Amino-acid derivatives

The numerous free amino-acids detected in and isolated from lichens are not listed in this review but the reader is referred to the publications by C. F. Culberson etal. (65, 78) for this material. 

The nonacyclic diketopiperazine derivatives scabrosin 4,4 -diacetate (13), scabrosin 4-acetate-4 -butyrate (14), scabrosin 4,4 -dibutyrate (15) and scabrosin 4-acetate-4 -hexanoate (16) have been isolated from a chemical strain of Parmelia scabrosa by Begg, Elix, and Jones (14). 

The structure of these compounds followed from the spectroscopic 

A cyclic tetrapeptide, roccanin (17), has been isolated by Bohman-Lindgren from Roccella canariensis (22). Acid hydrolysis of (17) yielded two amino-acids, L-proline (18) and / -P-phenyl- 3-alanine (19), and quantitative amino-acid analysis confirmed that (18) and (19) were formed in equimolar amounts. Mass spectrometry and the observed chemical reactivity confirmed that (17) was a cyclic peptide. Selective reduction of (17) at the more reactive acylproline linkage by treatment with lithium 

Allantoin (21) and xantholamine (22) have been isolated by Solberg from the lichen Xanthoria parietina (300, 301). The former compound was identified by comparison of the observed spectrum with those of authentic samples while the structure of (22) was based on elemental analysis and spectroscopic data. 

Trimethylsilyl esters of iV-trimethylsilylamino acids react with phosgene to give the products iliustrated below [1169]  

With excess of the silyl compound, or at lower temperatures, urea derivatives, such as (MejSiOCOCHRNH) jCO, are formed [1169]. The corresponding esters of 

Ai-siloxycarbonylamino acids combine easily with phosgene at temperatures above 0 C, also to 

These methods of synthesis of the Af-carboxyanhydrides do not involve elimination of hydrogen chloride, and thus permit retention of configuration of the ester groups. The silyl esters can be vacuum distilled without decomposition, and since (unlike their unsilylated analogues) they are readily soluble in non-polar solvents, the silylation methods constitute a suitable means of preparing this important class of compounds [1409]. 

The trimethylsilyl derivatives of aminobenzoic acids (H N-n-C jH COOSiMCg n = 2, 3 or 4) react with phosgene at 0-10 C in solutions containing triethylamine, to give the corresponding isocyanate, OCN-n-CjH COOSiMej. The 2-isomer, however, exists in equilibrium with the cyclic anhydride [1161]  

Hydrolase-catalyzed enantioselective N-acylation is an important tool for the preparation of enantiopure a- and P-aminoacids. It has been observed that the reactions of many amino acid esters with ester acyl donors catalyzed by CALB is sometimes complicated by interesterification reactions. CALA has, however, emerged as a very chemoselective catalyst in favor of N-acylation of P-aminoesters. Some reviews on CALA and other hydrolases as catalysts for N-acylations of aminoesters are available [109, 126, 127]. 

Kimmel and Saifer (1964) have recorded the infrared spectra of the 2,4-dini-trophenyl (DNP) and 3-phenyl-2-thiohydantoin (PTH) derivatives of 27 amino acids of importance in the study of biological materials, e.g., plasma, tissues, and urine. These workers have also made a quantitative study of the intensities of the major absorption bands according to the method of Flett (1962), and showed that the infrared spectra of DNP- and PTH-amino acids are a useful means for the determination of the N-terminal residues of various peptides and proteins, especially when used in conjunction with thin-layer chromatography. 

Murray and Smith (1968) have recorded the spectra of microgram amounts of amino acid phenylthiohydantoins eluted from thin layers of silica gel. Their analyses were performed upon fibrin samples, separated from both autopsy and surgical thrombi, and other protein specimens. 

In a paper discussing the alkylation and identification of the histidine residues at the active site of ribonudease, JafTe (1963) has analyzed infrared spectra of the 1-and 3-carboxymethylhistidines and of the 1- and 3-methylhistidines, and has confirmed spectroscopically the positions assigned to the carboxymethyl groups in the 

Reaction of Amino Acids and Amines with N-Substituted Maleimides 

Sharpless and Flavin (1966) have described the isolation and determination of the structures of the products arising from the reaction of certain primary and secondary amines and amino acids with N-substituted maleimides. Examples of the spectral properties are given in Table 9.2. 

One in-depth study involved the formation of m-DDP derivatives based on the reaction with histidine (17). This study will be described in some detail because it is important to understand the nature of the reaction and products when working with amino acids and other related amine-containing compoimds. 

When only the reactants are added to water, the reaction pH is about 2-3 and the reaction is complete after 3 4 days. Here the carboxyl group is largely proto-nated. When an equivalent of base is added to the histidine in this reaction, the pH started at about 7.2 and decreased again to about 4. Here the carboxyl group is largely deprotonated (the for COOH is about 2.0 for the free amino acid). 

The low pH of these reaction solutions indicates that protons are being produced in the system. There are several possible sources. First, displacement of a proton from one of the protonated functional groups in the amino acid by the metal ion is necessary for coordination at the metal site. The reactions of K2PtCl4 with amino acids has been extensively studied by Volshtein and others. According to Volshtein, reaction of the simple amino acid in the zwitterion form, AH, proceeds according to the following equations  

In the zwitterionic form, basic histidine is only protonated at the alpha amino group. Protons generated from this process then result from deprotonation of the third functional group, leaving this site available for coordination with the platimun. In this case, decreases in the pH are an indication of the extent of the reaction. 

Anionic histidine is flilly deprotonated. Thus, the protons must come from another source. An additional source is through the hydrolysis of K2PtCL(. While rarely isolated, the formation of hydroxy complexes is known to be responsible for the acidities of aqua complexes produced by the hydrolysis of K2PtCl4 as follows  

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Amino acid-derived hormones include the catecholamines, epinephrine and norepinephrine (qv), and the thyroid hormones, thyroxine and triiodothyronine (see Thyroid AND ANTITHYROID PREPARATIONS). Catecholamines are synthesized from the amino acid tyrosine by a series of enzymatic reactions that include hydroxylations, decarboxylations, and methylations. Thyroid hormones also are derived from tyrosine iodination of the tyrosine residues on a large protein backbone results in the production of active hormone. 

A variety of a-amino acid derivatives, including the acids themselves, haUdes, esters, and amides can be transformed iato hydantoias by coadeasatioa with urea (67). a-Hydroxy acids and thek nitriles give a similar reaction (68) ... 

Oxidative cleavage of P-aminoacyl complexes can yield P-amino acid derivatives (320,321). The rhodium(I)-catalyzed carbonylation of substituted aziridines leads to P-lactams, presumably also via a P-aminoacyl—metal acycHc compound as intermediate. The substituent in the aziridine must have 7T or electrons for coordination with the rhodium (322,323). 

Appllca.tlons. Various A/-derivatives of amino acids (qv) are resolvable on BSA columns. These /V-amino acid derivatives include ben2enesulfonyl-, phthalimido-, S-dimethylarnino-l-naphthalenesulfonyl- (DANSYL-), 2,4-dinitrophenyl- (DNP-), and 2,3,6-trinitrophenyl- (TNP-) derivatives (30). Amines such as Prilocain, ( )-2-(prop5lamino)-(9-propiono-toluidide, a local anesthetic (Astra Pharm. Co.), are also resolved on BSA. The aromatic amino acids DL-tryptophan, 5-hydroxy-DL-tryptophan, DL-kynurenine [343-65-7] C qH 2N 2 3 3-hydroxy-DT.-kynurenine [484-78-6] and dmgs... 

In contrast reaction with aprotic nucleophiles, e.g. alkoxides, LiAlILt and sulfur ylides (Z ), yields amino acid derivatives (341), resulting from sp C—N bond scission. The third possible way of ring opening, namely at the C—C bond, has also been observed in certain cases, i.e. (342) -> (343) (67TL5033). 

Fmoc-OSu (Su = succinimidyl), H2O, CH3CN. The advantage of Fmoc-OSu is that little or no oligopeptides are formed when amino acid derivatives are prepared. 

Cl3CCH20C0-0-succinimidyl, 1 N NaOH or 1 N Na2C03, dioxane, 77-96% yield/ This method does not result in oligopeptide formation when used to prepare amino acid derivatives. 

The configuration of the amine was retained, except in the case of amino acid derivatives, which racemized at the stage of the pyridinium salt product. Control experiments showed that, while the starting amino acid was configurationally stable under the reaction conditions, the pyridinium salt readily underwent deuterium exchange at the rz-position in D2O. In another early example, optically active amino alcohol 73 and amino acetate 74 provided chiral 1,4-dihydronicotinamide precursors 75 and 76, respectively, upon reaction with Zincke salt 8 (Scheme 8.4.24). The 1,4-dihydro forms of 75 and 76 were used in studies on the asymmetric reduction of rz,>S-unsaturated iminium salts. 

Heterocyclizations by reactions of electrophilic carbenes with a-amino acids derivatives 97T3425. 

Oxidation of pollutants catalyzed by metallophthalocyanins 97ACR470. Recent developments in the use of A-phthaloyl-amino acid derivatives in synthesis 98SL457. 

Development and application of hetero Diels-Alder reactions with participation of amino acid-derived chiral acylnitroso compounds 98T1317. 

Scheeren et al. reported the first enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of nitrones with alkenes in 1994 [26]. Their approach involved C,N-diphenylnitrone la and ketene acetals 2, in the presence of the amino acid-derived oxazaborolidinones 3 as the catalyst (Scheme 6.8). This type of boron catalyst has been used successfully for asymmetric Diels-Alder reactions [27, 28]. In this reaction the nitrone is activated, according to the inverse electron-demand, for a 1,3-dipolar cycloaddition with the electron-rich alkene. The reaction is thus controlled by the LUMO inone-HOMOaikene interaction. They found that coordination of the nitrone to the boron Lewis acid strongly accelerated the 1,3-dipolar cycloaddition reaction with ketene acetals. The reactions of la with 2a,b, catalyzed by 20 mol% of oxazaborolidinones such as 3a,b were carried out at -78 °C. In some reactions fair enantioselectivities were induced by the catalysts, thus, 4a was obtained with an optical purity of 74% ee, however, in a low yield. The reaction involving 2b gave the C-3, C-4-cis isomer 4b as the only diastereomer of the product with 62% ee. 

However, it was not until the beginning of 1994 that a rapid (<1.5 h) total resolution of two pairs of racemic amino acid derivatives with a CPC device was published [124]. The chiral selector was A-dodecanoyl-L-proline-3,5-dimethylanilide (1) and the system of solvents used was constituted by a mixture of heptane/ethyl acetate/methanol/water (3 1 3 1). Although the amounts of sample resolved were small (2 ml of a 10 inM solution of the amino acid derivatives), this separation demonstrated the feasibility and the potential of the technique for chiral separations. Thus, a number of publications appeared subsequently. Firstly, the same chiral selector was utilized for the resolution of 1 g of ( )-A-(3,5-dinitrobenzoyl)leucine with a modified system of solvents, where the substitution of water by an acidified solution... 

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. 

However, the use of a HPLC separation step enabled a remarkable acceleration of the deconvolution process. Instead of preparing all of the sublibraries, the c(Arg-Lys-O-Pro-O-P-Ala) library was fractionated on a semipreparative HPLC column and three fractions as shown in Fig. 3-2 were collected and subjected to amino acid analysis. According to the analysis, the least hydrophobic fraction, which eluted first, did not contain peptides that included valine, methionine, isoleucine, leucine, tyrosine, and phenylalanine residues and also did not exhibit any separation ability for the tested racemic amino acid derivatives (Table 3-1). 

The mixture of deprotected amino acid derivatives in solution was then immobilized onto a polymeric solid support, typically activated 5-)xm macroporous poly(hydroxyethyl methacrylate-co-ethylene dimethacrylate) beads, to afford the chiral stationary phases with a multiplicity of selectors. Although the use of columns... 

Several selective interactions by MIP membrane systems have been reported. For example, an L-phenylalanine imprinted membrane prepared by in-situ crosslinking polymerization showed different fluxes for various amino acids [44]. Yoshikawa et al. [51] have prepared molecular imprinted membranes from a membrane material which bears a tetrapeptide residue (DIDE resin (7)), using the dry phase inversion procedure. It was found that a membrane which contains an oligopeptide residue from an L-amino acid and is imprinted with an L-amino acid derivative, recognizes the L-isomer in preference to the corresponding D-isomer, and vice versa. Exceptional difference in sorption selectivity between theophylline and caffeine was observed for poly(acrylonitrile-co-acrylic acid) blend membranes prepared by the wet phase inversion technique [53]. 

For the separation of amino acids, the applicability of this principle has been explored. For the separation of racemic phenylalanine, an amphiphilic amino acid derivative, 1-5-cholesteryl glutamate (14) has been used as a chiral co-surfactant in micelles of the nonionic surfactant Serdox NNP 10. Copper(II) ions are added for the formation of ternary complexes between phenylalanine and the amino acid cosurfactant. The basis for the separation is the difference in stability between the ternary complexes formed with d- or 1-phenylalanine, respectively. The basic principle of this process is shown in Fig. 5-17 [72]. 

Table 6-3. Resolution of amino acid derivatives on a MIP imprinted with L-phenylalanine anilide (L-PA).

A number of studies have recently been devoted to membrane applications [8, 100-102], Yoshikawa and co-workers developed an imprinting technique by casting membranes from a mixture of a Merrifield resin containing a grafted tetrapeptide and of linear co-polymers of acrylonitrile and styrene in the presence of amino acid derivatives as templates [103], The membranes were cast from a tetrahydrofuran (THF) solution and the template, usually N-protected d- or 1-tryptophan, removed by washing in more polar nonsolvents for the polymer (Fig. 6-17). Membrane applications using free amino acids revealed that only the imprinted membranes showed detectable permeation. Enantioselective electrodialysis with a maximum selectivity factor of ca. 7 could be reached, although this factor depended inversely on the flux rate [7]. Also, the transport mechanism in imprinted membranes is still poorly understood. 

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