Common carboxylic acid protecting groups

Carboxylic acids are protected as their esters such as methyl esters, tert-hutyl esters, allyl esters, benzyl esters, phenacyl esters and alkoxyalkyl esters. The esters are formed by the reaction of carboxylic acid with alcohol, and the reaction is known as esterification. 

Methyl ester t-Butyl ester Allyl ester Benzyl ester 

The terf-butyl esters are usually prepared by the reaction of an acid with isobutylene in the presence of an acidic catalyst. In the modified procedure instead of isobutylene, fert-butyl alcohol (f-BuOH) is used in the presence of heterogeneous acid catalyst.  

Allyl esters can be prepared by the reaction of carboxylic acid with allyl bromide in the presence of CS2CO3 in DMF or allyl alcohol in the presence of TsOH in benzene. 

Alkoxyalkyl esters and silyl esters are also easily prepared and cleaved. For example, 2-(trimethylsilyl)ethoxymethyl esters are usually cleaved with HF in acetonitrile by fluoride ion. 

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A more commonly used carboxylic-acid-protecting group that is rather more stable towards attack by nucleophiles is the t-butyl ester. t-Butyl esters can be made by reacting the carboxylic acid with the cation generated from isobutene in sulfuric acid. 

In general, the methods for protection and deprotection of carboxylic acids and esters are not as convenient as for alcohols, aldehydes, and ketones. It is therefore common to carry potential carboxylic acids through synthetic schemes in the form of protected primary alcohols or aldehydes. The carboxylic acid can then be formed at a late stage in the synthesis by an appropriate oxidation. This strategy allows one to utilize the wider variety of alcohol and aldehyde protective groups indirectly for carboxylic acid protection. 

Proteins have primary, secondary, tertiary, and quaternary stmcture.The primary structure of a peptide can be determined by using a combination of enzymes and small molecule reagents. There are several analytical tools that can also be applied to this task. Peptides can be synthesized by employing protecting groups and activating reagents. The common procedures are amide formation vdth tBoc or Cbz for amine protection, esterification with ethanol for carboxylic acid protection, and acid activation with DCC. 

The use of protecting groups is common in penicillin chemistry the amino function is normally protected by a triryl, benzyloxycarbonyl. p-nitrobenzyloxycarbonyl. tridlloroethyloxycarbonyl. or trimethylsilyl group and the carboxylic acid is usually protected as a benzyl, p-nitrobenzyl. p-methoxybenzyl. or trichloroethyl ester. Acylations may thus be carried out... 

Carboxy terminal amino acid or peptide thiols are prepared from various p-amino alcohols by conversion into a thioacetate (R2NHCHR1CH2SAc) via a tosylate followed by saponification.Several methods have been used to prepare N-terminal peptide thiols, the most common procedure is the coupling of (acetylsulfanyl)- or (benzoylsulfanyl)alkanoic acids or add chlorides with a-amino esters or peptide esters, followed by deprotection of the sulfanyl and carboxy groups. 8 16 Other synthetic methods include deprotection of (trit-ylsulfanyl)alkanoyl peptides, 1718 alkaline treatment of the thiolactones from protected a-sulfanyl acids, 19 and preparation of P-sulfanylamides (HSCH2CHR1NHCOR2, retro-thior-phan derivatives) from N-protected amino acids by reaction of P-amine disulfides with carboxylic acid derivatives, followed by reduction. 20,21 In many cases, the amino acid or peptide thiols are synthesized as the disulfides and reduced to the corresponding thiols by the addition of dithiothreitol prior to use. 

Linkers are usually categorized according to the kind of functional group or substrate class they can selectively immobilize (linkers for carboxylic acids, alcohols, amines, etc.). Because a variety of types of linker is available for solid-phase synthesis, many belong to certain well-established classes of protecting group (Table 6.1.1) and can therefore be grouped into linker families. The members of each family have certain reactivity patterns in common. 

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. 

Because the acidic hydrogen is the usual cause of undesired reactivity, carboxylic acids are commonly protected as esters. Most often, simple methyl esters are used. The ester can be prepared via the acyl chloride or by Fischer esterification (see Section 19.4). The ester group can be converted back to the carboxylic acid by hydrolysis under acidic or basic (saponification) conditions (see Section 19.5). 

Esters of amino acids are often used as protected derivatives to prevent the carboxyl group from reacting in some undesired manner. Methyl, ethyl, and benzyl esters are the most common protecting groups. Aqueous acid hydrolyzes the ester and regenerates the free amino acid. 

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