterification. The simplest solution, the use of methyl or ethyl esters, is suitable for semipermanent blocking, although the commonly applied process of unmasking, alkaline hydrolysis, is far from unequivocal. It is accompanied by racemization, partial hydrolysis of carboxamide groups in the side chain of asparagine and glutamine residues and by several other side reactions which are initiated by proton abstraction (Cf. Chapter VII). Nevertheless, perhaps because of the attractively simple esterification of amino acids 

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  

Addition of the carboxyl group to isobutene, in the presence of strong acids, is used for the preparation of tert.butyl esters  

The salts of tert-butyl esters thus obtained can be converted to the free amines which are stable and can be stored while free methyl, ethyl and benzyl esters undergo self-condensation to diketopiperazines  

Benzyl esters are cleaved by catalytic hydrogenation and also by acidolysis albeit only under fairly drastic conditions. Electron-withdrawing substituents, such as the nitro group in / -nitrobenzyl esters, destabilize the benzyl cation and render the benzyl group even more resistant to acids. In contrast, the action of moderately strong acids, like dilute solutions of HCl in acetic acid or neat trifluoroacetic acid is sufficient for the acidolytic cleavage of /7-methoxybenzyl esters and, of course, of tert.butyl esters. 

Protecting groups for carboxylic acids are used to avoid reaction of the acidic COOH hydrogen with bases and nucleophiles or to prevent nucleophilic additions at the carbonyl carbon. Below are depicted several procedures for the protection of the carboxyl group by its conversion to the ester group.  

Aikyi Esters Classical methods for ester formation include the following approaches  

A mild method for the specific preparation of methyl esters is the reaction of carboxylic acids with diazomethane. Since diazomethane is very toxic and explosive, it must be handled with care, and is best suited for small-scale preparations. 

An operationally simple method for preparing methyl esters involves treatment of a carboxylic acid in methanol with of two equivalents of Me3SiCl. The esterification proceeds via initial formation of the trimethylsilyl ester followed by displacement of the silanol by methanol. 

The Mitsunobu esterification of carboxylic acids with alcohols in the presence of Ph3P and DEAD (diethyl azodicarboxylate) occurs under neutral conditions and provides the corresponding esters in high yields. 

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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. 

Hydrolytic ring opening of the 1,3-oxazine ring of the tetrahydro-[l,3]oxazino[3,4- ][l,2]oxazin-8-one 389 and subsequent protection of the carboxyl group has been performed (Scheme 61) <1999TL4391>. 

In a quite different approach, shown in Scheme 204, cycloaddition of nitrile 1232 to trimethylsilyldiazomethane provides silylated triazole 1233, isolated in 75% yield. Treatment with tetrabutylammonium fluoride removes the trimethylsilyl group and simultaneously the silyl protection of the carboxylic group to afford 4-substituted triazole derivative 1234 in 81% yield <2003PEN699>. 

Methods for the protection of the carboxyl group are considered in Section 5.11.8. 

For some purposes protection of the carboxyl group by conversion into p-phenylphenacyl, p-bromophenacyl, and p-nitrobenzyl esters is useful. General procedures for their formation are described in Section 9.6.15, p. 1261. 

Allyl, benzyl, phenylacyl and f-butyl esters are commonly used for protection of the carboxyl group. These esters can be removed without affecting the Fmoc group, and the resulting deprotected glycosylated amino acids can be used in glycopeptide synthesis. 

E. Haslam, Recent developments in methods for the esterification and protection of the carboxyl group, Tetrahedron 1980, 36, 2409. 

Cleavage of benzhydryl esters Protection of the carboxyl group... 

Another elegant reaction is the use of the 2-trimethylsilylethyl residue for protection of the carboxyl group by Sieber and colleagues in 1977 (for Ref. see e.g. in [44]). In some cases, saponification of methylesters requires alkaline conditions too strong to leave intact a sensitive peptide. Trimethylsilylethyl esters, however, in a type of jS-elimination, are decomposed at neutral pH by fluoride ions to yield trimethylfluorosilane, ethylene, and the carboxylic acid. 

A novel approach to peptide synthesis has been the use of a chloromethylated polystyrene polymer as an insoluble but porous solid phase on which the coupling reactions are carried out. Attachment to the polymer, constitutes protection of the carboxyl group (as a modified benzyl ester), and the peptide is lengthened from its amino-end by successive carbodiimide couplings. The method has been applied to the synthesis of a tetrapeptide, but incomplete reactions lead to the accumulation of by products. Further development of this interesting method is awaited. 

The reactivity of ketenimines such as 146 is related to substituent R. Ketenimines were isolable when R was phenyl or alkyl. In contrast, ketenimines wherein R was halogen, thienyl, phenylthio, methylthio, or methylsulfonyl were sufficiently reactive to afford iminoethers (147) at -78°C in the presence of excess lithium methoxide. The trimethyl-chlorosilane-quinoline procedure satisfactorily converted all these substituted iminoethers to amides in good yields. The overall sequence proved amenable for use with cephalosporin acids, by prior protection of the carboxyl group as a silyl ester. Extension of this method to the penicillin series permitted the preparation of 6a-methoxyketenimine 149 and 6a-methoxyimino ether 150 from the corresponding methyl 6p-(2-chlorophenyl)acetamido and fi -dichloroacetamidopenicillanates, respectively. No further transformations of these substances were reported. 

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