Protection of carboxylic acids

FIGURE 20.50 Formation and hydrolysis of ferf-butyl esters. 

Hydrogenolysis is used to describe the cleavage of a single bond by molecular hydrogen in the presence of a catalyst. It is distinct from hydrogenation, where hydrogen is added across a multiple bond. 

FIGURE 20.52 Formation and cleavage of 2-(trimethylsilyl)ethyl esters. 

The mechanism of action of dicyclohexylcarbodiimide (DCC) as a coupling reagent will be discussed in detail in Chapter 22. There, we will also discuss in detail the sort of protection for carboxyl groups that is used for the preparation of peptides. 

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Two new sections on the protection of phosphates and the alkyne-CH are included. All other sections of the book have been expanded, some more than others. The section on the protection of alcohols has increased substantially, reflecting the trend of the nineties to synthesize acetate- and propionate-derived natural products. An effort was made to include many more enzymatic methods of protection and deprotection. Most of these are associated with the protection of alcohols as esters and the protection of carboxylic acids. Here we have not attempted to be exhaustive, but hopefully, a sufficient number of cases are provided that illustrate the true power of this technology, so that the reader will examine some of the excellent monographs and review articles cited in the references. The Reactivity Charts in Chapter 10 are identical to those in the first edition. The chart number appears beside the name of each protective group when it is first introduced. No attempt was made to update these Charts, not only because of the sheer magnitude of the task, but because it is nearly impossible in... 

Other reactions useful for the hydrolysis of esters may be found in Section 30A (Protection of Carboxylic Acids). 

Other reactions useful for the protection of carboxylic acids are included in Section 107 (Esters from Carboxylic Acids and Acid Halides) and Section 23 (Carboxylic Acids from Esters). 

Protection of carboxylic acids 2,6-Dimethoxybenzyl esters on treatment with DDQ (1 equiv.) at 25° in CH2C12 containing some water are slowly converted into the corresponding acids in 90-95% yield. 4-Methoxybenzyl esters are stable to this oxidation, whereas 2,4,6-trimethoxybenzyl esters are hydrolyzed in the presence of silica gel. 

Trimetkylsilyl esters.5 These esters are inert to diborane in THF and thus are useful for protection of carboxylic acids during hydroboration. 

Protection of carboxylic acids.2 N-Acyl derivatives of 1 are hydrolyzed in high yield (85-100%) when irradiated in CH2Cl2-dioxane-water at 350 nm (5-10 hours), with recovery of 1 in about 90% yield. The 7-nitro group is essential for this photoreaction. 

Based on facile formation of 7i-allylpalladium intermediates from various allylic compounds, allyl groups can be used for the protection of carboxylic acids, amines and alcohols. Deprotection can be achieved by two methods using Pd(0) catalysts [128,138]. In one method, the allyl group can be removed as propylene by Pd-... 

Chakraborti, A. K. Basak, A. Grover, V. Chemoselective protection of carboxylic acids as methyl esters a practical alternative to the diazomethane protocol. J. Org. Chem. 1999,... 

Protection of—COOH.1 Trimethylsilyl esters are useful for temporary protection of carboxylic acid groups during hydroboration of an unsaturated acid. The silyl esters need not be isolated and deprotection occurs spontaneously during the oxidation or iodination step. 

Protection of carboxylic acids.1 MEC esters (1) are stable to weak acid or base, but are cleaved selectively by reaction with the thiostannane (CH3)2Sn(SCH3)2 (2) and BF3 0(C2H5)2 (1 equiv.) at 0°. 

Trialkylsilyl protection of carboxylic acids and amines is rare owing to hydrolytic lability. Nevertheless, synthetically useful silicon protecting groups have been developed for these functional groups in which the requisite stability is achieved by incorporating the silicon atom into a 2-(trimethylsilyl)ethyl substituent. The principle is illustrated [Scheme 1.9] by the reaction of 2-(trimethylsilyl)ethyl esters with tetrabutylammonium fluoride the pentavalent siliconate intermediate fragments with loss of ethylene and fluorotrimethylsilane14-15 to liberate a carboxylic arid as its tetrabutylammonium salt. 

Protection of carboxylic acids. The 2-(2-pyridyl)ethyl group is useful for protection of amino acids. The esters are obtained by reaction with 1 and DCC/1-hydroxybenzo-triazole. The group provides higher solubility in protic solvents, and is stable to both acids and bases. It is removed by treatment with methyl iodide and a weak base. 

Protection of carboxylic acids. Esters of this alcohol are converted in the presence of catalytic amounts of Pd[P(QH5)3]4 into butadiene and trimethylsilyl esters, which are readily hydrolyzed by water or an alcohol. This protecting group is thus useful for protection of highly functionalized and sensitive acids. The same procedure can be used for deprotection of carbonates or carbamates containing this unit. 

Protection of carboxylic acids and sulfenic acids requites efficient sdyl donors, eg, BSA, MTSA, and bis(ttimeth5isd5d)urea [18297-65-7] (BSU). BSU is often prepared in situ from hexamethyldisdazane and urea to yield over 90% of the sdylated derivative in synthesis of cephalosporins (5). 

Protection of carboxylic acids. The reagent reacts with darboxylic acid derivatives (the acyl chloride or mixed anhydride) to give a monoacylhydrazidc, RCON(CHMe2)-NHfCHMcj). The derivatives arc stable to both acids and bases. They are reconverted into carboxylic acids by selective oxidation, preferably with lead tetraacetate. The new method of protection has been used for penicillins. 

Protection of acids and phenols. Carboxylic acids can be protected as the p-bromophenacyl esters, prepared by the reaction of the carboxylate anion with p-bromophenacyl bromide in water or DMF. The protecting group is removed at room temperature by zinc in glacial or aqueous acetic acid. The new method is comparable to Woodward s protection of carboxylic acids as /3-trichloroethyl esters, which are also cleaved by zinc (see Trichloroethanol, this volume), y-Lactones are converted into y-hydroxy esters. 

Protection of carboxylic acids. Esters are prepared using DCC-DMAP, and they are cleaved on contact with 1% trifluoroacetic acid in CH2CI2 at room temperature for a short time. The deblocking conditions do not affect r-butyl esters and t-Boc amines. 

Cleavage of p-nitrobenzyl group. Protection of carboxylic acids and amines as the esters and carbamates can take advantage of the selective reduction-induced fragmentation by zinc dust, as C=C bonds, S-N bonds, benzyloxycarbonyl, and diphenylmethyl groups are not affected during the operation. 

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