Reactions of the carboxy group

The most representative general reactions (most of which are reversible) are esterification oxidative decarboxylation, successive reduction to the aldehyde and then to the primary alcohol, and acyl halideformation, giving derivatives useful for conversion into L-a-acylamido-ketones (RNH—(CR R2—) COCl— RNH—(CR R2—) COCH3) 

Schiff base formation with RCHO/base —t R-CH=N-(CR1R2-)nC02H 

Quaternary ammonium salts of amino acids can be formed in the usual way (Equation (4.1) Lansbury et al., 1989) and have the particular advantage that they are soluble in aprotic organic solvents (particularly the tetra-n-butylammonium salts), so opening up to amino acids (which are not significantly soluble in these solvents) a wider range of reactions (Nagase et al., 1993). 

These routine reactions are the basis of the growing numbers of applications of natural amino acids in stereoselective synthesis (Coppola and Schuster, 1987). They are also used for the selective introduction of often exotic structures that are used as protecting groups for amino acids, giving intermediates for peptide synthesis, as illustrated in Chapter 7. 

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The mechanism of such reactions using unsaturated carboxylic acids and Ru(BINAP)(02CCH3)2 is consistent with the idea that coordination of the carboxy group establishes the geometry at the metal ion.26 The configuration of the new stereocenter is then established by the hydride transfer. In this particular mechanism, the second hydrogen is introduced by protonolysis, but in other cases a second hydride transfer step occurs. 

Imipenem (5.46) has not completely fulfilled such expectations [122], Indeed, this compound is unstable in both acidic and alkaline media. In weakly acidic solutions, imipenem undergoes complex oligomerization, a reaction initiated by the intermolecular attack of the carboxy group on the /3-lactam Fig. 5.17) and yields, finally, a diketopiperazine compound. In weakly alkaline solution, an intermolecular reaction between the /3-lactam and (iminome-thyl)amino group was observed Fig. 5.18). This reaction proceeds via an unstable dimer that breaks down to thienamycin (5.45) and a /3-lactam ring-opened compound bearing a Ai-formyl group [123],... 

Coenzyme A (see also p. 106) is a nucleotide with a complex structure (see p. 80). It serves to activate residues of carboxylic acids (acyl residues). Bonding of the carboxy group of the carboxylic acid with the thiol group of the coenzyme creates a thioester bond (-S-CO-R see p. 10) in which the acyl residue has a high chemical potential. It can therefore be transferred to other molecules in exergonic reactions. This fact plays an important role in lipid metabolism in particular (see pp. 162ff), as well as in two reactions of the tricarboxylic acid cycle (see p. 136). 

Competitive inhibitors often closely resemble in some respect the substrate whose reactions they inhibit and, because of this structural similarity, compete for the same binding site on the enzyme. The enzyme-inhibitor complex either lacks the appropriate reactive groups or is held in an unsuitable position with respect to the catalytic site of the enzyme which results in a complex which does not react (i.e. gives a dead-end complex). The inhibitor must first dissociate before the true substrate may enter the enzyme and the reaction can take place. An example is malonate, which is a competitive inhibitor of the reaction catalysed by succinate dehydrogenase. Malonate has two carboxyl groups, like the substrate, and can fill the substrate binding site on the enzyme. The subsequent reaction, however, requires that the molecule be reduced with the formation of a double bond. If malonate is the substrate, this cannot be achieved without the loss of one of the carboxy-groups and therefore no reaction occurs. 

Elimination sometimes accompanied tosyloxylactonization then, the crude reaction mixture was treated with 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and unsaturated lactones were obtained directly. A series of suitably constructed unsaturated diacids were produced with HTI bis-lactones, as the result of stereoselective ds-addition of the carboxy groups to the double bond, for example [7] ... 

Aldehyde functionalities are very reactive toward amino and hydroxy groups. As a result, polymers 1 can bind to cellnlose or protein snrfaces. Their reactivity toward nucleophiles enables them to take part in varions crosshnking reactions, e.g. with amines. Carboxy fnnctional polysiloxanes 2 are also able to bind to surfaces because of the carboxy group s high polarity. They can nndergo crosslinking reactions, e.g. with epoxides. Their salts are good snrfactants. 

Unfortunately, introduction of the N-Dts group requires two steps, the first being reaction of the amino group with 0-ethyl S-carboxy methyl dithiocarbon-ate or 0,0-diethyl trithiodicarbonate [Scheme 8.20].32 The intermediate ethoxy-thiocarbonyl derivative is then treated with chlorocarbonylsulfenyl chloride, whereupon chloroethane is extruded to give the JV-Dts derivative. Since the first step is often accompanied by some noisome minor products, a solid-phase variant has been developed for the synthesis of N-Dts-protected amino acids.33... 

Pictet-Spengler cyclization of L-tryptophan with formaldehyde afforded the monochiral carboxylic acids 20a,b, whereas cyclization with acetaldehyde yielded the diastereomeric carboxylic acids 21a,b (23). Acids 20a,b with a hydrogen at C-1 are enantiomers, but acids 21a,b are diaste-reomers the cis isomer 21a was the major reaction product when the cyclization of L-tryptophan with acetaldehyde was carried out in the presence of sulfuric acid. Direct removal of the carboxy group in these acids is difficult, but it can be accomplished in several steps dehydration of the amides prepared from the acids with phosphorus oxychloride affords nitriles, and the nitrile group can be removed by reduction with sodium borohydride in pyridine-ethanol (31). 

Decarboxylation—Carboxyacids and -esters, previously subjected to acid hydrolysis, undergo decarboxylation. The reaction has been performed on azabicycloketones in refluxing aqueous hydrogen chloride. The replacement of the carboxy group by deuterium is also fxissible. - - Further examples of decarboxylation are reported in Sec. A.2 and in Chap. I, C.5. 

In addition to suitable protection of other coreactive functionalities, activation of the carboxy group prior to reaction with the amino group is required for a controlled formation of the amide bond between two a-amino acid or peptide components (Scheme 1). For this purpose activated species can be generated separately, isolated, and stored for subsequent use. Alternatively, the activation can be carried out in situ with specific coupling reagents. Independently of the mode of activation, an electron-withdrawing group X must be incorporated at the acyl carbon in a transient mode in the in situ activation or in the formation of reactive intermediates. 

The cysteine 5-(tert-butyl) derivative is obtained by reaction of cysteine with isobutenef ° l or teri-butyl acetatef under acid catalysis. Under both of these reaction conditions, the carboxy group is esterified and has to be deprotected by TFA treatment. A more general procedure, applicable for the synthesis of both 5-(tert-butyl) (tBu) and 5-(l-adamantyl) (1-Ada) derivatives (Scheme 10), is based on S-alkylation of cysteine with the teri-alcohols under acidic conditions.The related A -Boc and A -Fmoc derivatives are obtained by standard procedures. 

The preparation of arylazo derivatives from hydroxypyrazines has been described in Section VI.6E and from l,4,6-trimethyl-3-methylene-2-oxo-l,2,3,4-tetrahydro-pyrazine to give l,4,6-trimethyl-2-oxo-3-phenykzomethylene-l,23,4-tetrahydro-pyrazine in Section VI.9B. In addition to these reactions Princivalle (1122) reports that 2reacted with benzenediazonium chloride and p-toluenediazonium chloride by elimination of the carboxy group para to the hydroxy group and coupling to form 2-hydroxy-3,6-dimethyl-5-phenyl-azo(and p-tolueneazo)pyrazines, respectively (1122), identical to those prepared from 3-hydroxy-2,5 -dimethylpyrazine. 

The configurations of these hydroxy acids were assigned by NMR spectroscopy and comparison with the data of some alkylated cyclopropanecarboxylic acids and 1-hydroxycyclo-propanecarboxylic acids. Chemical evidence for the exo configuration of the carboxy group and endo configuration of the hydroxy group resulted from the preparation and reaction of a norcarene-7-carboxylic acid, i.e. the 7-hydroxy-cw-bicyclo[4.1.0]hept-3-ene-exo-7-carboxylic acid (10a). 

Heterocyclic radicals with two ring heteroatoms, such as the reactions of tartaric acid derivatives, have been investigated39. Here, the isopropylidene-protected hydroxy groups define the cyclopentyl unit and one of the carboxy groups is utilized as the precursor functionality. Irradiation leads to a radical chain process, in which addition of alkenes to the intermediate radical occurs preferentially tram to the /Lcarboxy group. Only the /ram-isomer is observed in the H-NMR spectrum of the product in all cases and d.r. (trans/cis) 25 1 is estimated from HPLC measurements after degradation of the monoadducts to known compounds. 

Studies on the metabolism and saturation of sorbic acid have shown that fungi are capable of producing /ra .s-4-hexenol60-61. This bioconversion comprises the reduction of the carboxy group to the alcohol which seems to be the initial reaction, followed by hydrogenation of the a,/(-double bond of the unsaturated alcohol (see Section 2.5.1.3.1.2.). The remote double bond... 

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