Protecting groups carboxylic acids

The C. 100-C. 101 diol group, protected as an acetonide, was stable to the Wit-tig reaction used to form the cis double bond at C.98-C.99, and to all the conditions used in the buildup of segment C.99-C. 115 to fully protected palytoxin carboxylic acid (Figure 1,1). 

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... 

The next major obstacle is the successful deprotection of the fully protected palytoxin carboxylic acid. With 42 protected functional groups and eight different protecting devices, this task is by no means trivial. After much experimentation, the following sequence and conditions proved successful in liberating palytoxin carboxylic acid 32 from its progenitor 31 (see Scheme 10) (a) treatment with excess 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) in ie/t-butanol/methylene chloride/phosphate buffer pH 7.0 (1 8 1) under sonication conditions, followed by peracetylation (for convenience of isolation) (b) exposure to perchloric acid in aqueous tetrahydrofuran for eight days (c) reaction with dilute lithium hydroxide in H20-MeOH-THF (1 2 8) (d) treatment with tetra-n-butylammonium fluoride (TBAF) in tetrahydrofuran first, and then in THF-DMF and (e) exposure to dilute acetic acid in water (1 350) at 22 °C. The overall yield for the deprotection sequence (31 —>32) is ca. 35 %. 

Allyl carboxylates can serve as protecting groups for acid functionalities removable by formate and... 

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-... 

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. 

Cleavage of the silyl protecting groups under acidic conditions, followed by exposure to MeS03H. results in ketalization of 26 to the pyran-lactol 27 (Figure 8) [20]. To complete the synthesis of the CP compounds, the primary alcohol has to be oxidized to the carboxylic acid and the carboxylic acid side chain has to be elongated by means of an Arndt-Eistert reaction. 

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. 

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. 

Recently, it has been shown that nucleophilic addition of neat dimethyl trimethylsilyl phosphite to serine-derived P-lactonc at I ()() C for 24 h leads specifically to the carboxylic trimethylsilyl ester by preferential transfer of the trimethylsilyl group. A simple aqueous workup induces hydrolysis of the silyl ester to give the N- and P-protected free carboxylic acid ready for activation and coupling. 

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. 

The 8-bromo-7-hydroxyquinoline moiety, as found in (41) (Scheme 6), has been proposed as a novel photolabile protecting group for carboxylic acids. This system has a greater single photon quantum efficiency than other commonly used photocleavable protection for carboxylic acids, and has sufficient sensitivity to multiphoton-induced photolysis to be used in vivo. 

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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