Hydroxyamino Acids, Oxidation

An adapted Strecker reaction using NaCN and NH2OH was the first procedure used for obtaining racemic TV-hydroxyamino acids 14 Although it has been modified repeatedly, 15-19 the yields are rather low. Racemic TV-hydroxyamino acids were also prepared as early as 1894 by addition of nitrogen oxide to the sodium salt of diethyl C-alkylmalonate, followed by acidolysis with concentrated hydrochloric acid.120,21 The procedure has been reinvestigated later with a 45-65% overall yield 19 ... 

The imidazolidine-4-one 29, obtained by heating the methanol solution of an a-aminoamide and a 4-substituted benzaldehyde, is a mixture of two diastereomers which can be separated by chromatography. They are oxidized by MCPBA, separately or as a mixture, into the two diastereomeric l-hydroxyimidazolidine-4-ones 30. Hydrolysis of 30 by ethanolic HC1 and hydroxylamine hydrochloride gives the optically pure TV-hydroxyamino acid amide 31 (Scheme 9).[12]... 

That the hydroxyamino group is in all cases attached to the 8 carbon is evident from the fact that periodate oxidation yields nitrosodimer (rather than N2O, which would arise from an N -hydroxyamino acid (42, 89)), performic acid oxidation affords glutamic acid (136) and, finally, deacylation followed by catalytic hydrogenation, reaction with fluoro-dinitrobenzene and hydrolysis gives N8-dinitrophenylornithine (63). 

Incorporation of natural amino acids (114, 115,116, 117, 118) and homologs (119,120,121) without further chain lengthening (VII to XVI) proceeds with retention of the a-amino nitrogen (119, 120, 122). An enzyme catalyzing the oxidation and decarboxylation of the N-hydroxyamino acid VIII to the aldoxime XI (123,124) has been purified 1400-fold (125). It is stimulated by FMN, O2 uptake is observed, and the a-keto acid oxime V is not used as a substrate (124,125). Decarboxylation may occur via the a-nitroso acid IX. Incorporation of the nitro compound XIII (126) presumably occurs via the acf-nitro compound XII which was suggested by Ettlinger and Kjaer (72) as an intermediate. The addition of thiols to... 

Enantioselective oxidation of the D-amino acid by D-amino acid oxidase has been utilized to transform racemic mixtures of methionine and thionine to the corresponding L-amino acid [256, 257]. The separation of L-amino acid from a racemic y9-hydroxyamino acid mixture using D-amino acid oxidase (D-ASOX), was used as a key step in the synthesis of bleomycine (Scheme 37) [258]. 

Periodic acid has proved to be a useful reagent for the analysis of certain iw.-hydroxyamino acids. Since the oxidation produces one mole of ammonia the determination of the ammonia generated provides a... 

Hydroxyamino acids are useful because the OH group can be converted into a leaving group. We saw serine 138 earlier in the chapter. The other three have a secondary alcohol at a potentially useful chiral centre. Threonine 347 is found in normal proteins. The other two are present in collagen and the extra hydroxyl groups are added by oxidation after the protein is formed ( post-translational modification ). Hydroxyproline 331 is abundant, hydroxylysine 330 less so. We might also add synthetic phenylglycine as a new member. 

N-Hydroxyamino acids, just like N-hydroxyamines, are strong reducing agents. At room temperature they reduce solutions of salts of such metals as silver, copper, mercury and lead (1). They also reduce Fehling s reagent (1) and decolorize iodine solutions in neutral or alkaline but not acidic media (36). As the result of the above reactions compounds of type (1) are oxidized to the oximes of a-keto acids (31). Esters of N-hydroxyamino acids (90), like N-alkylhydroxylamines, undergo oxidation to dimers of cw-nitroso compounds with a characteristic absorbance at 264 nm, this being analytically important (91). 

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 basis of this old method is the addition of nitric oxide to alcoholic solutions of sodium salts of C-alkyl derivatives of ethyl ace-toacetate (54) 128,129) (Scheme 17). Salts of alkyl derivatives of diethyl malonate (55) were used in Neelakantan s modification (79). In both cases sodium salts of isonitramine (56), stable only in alkaline solution, were formed initially and subsequently transformed into N-hydroxyamino acids (1) by means of concentrated hydrochloric acid. This method using common substrates is quite general and may be used for the synthesis of N-hydroxyamino acids (1) of different types 36, 79). Usually it has been used for the synthesis of N-hydroxyglycine (28) 129) and N-hydroxyphenylalanine (35) (79, 94,129). 

This method was introduced by Polonski and Chimiak 192,193) in 1974 (Scheme 47). It is based on the oxidation of Schiff bases (239) to appropriate oxaziridines (240) in ether using monoperphtalic acid (MPP). Bases (239) are obtained from esters of amino acids and anisyl aldehyde (238) and are oxidised without isolation. Oxaziridines (240) are next hydrolyzed with hydrochloric acid to N-hydroxyamino acids (1) or give p-toluenesulfonates of (76, 213), which crystallize readily, by splitting with hydroxylamine j7-toluenesulfonates in alcohol. Use of benzaldehyde is unfavourable and leads to nitrones. Use of mono-perphthalic acid permits one to follow the progress of the reaction due to precipitation of phthalic acid. This method is general. Because bases (239) racemize only very slowly it is possible to obtain 193) optically active compounds (1,76, 213). 

Moller, B.L., and E.E. Conn N-Hydroxyamino Acids as Intermediates in the Biosynthesis of Cyanogenic Glucosides in Plants. In Biological Oxidation of Nitrogen. (Gorrad, J.W., ed.). Amsterdam Biomedical Press 1978, p. 437. 

Polonski, T., and A. Chimiak Oxaziridines as Intermediates in the Oxidation of Amino Acid Esters into N-Hydroxyamino Acid Derivatives. Bull. Acad. Polon. Sci. Ser. Chem. 27, 459 (1979). 

Oxidation of Amino Acid Esters into N-Hydroxyamino Acid Derivatives. Tetrahedron Letters 1974, 2453. 

Any material capable of being oxidized by periodic acid to give formaldehyde or acetaldehyde should be absent, e.g. o-amino alcohols, hydroxyamino acids and polyalcohols. Monohydroxy alcohols such as methanol or ethanol, do not interfere in the determination. 

An important aromatic hydroxyamino acid is l-3,4-dihydroxyphenylalanine, known by the acronym DOPA (from the name dioxyphenylalanine, 2-48). It is formed by enzymatic oxidation of tyrosine and becomes the precursor of brown and black pigments (pigments of the eyes, hair, skin or fur of animals) termed melanins (see Section 9.3.1.1). Melanins are formed from DOPA by enzymatic browning reactions that proceed in vivo. 

Yura and Vogel 18S) discovered an enzyme in Neurospora, w-hydroxy-a-amino acid dehydrogenase which oxidizes c-hydroxynorleucine to the semialdehyde. A number of hydroxyamino acids of varying chain lengths were found to serve as substrates for this enz3mie. Only the L-forms of the amino acids were active. A phosphopyridine nucleotide was required as the hydrogen acceptor. The equation for the reaction is shown below. 

V-Benzylidene-yV-oxides of a-amino acid esters may be hydrolysed to the corresponding A-hydroxyamino acid esters by treatment with hydroxylamine salts, in contrast to hydroxylamine which also causes ester cleavage.The A-oxide esters can be obtained from sodium oA7t/-benzaldoximate and a-bromoesters, or by esterification of the corresponding free acid (Scheme 54). 

Leucine is known to be a precursor of neoaspergillic acid and pulcherriminic acid, and MacDonald s results would seem to rule out a role of the N-hydroxyamino acids as intermediates in the biosynthesis of these hydroxamates, although direct experiments using the hydroxylamino acids as substrates would be desirable. In the aspergillic acid family, it thus appears that the amino acid nitrogen undergoes substitution by carbon prior to its oxidation (oxygenation ). 

Gruen (757) found that the presence of most of the amino acids tested during hydrolysis does not affect the tryptophan recovery. Of the hydroxyamino acids, threonine had no effect at all, while tyrosine has a small effect. On the other hand serine was found to reduce the recovery of tryptophan by about 10% due to a deamination reaction of serine. This produces pyruvic acid which, as a ketoacid, interacts with the indole nucleus of tryptophan (287). Whereas cysteine had no effect, cystine caused a substantial loss of tryptophan (about 40%), and was itself recovered on the analyzer partly in the reduced cysteine form. These results would indicate that a major factor in the loss of tryptophan during acid hydrolysis of a protein is degradative oxidation by cystine. 

The one-pot MCR of methylene active nitriles 47 has been used in the synthesis of both pyrano- and pyrido[2,3-d]pyrimidine-2,4-diones in a single-mode microwave reactor [90]. Microwave irradiation of either barbituric acids 61 or 6-amino- or 6-(hydroxyamino)uracils 62 with triethyl-orthoformate and nitriles 47 (Z = CN, C02Et) with acetic anhydride at 75 °C for 2-8 min gave pyrano- and pyrido[2,3-d]pyrimidines in excellent yield and also provided a direct route to pyrido[2,3-d]pyrimidine N-oxides (Scheme 27). 

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