Side-chain Acids

Unsaturated side-chains are present in the cinnamic acids, some of which occur naturally in the trans form 12. Syntheses of the acids and their esters by the Claisen condensation and the Perkin and Knoevenagel reactions are discussed in Chapter 6. 

2-Hydroxycinnamic acids spontaneously cyclize to give a coumarin  

Some coumarins possess anticoagulant properties (warfarin is a widely used example) and other derivatives are used as fluorescent brightening agents. A number of laser dyes are based on coumarin. Cinnamic acid esters are commonly used in sun-tan lotions to absorb UV light, 

Benzenesulfonic acids are prepared by direct sulfonation of aromatic hydrocarbons. 

Aromatic carboxylic acids can be prepared by oxidation of an alkyl side-chain and by the reaction of an aryl Grignard reagent with CO2. 

Benzenesulfonic acids arc prepared by direct suifonation of aromatic hydrocarbons. 

Both carboxylic and sulfonic acids can be converted into esters, anhydrides and amides. 

Sulfonic acids are stronger acids than the corresponding carboxylic acids. Electron-withdrawing groups increase the acidity of both types, but electron-releasing groups decrease the acidity. 

The sulfonic acid group can be displaced by a variety of nucleophiles. 

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Some ammo acids have side chains that bear acidic or basic groups As Table 27 3 indicates these ammo acids are characterized by three values The third pK reflects the nature of the side chain Acidic ammo acids (aspartic and glutamic acid) have acidic side chains basic ammo acids (lysine arginine and histidine) have basic side chains The isoelectric points of the ammo acids m Table 27 3 are midway between the pK values of the zwitterion and its conjugate acid Take two examples aspartic acid and lysine Aspartic acid has an acidic side chain and a pi of 2 77 Lysine has a basic side chain and a pi of 9 74... 

Both Glu and Asp are present as their side-chain amides (Gin and Asn) rather than as free side-chain acids. 

In some cases the N-terminal component can be converted into a thiol [NH2-CH(R)-CH2SH] which is then used to displace the halogen of an a-bromo acid. This approach was used to prepare Boc-Ser t t[CFI2-S]Leu analogues by a role-reversal of the side-chain/acid group of Cys, once the amino acid was converted into an amino alcohol (Scheme 7).[38]... 

Flaxseed mucilage, associated with hull of flaxseed, is a gum-like material and composed of acidic and neutral polysaccharides. The neutral fraction of flaxseed mainly contains xylose (62.8%), whereas the acidic fraction of flaxseed is comprised mainly of rhamnose (54.5%), followed by galactose (23.4%) (Cui et al., 1994a). A study by Warrand et al. (2005) found that the neutral monosaccharides were a mixture of three major families of polymers, arabinoxylans with a constant A/X ratio of 0.24, and various amount of galactose and fucose residues in the side chains. Acidic hydrolysis yields xylose, galactose, arabinose, rhamnose, galacturonic acid, fucose, and glucose (BeMiller, 1973 Erskine and Jones, 1957). 

This approach has been elegantly demonstrated by Biemann and co-workers [174]. They have adapted one of their earlier methods of modifying peptides [193] by esterification, N-terminal acetylation and then reduction with LiAlH4 (or LiAlD4) to give the polyamino-alcohol. These steps are preceded by chemical or enzymatic hydrolysis of the protein to di, tri- and tetrapeptides and concluded by O-silylation of the alcohol and side chain acid or hydroxyl function (see Scheme 1.1). 

The hydrophilic amino acids can be further subdivided into polar with no charge, polar with negatively charged side chains (acidic), and polar with positively charged side chains (basic). 

A stereocontrolled synthesis of the side-chain acid 186 of isoharringtonine from (R,R)-(-l-)-tartaric acid was reported by Zhang etal. (63) (Scheme 30). Dimethyl (2R, 3i )-tartrate acetonide (182) was allylated in the presence of lithium diisopropylamide to give 183, which underwent base-catalyzed epimerization to 184. Catalytic hydrogenation, followed by hydrolysis and by treatment with methanol in the presence of sulfuric acid, yielded the half ester 185, which was treated with aqueous trifluoroacetic acid to provide the side-chain acid of isoharringtonine (186) with the appropriate stereochemistry. 

Acylation of 3-substituted indoles is more difficult, however 2-acetylation can be effected with the aid of boron trifluoride catalysis." " Indoles, with a carboxyl-containing side-chain acid at C-3, undergo intramolecular acylation forming cyclic 2-acylindoles." Intramolecular Vilsmeier processes, using tryptamine amides, have been used extensively for the synthesis of 3,4-dihydro-p-carbolines, a sub-structure found in many indole alkaloids (P-carboline is the widely used, trivial name for pyrido[3,4-fc]indole). Note that it is the imine, rather than a ketone, that is the final product the cyclic nature of the imine favours its retention rather than hydrolysis to amine plus ketone as in the standard Vilsmeier sequence " this ring closure is analogous to the Bischler-Napieralski synthesis of 3,4-dihydro-isoquinolines (9.15.1.7). 

Aminotransferases are potentially applicable to the production of a wide range of amino acids, because enzymes are available for d- and L-amino acids. In addition, a wide range of aminotransferases with side-chain specifidty are known, including enzymes for the production of amino acids with aromatic side chains, acidic side chains, branched alkyl side chains, etc. 

Other catalysts, sensitive to environmental conditions [110-112], were designed by placing ionic residues at the e and g positions of the helical heptad repeats of the coiled coil. With glutamic acids at these positions, the duplex is stable under acidic conditions. Under physiological conditions, the side chain acids are negatively charged and the coiled coil is destabilized. With lysine residues at these positions, either basic conditions. 

Indoles, with a side-chain acid located at C-3, undergo cyclising acylation forming cyclic 2-acylindoles. Intramolecular Vilsmeier processes using tryptamine amides lead to the imine, rather than a ketone, as the final product the cyclic nature of the imine favours its retention rather than hydrolysis to amine plus ketone. ... 

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