Carboxylic acid derivatives protection

In 2000, an efficient three-step procedure for the synthesis of 5-substituted 3-isoxazolols (without formation of undesired 5-isoxazolone byproduct) was published. The method uses an activated carboxylic acid derivative to acylate Meldrum s acid, which is treated with A,0-bis(ten-butoxycarbonyl)hydroxylamine to provide the N,0-di-Boc-protected P-keto hydroxamic acids 14. Cyclization to the corresponding 5-substituted 3-isoxazolols 15 occurs upon treatment with hydrochloric acid in 76-99% yield. 

The magnesium bromide salt of indole gives the 3-carboxy derivatives in about 30% yield on reaction with carbon dioxide (56JCS2853). Ethyl indole-3-carboxylate can be obtained directly, but in modest yield, using ethyl chloroformate (62JOC496, 6602805). Indole-2-carboxylic acid derivatives can be obtained via the benzenesulfonyl-protected 2-lithio derivative (equation 181) (73JOC3324). 

Couplings with N-protected isoxazolidine-3-carboxylic acid can be performed without particular restrictions of the method, and the use of a mixed anhydride for acylation of amino acids or amide formation has been reported. 179 A similarly free choice of coupling methods is available for the acylation of isoxazolidine-3-carboxylic acid derivatives so far the use of carbodiimide and mixed anhydrides have been reported. 168179 Isoxazolidine-3-carboxylic acid derivatives are listed in Table 7. 

There are two approaches to the production of peptide a-oxo derivatives (1) the Dakin-West acylation directly from N-protected peptides (Section 15.1.5.1), and (2) oxidation of N-protected peptidyl a-substituted carboxylic acid derivatives (Section 15.1.5.2), which are prepared from N-protected peptides or nonpeptidyl intermediates. The oxidation approach has a synthetic advantage over the Dakin-West acylation as there can be retention of configuration in the final product, but it can be tedious to perform and, in some cases, it requires particular care. 

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. 

R. Sustmann, H. G. Korth, Protecting Groups for Carboxylic Acids, in Methoden Org. Chem. (Houben-Weyl) 4th ed. 1952-, Carboxylic Acids and Carboxylic Acid Derivatives (J. Falbe, Ed.), Vol. E5, 496, Georg Thieme Verlag, Stuttgart, 1985. 

An amide is one of the more stable carboxylic acid derivatives, and rather vigorous conditions are required to hydrolyze it to regenerate the unprotected amine. Therefore, several special protecting groups that can more readily be removed have been developed. These groups still employ an amide to deactivate the nitrogen, but they all contain some feature that allows them to be removed under milder conditions. They are especially useful in the synthesis of peptides from amino acids, described in Chapter 26. 

Carboxylic acid derivatives, like esters or acid chlorides, behave as reactive electrophiles, acylating species. This activity is greatly reduced for acid amides. Thus the latter derivatives can be utilized for the protection of carboxyl groups in a number of reactions.In general, it is not considered to be a convenient protecting group because its removal may require rather drastic conditions. 

The full capacity of the lipase-mediated technique for C-terminal deprotection is demonstrated in the synthesis of complex C>-glycopeptides, which are sensitive to both acids and bases, The key starting material, serine glycoside heptyl ester 11, is selectively depro-tected at the C-terminus by lipase obtained from the fungus Mucor javanicus (Scheme 22). The free carboxylic acid derivative 12 is coupled with an N-terminally protected glyco-dipeptide 13 to generate the tripeptide 14. 

E. Lee and co-workers demonstrated that the chlorohydrin derived from (+)-carvone undergoes a stereoselective Favorskii rearrangement to afford a highly substituted cyclopentane carboxylic acid derivative. This intermediate was then converted to (+)-dihydronepetalactone. When the THP-protected chlorohydrin was treated with sodium methoxide in methanol at room temperature, the rearrangement took place with excellent stereoselectivity (10 1) and high yield. Interestingly, the major product was the thermodynamically less stable cyclopentanecarboxylate. 

Canderel aspartame, candesartan candesartancilexetil. eandesartan cilexetil (Amias ) is a benzimidazole-carboxylic acid derivative, an (AT,) ANGIOTENSIN RECEPTOR ANTAGONIST, used as an antihypertensive. It is an ethyl ester prodrug of candesartan (CV 11974). It has experimental renal protective effects. 

This hydrazine is available by catalytic reduction of acetone azine.1 Protection of carboxylic acids.2 The reagent reacts with carboxylic acid derivatives (the acyl chloride or mixed anhydride) to give a monoacylhydrazide, RCON(CHMe2)-NH(CHMe2). The derivatives are 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. 

Various solid-phase syntheses have been reported including the phosphinic acid dipeptide analogues 209 which were constructed by coupling the appropriate Wang Resin-bound amino acid to the phosphinate carboxylic acid 210 using Fmoc chemistry. Similar phosphinate carboxylic acid derivatives (211) protected at phosphorus as their 1-adamanyl esters have also been used in solid-phase synthesis directed towards zinc metallo protease inhibitors. ... 

S,S-dioxides, those authors applied spHt/pool methodology. TWo different series of compounds were prepared such as compounds 376 containing an amino acid group acylated at the nitrogen atom. According to strategy 1 shown in Scheme 90, a series of structurally diverse carboxylic acid derivatives were prepared from supported aldehyde 373 condensed with different protected amino acids in the presence of NaBH(OAc)3 to afford intermediate 374, which was then acylated affording 375. After hydrolysis of ester and reaction with bromo derivative 368 (R = H) in PTC conditions, compounds 376 were obtained. 

Obtained by exposure of the carboxylic acid derived from the Claisen rearrangement to the esterification conditions (OH, OH,SOCl,), resulting in loss of the MOM protecting group. 

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

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

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