Carboxylate activation

A variety of carboxylate activating groups convert certain aziridine carboxylates (307) into 3-halogenoazetidin-2-ones (309). The reaction is stereospecific and is believed to proceed via a l-azabicyclo[1.1.0]butan-2-one cation (74JOC902). 

Carbamates can be used as protective groups for amino acids to minimize racem-ization in peptide synthesis. Racemization occurs during the base-catalyzed coupling reaction of an A-protected, carboxyl-activated amino acid and takes place in the intermediate oxazolone that forms readily from an A-acyl-protected amino acid (R = alkyl, aryl) ... 

Zhang et al. isolated Clostridium hydroxybenzoicum containing two inducible 4-hydroxybenzoate decarboxylase and 3,4-dihydroxybenzoate decarboxylase that form phenol and catechol (1,2-dihydroxybenzene), respectively. The organism does not further metabolize phenol and catechol produced by these reactions. The carboxylation activities of the two purified decarboxylases are not... 

The reaction product of the reserve carboxylation reaction was isolated and identified to be 3,4-dihydroxybenzoic acid by NMR and NMR with the authentic 3,4-dihydroxybenzoic acid as a reference. The carboxylation reaction of catechol to 3,4-dihydroxybenzoate was affected by the concentration of KHCO3. The carboxylation activity of E. cloacae P241 3,4-dihydroxybenzoate decarboxylase in the presence of 0.1 M KHCO3 was only 15% of that in the presence of 3 M KHC03. In the case of C. hydroxybenzoicum 3,4-dihydroxybenzote decarboxylase, only 0.01 mM 3,4-dihydroxybenzoate was formed from 6mM catechol in the presence of 50 mM NaHC03 by 40 min incubation. The difference in molar conversion ratios might be caused by the concentration of bicarbonate added to the reaction mixture. 

Recently, the distribution of 2,3-dihydroxybenzoate decarboxylase has been found in a variety of fungal strains (unpubhshed data), and the carboxylation activity for catechol is confirmed by the reaction using resting cells (or cell-free extract) in the presence of 3M KHCO3. The detailed comparative studies of enzyme structures and catalytic properties between 2,3-dihydroxybenzoate decarboxylase and 3,4-dihyroxybenzoate decarboxylase might explain how the decarboxylases catalyze the regioselective carboxylation of catechol. 

The combination of carboxyl activation by DCCI and catalysis by DMAP provides a useful method for in situ activation of carboxylic acids for reaction with alcohols. The reaction proceeds at room temperature.119... 

Syntheses of Peptides via Carboxyl-Activation of Amino Acids... 

The amino acid attached to a polymer is treated with an vV-protected, carboxyl-activated amino acid to give the supported peptide. In the following reaction the triazolide was formed in situ from the p-nitrophenyl ester and 1,2,4-triazole 1341... 

Sequential acylation reactions were carried out at ambient temperature for 1.5 h using a DMF solution (1.3 mL) of the appropriate A-Fmoc-protected amino acids [Fmoc-Arg/D-Arg(Pmc)-OH, 265 mg Fmoc-Trp/D-Trp(Boc)-OH, 211 mg 0.4 mmol) and then carboxyl activated using TBTU (154 mg, 0.4mmol), HOBt (54mg, 0.4mmol), and DIEA (140pL, 0.8 mmol). Repetitive A"-Fmoc deprotection was achieved using 20% v/v piperidine in DMF (6 min, 2.5 mL min - ). 

Fig. 12 Illustration of the chemistry employed for preparation of a modified Si(lll) surface. Firstly, a layer of alkenyl acid is bound to the surface by covalent attachment. Secondly, a layer of polylysine is electrostatically bound to the carboxylic activated surface and finally the DNA is bound to the surface in a reaction mediated by sulfosuccinimidyl 4-(N-maleimidomethyl)-cyclohexane-l-carboxylate [27]...

It therefore appeared that a general mechanism for enzymatic esterification of phenolic acids with glucose was operative, whereas the reaction with other alcoholic moieties proceeded via carboxyl-activated acyl derivatives. [In this context it should be emphasized that glucose esters must not be confused with glucosides different enzymes are involved in the biosynthesis of these two types of phenolic glucose derivatives (36)]. 

Acyl triflamides are excellent acylating agents for alcohols and amines [52], Classical methods for carboxyl activation include formation of anhydrides, either homo- or mixed (e.g. phosphoryl, sulfonyl, etc.). Further activation is possible by adding 4-dimethylaminopyridine as catalyst [53], The active acylating agents are throught to be... 

EEDQ is a valuable reagent for carboxyl activation in the coupling of amino acids [55]. Ideal d-a pairings of various reactive moieties facilitate the formation of the semicarbonate intermediates. Of course, a major driving force for this transformation is the aromatization of the dihydroquinoline system. 

Other effective ways of carboxyl activation involves the use of carboxylphos-phonium [56] and 0-acylisourea intermediates [57]. 

Schematic diagram illustrating the chemical method for peptide synthesis. First the amino acids to be linked are selected. The carboxyl group and the amino group that are to be excluded from peptide synthesis are protected (steps 1 and 1 ). Next the amino acid containing the unprotected carboxyl group is carboxyl-activated (step 2). This amino acid is mixed and reacted with the other amino acid (step 3). Protecting groups are then removed from the product (step 4).

As with the synthesis of cyclic peptides, various methods have been employed to effect head-to-tail cyclization of these peptides. The most straightforward method remains N-to-C-terminus amide bond formation in solution of the appropriately side-chain-protected peptide in the presence of carboxyl activating agents under basic conditions. 23 However, cyclodimerization reactions have also been employed to produce cyclic decameric peptides whereby two appropriately protected linear pentameric peptides are dimerized and cyclized in the presence of carboxyl activating agents under basic conditions in the same reaction. 23,24 The use of the cyclodimerization reactions, however, has limitations in that it can only be applied to produce symmetrical peptides, and that formation of the cyclic pentapeptide presents a side reaction and thus results in decreased yields of the desired product. 

Possibly the most important condensation reaction is that between a carboxylic acid and an amine to give an amide. A great many methods are known by which this formal dehydration process may be carried out, almost all of which involve the two step sequence (i) activation of CO2H COX, where X is a leaving group and (ii) aminolysis of RCOX. Japanese workers have recently advocated the use of 2,2-dichloro-5-(2-phenylethyl)-4-trimethylsilyl-3-furanone (1, "DPTF") for carboxyl activation, and its use for peptide formation is illustrated by the representative conversion 2 —> 3. The byproduct formed from DPTF in these reactions is 5-(2-phenylethyl)-4-trimethylsilylfuran-2,3-dione. 

Another example of promising research is the efficient electrochemical dicarbo-xylations of aryl-acetylenes with C02, using an uncomplicated bimetallic redox couple as the catalytic system. In this case, metallic nickel was used as the cathode and aluminum as the anode, to generate in situ carboxylation-active nickel species (Scheme 5.20) [61]. 

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