Deprotection of carboxylic acids

In addition to the preparation of l-alkenes, the hydrogenolysis of allylic compounds with formate is used for the protection and deprotection of carboxylic acids, alcohols, and amines as allyl derivatives (see Section 2.9). 

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. 

Photodeprotection of phenacyl and substituted phenacyl esters promises to be an efficient and mild method for the deprotection of carboxylic acids in biological systems. - ... 

Hydrolytic deprotection of carboxylic acids from their correspondent allyl esters, under dry conditions on montmorillonite KIO day, under the action of MW irradiation, has also been reported (Scheme 8.8) [43]. 

C. PROTECTION-DEPROTECTION OF CARBOXYLIC ACIDS C.i. Allyl Esters... 

Another method for deallylation of ally esters is the transfer of the allyl group to reactive nucleophiles. Amines such as morpholine are used[415-417], Potassium salts of higher carboxylic acids are used as an accepter of the allyl group[418]. The method is applied to the protection and deprotection of the acid function in rather unstable /f-lactam 664[419,420]. 

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... 

On the other hand, following the same sequences from the differently protected serine-derived nitrone 168, through the formation of hydroxylamines 169, C2 epimers of carboxylic acid and aldehydes are obtained, i.e., (2S,3R)-170 and (2S,3R)-171. Moreover, the syn adducts 164 were exclusively obtained in the addition of Grignard reagents to the nitrone 163, whereas the same reactions on nitrone 168 occurred with a partial loss of diastereoselectivity [80]. Q, j6-Diamino acids (2R,3S)- and (2R,3R)-167 can also be prepared from the a-amino hydroxylamines 164 and 169 by reduction, deprotection and oxidation steps. The diastereoselective addition of acetylide anion to N,N-dibenzyl L-serine phenyhmine has been also described [81]. 

FIGURE 3.8 Deprotection of carboxyl groups by acid-catalyzed hydrolysis (A) of amides and (B) of esters. Protonation generates a relatively stable carbenium ion that usually requires heat to fragment it. 

Protection2 and activation1 of carboxylic acids. Carboxylic acids react with 1 in the presence of a 2-chloropyridinium salt, proton sponge, and DMAP to form amides (2). These amides are stable to acids and bases but deprotection is possible with oxidative hydrolysis with ceric ammonium nitrate (CAN). If the oxidation is carried out in the presence of an amine, an amide is obtained in 70-95% yield. For this purpose, the combination of copper(II) oxide and ceric pyridinium chloride is far superior to CAN.4 No racemization was observed in the benzoylation of an a-amino ester. 

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. 

The methodology was successfully extended to a one-pot total synthesis of complex heterocyclic systems such as pyrazino [2,1-b] quinazolines 79, encountered in nature as alkaloids 80-82 (Scheme 50) [125]. To assemble the pyrazino[2,l-fo]quinazoline core, N-Boc protected amino acid 76 was employed instead of carboxylic acid 72 (Scheme 49) in the synthesis of the corresponding intermediate benzoxazinones 77. The subsequent reaction with an amine moiety of another amino acid ester 78 was accompanied by concomitant cleavage of the N-Boc protecting group and diketopiperazine-like cyclization (for the one-pot deprotection-cyclization reaction of N-Boc dipeptide esters to afford 2,5-piperazinedione under microwave dielectric heating, see [128]) to afford the target heterocycle 79. Hence, the total... 

Another general method for the synthesis of these macrocycles is the reaction of amines with (active) esters of carboxylic acids leading to oxoderivatives of the cycles. The amides can be reduced to amines or directly used for further transformations or complexation of metal ions. Two cyclens 55 and 56, as intermediates for the synthesis of bifunctional DOTA derivatives, were obtained by condensation shown in Scheme 10 between appropriate diamine-amide and active ester of AT-BOC-iminodiacetic acid (BOC = /-butoxycarbonyl), followed by deprotection and reduction <2003NMB581>. 

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. 

The oxidative addition of allylic esters is also gaming popularity as a means of deprotecting a carboxylic acid or alcohol (concomitant loss of CO2 from a carbonate). ... 

The enantioselective synthesis (51) of the side chain 30 of taxol had been achieved by way of stereospecific Sharpless epoxidation of cij-cinnamyl alcohol (29a), giving 29b (see Scheme 6). Following oxidation of the alcohol group, protection of the resulting carboxylic acid, regioselective opening of the epoxide with azide, benzoylation, and reduction, a suitably substituted moiety (28) was available which, after protection and deprotection of the acid function to form 30, was coupled to baccatin III. 

It is noteworthy that Takeda and coworkers (Ref. 154) recently proposed allyl isopropenyl dicarbonate made from isopropenyl chloroformate and sodium allyl carbonate as a convenient reagent for the preparation of allyl esters of carboxylic acids. Allyl isopropenyl dicarbonate reacts with carboxylic acids in the presence of DMAP under mild neutral conditions to give allyl esters in high yields. Allyl esters which could be deprotected by palladium catalysts are especially useful in the case of unstable compounds under acid or basic conditions, for example O-glycopeptides, penicillin derivatives, etc. 

The use of carboxylic acid esters as protective groups for alcohols is limited since they may undergo acyl substitution, hydrolysis or reduction. Reagents used for the preparation of esters in the presence of EtgN or pyridine are AcjO, AC2O-DMAP (note that DMAP increases the rate of acylation of alcohols with AcjO by a factor of 10" ), PhCOCl, (PhC0)20, and r-BuCOCl (pivaloyl chloride)." Deprotection of esters is usually done under basic conditions. ... 

Amides can in most cases be readily synthesized from activated derivatives of carboxylic acids and amines. They are fairly stable and often need harsh conditions for their removal. On the one hand this prompted a search for advanced methods for their selective cleavage on the other, however, amides generally are used for the protection of chemically stable compounds, e.g. in nucleotide chemistry. In more recent developments, acceleration of the deprotection reaction by intramolecular attack and the advantageous properties of amido hydrolases have been exploited. 

The alkyl groups of two identical carboxylic acids can be coupled to symmetrical dimers in the presence of a fair number of functional groups (equation 1). Since free radicals are the reactive intermediates, polar substituents need not be protected. This saves the steps for protection and deprotection that are necessary in such cases when electrophilic or nucleophilic C—C bond-forming reactions are involved. Furthermore, carboxylic acids are available in a wide variety from natural or petrochemical sources, or can be readily prepared from a large variety of precursors. Compared to chemicd methods for the construction of symmetrical compounds, such as nucleophilic substitution or addition, decomposition of azo compounds or of diacyl peroxides, these advantages make the Kolbe electrolysis the method of choice for the synthesis of symmetrical target molecules. No other chemical method is available that allows the decarboxylative dimerization of carboxylic acids. 

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