Other 4-Hydroxyproline-derived Amino Acids

Early examples of enantioselective extractions are the resolution of a-aminoalco-hol salts, such as norephedrine, with lipophilic anions (hexafluorophosphate ion) [184-186] by partition between aqueous and lipophilic phases containing esters of tartaric acid [184-188]. Alkyl derivatives of proline and hydroxyproline with cupric ions showed chiral discrimination abilities for the resolution of neutral amino acid enantiomers in n-butanol/water systems [121, 178, 189-192]. On the other hand, chiral crown ethers are classical selectors utilized for enantioseparations, due to their interesting recognition abilities [171, 178]. However, the large number of steps often required for their synthesis [182] and, consequently, their cost as well as their limited loadability makes them not very suitable for preparative purposes. Examples of ligand-exchange [193] or anion-exchange selectors [183] able to discriminate amino acid derivatives have also been described. 

Note It is possible to differentiate amino acids by color on the basis of the markedly different shades produced [2, 3]. Proline and hydroxyproline, that only react weakly with ninhydrin, also yield pink-red colored derivatives [2]. Ergot alkaloids and LSD are detected by spraying with 10% hydrochloric add and then heating to 110°C for 20 min after they have been treated with the reagent [9]. Ergot alkaloids and LSD yield red to purple zones when treated in this manner other alkaloids, e.g. reserpine, emetine, quinine, strychnine, pilocarpine, atropine, scopolamine, cocaine and opium alkaloids, do not give a reaction [9]. 

In addition to the 20 common amino acids, proteins may contain residues created by modification of common residues already incorporated into a polypeptide (Fig. 3-8a). Among these uncommon amino acids are 4-hydroxyproline, a derivative of proline, and 5-hydroxylysine, derived from lysine. The former is found in plant cell wall proteins, and both are found in collagen, a fibrous protein of connective tissues. 6-N-Methyllysine is a constituent of myosin, a contractile protein of muscle. Another important uncommon amino acid is y-carboxyglutamate, found in the bloodclotting protein prothrombin and in certain other proteins that bind Ca2+ as part of their biological function. More complex is desmosine, a derivative of four Lys residues, which is found in the fibrous protein elastin. 

Yamaguchi et al. also showed that Rb-L-prolinate catalyzes enantioselective addition of nitroalkanes to several acyclic and cyclic enones [25, 26]. For acyclic enone acceptors the best result, i.e. 74% yield and 68% ee of the S product, was achieved in the addition of 2-nitropropane to -3-penten-2-one (40a, Scheme 4.13) [25]. Screening of several proline derivatives and cyclic amino acids of other ring size resulted in the identification of the O-TBDMS-derivative of 4-hydroxyproline as the best catalyst for addition of nitrocyclohexane to cycloheptenone. In this particular reaction 74% yield and 86% ee were achieved [26]. 

The high level of conservation of tyrosine and lysine residues suggests an important role for these amino acids and their post-translational derivatives in both adhesive and cohesive processes. As mentioned earlier, Waite has proposed that lysine and quinone residues are involved in protein crosslinking. Substitutions at other positions generally result in the presence of serine, threonine, proline (perhaps hydroxyproline), alanine, and isoleucine residues, with an emphasis on polar residues that can interact with most biological surfaces. The resulting protein is rich in the six amino acids tyrosine, lysine, alanine, serine, threonine and proline. Preliminary characterization of cDNA clones encoding... 

Other Oxazolidine as well as Thiazolidine Derivatives for Branching Amino Acids. The cyclic derivative of alanine and other amino acids employed most frequently for a-allq lation is not (1) but rather the benzaldehyde acetal (5), either with a benzoyl or with a Cbz group on nitrogen. These compounds were used for the preparation of 2-methyl-2-aminobutanoic acid, a-methylphenylalanine, a-methyllysine, 2-methylaspartic acid, and 2-methylglutamic acid. Bicyclic compounds containing oxazolidinone rings such as (6) (from alanine, leucine, and phenylalanine) and (7) (from azetidinecaiboxylic acid, proline, " hydroxyproline, and cysteine ) have also been applied to the synthesis of branched amino acids. 

Simple L-alanine, L-valine, L-norvaline, L-isolecucine, L-serine and other linear amino acids [ 121 ] or chiral amino acids with a binaphthyl backbone [ 122] and peptides have also been used as asymmetric catalysts [123,124,125,126]. Solid-supported proline-terminated peptides have been used for heterogeneous catalysis of the asymmetric aldol reaction [ 127]. Apart from proline and derivatives, other cyclic compounds such as 5,5-dimethyl thiazolidinium-4-car-boxylate (DMTC) [128], 2-fert-butyl-4-benzyl imidazolidinones [129], (l/ ,25)-2-aminocy-clopentanecarboxylic acid [130], (5 -5-(pyrrolidin-2-yl)tetrazole, (5)-l,3-thiazolidine-4-car-boxylic acid, (5)-5,5-dimethyl-l,3-thiazolidine-4-carboxylic acid, and (5)-hydroxyproline are effective catalysts in asymmetric aldol reactions [126,131,132,133,134,135]. 

Most amino acids react with ninhydrin at ambient temperatures to form a blue color that becomes purple on heating. However, proline and hydroxyproline yield yellow compounds that are measured at a different wavelength. Other postcolumn derivatizations use fluorogenic reagents, such as o-phthaldialdehyde or fluorescamine. Precolumn derivatization techniques using o-phthaldialdehyde, dansyl, phenyl isothiocyanate, or 9-fluorenylmethyl chloroformate derivatives have been used with reversed-phase HPLC. Electrochemical detection has also been coupled with derivatization methods to enhance analytical sensitivity. 

However, soluble metal chiral complex catalysts are better, even though ketone hydrogenation under these conditions is more difficult to run than olefin hydrogenation. Notable achievements have been made using Rh and Ru metals. Phosphine ligands are often used, which contain either an asymmetric alkyl group have the phosphorous atom as the asymmetric center, or have an axial element of chirality (atropisomerism) . Other chiral ligands commonly used are derived from amino acids, from L-hydroxyproline and from ferrocene. 

Many other amino acids, in addition to the ones listed here, are known to exist. They occur in some, but by no means all, proteins. Figure 3.4 shows some examples of the many possibilities. They are derived from the common amino acids and are produced by modification of the parent amino acid after the protein is synthesized by the organism in a process called posttranslational modification. Hydroxyproline and hydroxylysine differ Ifom the parent amino acids in that they have hydroxyl groups on their side chains they are found only in a few connective-tissue proteins, such as collagen. Thyroxine differs from tyrosine in that it has an extra iodine-containing aromatic group on the side... 

Fales and Pisano (1964) have discussed the gas chromatography of amines, alkaloids, and amino acids. Pollock and Kawauchi (1968) have resolved derivatives of serine, hydroxyproline, tyrosine, and cysteine, as well as racemic aspartic acid and tryptophan. VandenHeuvel and Horning (1964) have listed derivatives of steroids that can be separated. VandenHeuvel et al. (1960) first described the separation of bile acid methyl esters and Sjovall (1964) has extended the methods to bile acids. Gas liquid chromatography (GLC) is useful in the analysis of pesticides, herbicides, and pharmaceuticals (Burchfield and Storrs, 1962). Analysis of alkaloids, steroids, and mixtures of anesthetics and expired air are other examples of the application of this very useful technique. Beroza (1970) has discussed the use of gas chromatography for the determination of the chemical structure of organic compounds at the microgram level. 

Given the overall positive effect of the tertiary hydroxyl group on stereoselectivity, other amino acid derivatives were also evaluated [39, 40]. Notably, 4-hydroxyproline derivative 16 furnished the desired aldol in 95% yield, even for the most difficult substrate, 4-methoxybenzaldehyde [39]. 

Figure 13.23 HPLC of amino acid derivatives detected by 254 nm UV absorption (a) 200 pmol of PTC-amino acid standard, including PH-S PH-T, hydroxyproline (OH-P), galactosamine (Gal), norleucine (NLE, 1 nmol IS), excess reagent (Re), and other amino acids designated by one-letter codes listed in Figure 13.22 and (b) analysis of a human fingerprint, taken up from a watch glass using a mixture of water and ethanol. (Courtesy of National Gallery of Art and the Andrew W. Mellon Foundation From Cazes, J., Encyclopedia of Chromatography, Marcel Dekker, Inc., New York, 2001. With permission.)...

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