N-Hydroxy amino acid

It has recently been claimed that peptide-bound N-hydroxy amino acids occur in human brain tumor, in virus-induced tumor of mouse spleen, and in carcinogen-induced tumors in the rat (112). 

The N-hydroxy amino acid derivatives are likely to be applicable to other metalloproteases. Thermolysin is inhibited irreversibly at pH 7.2 by ClCH2CO-DL-HOLeu-OCH3 where HOLeu is N-hydroxyleucine (47). The inhibition reaction involves coordination of the hydroxamic acid functional group to the active-site zinc atom of the enzyme. This then places the chloroacetyl group adjacent to Glu-143, an essential catalytic residue of thermolysin (see Figure 9). An ester linkage is formed and the enzyme is inactivated irreversibly. This reagent also inactivated two neutral metalloproteases from B. subtilis, but reacted only very slowly with carboxypeptidase A (t1/2 > 3 d). 

The first synthesis of a siderophore was the preparation of ferrioxamine B over 20 years ago in order to confirm the chemical structure of this natural product67). Synthesis of the other hydroxamate containing siderophores has as a central problem preparation of the constituent to-N-hydroxy amino acid in an optically pure form. The most important such subunit in hydroxamate siderophores is Ns-hydroxy ornithine. This is a chiral building block of the diketopiperazine-containing siderophores (rhodo-torulic acid 68), dimerum acid 69), coprogen 70) and coprogen B 69>), the cyclic hexa-peptides of the ferrichrome family27), the fusarinines 71 -73) and the antibiotic ferri-chrome derivatives albomycines Sl5 S2 and e 61-62). 

The amino acids present can be identified and determined quantitatively by GC/MS analysis of the trifluoroacetyl n-butyl ("TAB") derivatives after total hydrolysis. It should be noted, however, that N-hydroxy amino acids will be reduced if the hydrolysis is effected by HI (but not if HCl is used) and that, e.g., N-acyl groups will be lost. The a-configuration (D or L) can be determined by chromatography of the heptafluoro-butyryl isopropyl derivatives on a chiral column (ref. 18). 

N-Hydroxyamino acids are similar in structure to amino acids but with the hydroxyamine group replacing the amine group. Therefore a-N-hydroxy amino acids can be represented by formula (1) and co-N-hydroxyamino acids by formula (2). 

N-Hydroxy-amino acid Natural product Isolated from Ref. 

Rf coefficients of several N-hydroxy amino acids are given in Table 3. Their values are higher than those of the corresponding amino acids. 

The above facts strongly support the unusual role of N-hydroxy-amino acids as amino acid antagonists. Powers stated that the methyl ester of chloroacetyl-N-hydroxyleucine (50) 108) and the formyl-N-hydroxyleucyl-alanyl-glycine amide (51) 109) are the first specific non-reversible termolysine inhibitors. They act through coordination of the zinc atom of this metalloprotein, as has been determined by X-ray crystallography 110). Compound (51) is also an inhibitor of elastase 111). 

An important hypothesis concerning the function of N-hydroxy-amino acids has been formulated recently by Ottenheijm 126). There are indications that the metabolism of several types of non-protein amino acids such as N-hydroxyamino acids, dehydroamino acids and a-substituted amino acids is connected with the process of oxidation of amino acids or peptides. Hence it is suggested that N-hydroxy amino acids play an important role in the biosynthesis of dehydroamino acids 18 natural antiviral, antifungal or antibacterial products (as e.g. glio-toxin) 127) and some other fungal metabolites as sporidesmine 126), as sketched in Scheme 16. 

The first methods for synthesis of N-hydroxyamino acid were developed as early as the end of the last century (7) but only after 1958 (79) did this subject again arouse interest. The difficulties caused by the instability of N-hydroxy amino acids were the reason for only occasional work of most authors in this field. 

This method was first applied by Weisbalt 135) to the synthesis of ethyl a-hydroxyamino-a-carboethoxy-P-(3-indole)-propionate. The reduction of nitrohydantoins (72) with zinc dust in the presence of ammonium chloride 136,137) or isopropylamine hydrochloride (97) was the basis for the first syntheses of N -hydroxyomithine (73) and N -hydroxylysine (74), but gave only low yields (Scheme 20). Further attempts at synthesis of N -hydroxyornithine (73) 138) and N -hyd-roxylysine (74) 139) based on such reductions were unsuccessful. The conditions for reduction of nitroester (75) to the ester of N-hydroxy-amino acid (76) were investigated by CfflMiAK 80), who obtained (78, 79) in aqueous methanol solution. Shin 140) also reduced nitro-esters (75) to (76, 77) using aluminium amalgam (Scheme 21). 

In 1896 Hantzsch 155) obtained N-hydroxyglycine (28) by reaction of benzaldoxime with chloroacetic acid and hydrolysis of the intermediate nitrone (190) with hydrochloric acid. Much later Buehler 177) observed that alkylation of Z-benzaldoxime (187) leads to nitrone formation and he generalized this method for synthesis of N-hydroxy-amino acids (1) 178) (Scheme 39). Sodium or potassium salts of Z-benzaldoxime (187) 179) as well as thallium salts (180), can be used... 

N-Hydroxypeptides with a N-terminal N-hydroxy amino acid residue were also obtained from appropriate nitrones (334) (Scheme 69), among them some interesting N-hydroxypeptides (335,336) of 7-amino-cephalosporanic acid and 6-aminopenicillanic acid 185). The mixed anhydride method was applied in the last case to form the amide bond in the presence of the nitrone group. Contrary to the above results Palacz 217) observed that nitrone (190) easily rearranges into isomeric N-benzoyl derivatives (337) during activation and aminolysis. 

Although N-hydroxyamino acids are found widespread as components of hydroxamic acids, free N-hydroxy amino acids have not been reported as cellular constituents. A search for traces of N-hydroxyglycine in extracts of P. aurantio-... 

As mentioned in the Introduction, a variety of unusual carbohydrate -protein linkages is found in Nature. These may be placed in several categories (i) carbohydrates O-glycosylated to jff-hydroxy amino acids (ii) carbohydrates S-glycosylated to cysteine (Hi) carbohydrates N-gly-cosylated to the N-terminal amino group of the protein or (iv) in some... 

For this selective addition, the best catalyst precursors were Ru(methallyl)2(dppe) 1 and Ru(methallyl)2(dppb) 2. The choice of the appropriate complex depended on the steric demand of both the alkyne and the carboxylic acid. A large variety of carboxylic acids and alkynes have been used, including N-protected amino acids, a-hydroxy acids, and functionalized alkynes such as enynes, diynes and propargylic ethers [21-23] (Scheme 10.4). The addition took place under mild conditions and carboxylic adds of... 

Access to peptides with internally positioned aziridine-2-carboxylic acid is only possible by coupling N-protected amino acids to 2-carbonylaziridine amino acids or peptides, 63 since cyclization of Ala-aminoacylated (3-hydroxy a-aminoacyl peptides leads to oxazolines, as... 

From the beginning of the 1960s, the progress in depsipeptide chemistry was connected with the utilization and further development of the mixed anhydride approach for the initial formation of the ester link between a suitably N-protected amino acid and the hydroxy acid ester. The reagent predominantly applied for the construction of the depsipeptide unit was benzenesulfonyl chloride in pyridine. This reagent, introduced by Shemyakin and co-workers in depsipeptide chemistry, was shown to be an efficient reagent for the formation of the ester bond between a protected amino acid and the hydroxy add component (Scheme 4).[21 22 ... 

In addition to the more or less popular methods of depsipeptide synthesis discussed vide supra, there are also a limited number of complementary and effective synthetic procedures that have been described for this purpose. Among these, the well-known method of symmetric anhydrides from N-protected amino acids has to be considered. This method has found successful use in the esterification of hydroxy acids in the presence of some catalyst additives. Initially, the addition of pyridine11091 or 1-hydroxybenzotriazole in pyridine1 101 to a symmetric anhydride was utilized for ester bond formation. As an example, Katakai has prepared a number of didepsipeptides in 85-96% yield by means of a 2-nitrophenylsulfenyl /V-carboxy anhydride with lactic acid derivatives in the presence of pyridine.1 09 ... 

A method utilizing the Dess-Martin periodinane[12 for the conversion of a peptide a-hy-droxy ester into the corresponding a-oxo ester was reported by Burkhart et al.[8l The final product, peptide a-oxo ester, obtained in this process contains a mixture of enantiomers at C2 in PI of the peptide. The optical impurity arises not from the oxidation reaction but the synthesis of one of the intermediates, 2-hydroxy-3-nitro-4-phenylbutanoic acid, which generates four diastereomers at two adjacent chiral carbons. This procedure is limited to the synthesis of peptide a-oxo esters with the phenylalanine residue at the PI position. A more diversified approach is achieved by using a-hydroxy- 3-amino acids 14 as the key intermediate that permits selective introduction of an amino acid residue at PI of the peptide it can also be coupled to N-protected amino acids or N-protected peptides and further transformations give a-oxo esters 19, a-oxo acids 20, and a-oxoamides 22 (Scheme 4)J3 61... 

Analytical Properties Substrate has 38 chiral centers and 7 aromatic rings surrounding 4 cavities (A, B, C, D), making this the most structurally complex of the macrocyclic glycopeptides substrate has a relative molecular mass of 2066 this phase can be used in normal, reverse, and polar organic phase separations selective for anionic chiral species with polar organic mobile phases, it can be used for a-hydroxy acids, profens, and N-blocked amino acids in normal phase mode, it can be used for imides, hydantoins, and N-blocked amino acids in reverse phase, it can be used for a-hydroxy and halogenated acids, substituted aliphatic acids, profens, N-blocked amino acids, hydantoins, and peptides Reference 47, 48... 

For example, N-(2-hydroxyphenyl)imines 9 (R = alkyl, aryl) together with chiral zirconium catalysts generated in situ from binaphthol derived ligands were used for the asymmetric synthesis of a-amino nitriles [17], the diastereo- and/or enantioselective synthesis of homoallylic amines [18], the enantioselective synthesis of simple //-amino acid derivatives [19], the diastereo- and enantioselective preparation of a-hydroxy-//-amino acid derivatives [20] or aminoalkyl butenolides (aminoalkylation of triisopropylsilyloxyfurans, a vinylogous variant of the Mannich reaction) [21]. A good example for the potential of the general approach is the diastereo- and enantioselective synthesis of (2R,3S)-3-phenylisoserine hydrochloride (10)... 

Benzylic oxidation (11, 441). Oxidation of the N-Boc-L-tyrosine 1 with K2S20 with CuS04 as catalyst gives the syn-cyclic carbamate 2, which can be converted to the (J-hydroxy amino acid 4 as shown. 

For further elongation of the peptide chain, successive coupling reactions with other polymeric active esters may be carried out until the desired sequence is obtained. The polymeric active esters are prepared by the attachment of the N-protected amino acids or peptides to a suitable insoluble polymer. Potentially useful polymeric supports in this case should carry a free hydroxyl function to which the carboxyl group of the amino acid derivatives may be coupled. Crosslinked poly(4-hydroxy-3-... 

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