N-Hydroxyamino acids

Benzyl-oxygen bonds may be cleaved under conditions mild enough to leave an allylic hydroxy group (759) or an easily reduced N—OH bond intact (65,80). N-Hydroxyamino acids can be prepared in good yield by hydrogenolysis of benzyl hydroxamates as shown in the synthesis of N -hydroxylysine (6) from 5 (777). 

Scheme 7 Synthesis of N-Hydroxyamino Acid Derivatives by Oxime Reduction131"331...

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). 

No substances containing only a single hydroxamic acid bond have thus far been isolated from natural materials as the metal complex. They are included here, however, in view of the known affinity of even monohydroxamic acids for iron (2) and also because some are related to higher hydroxamates for which a role in iron metabolism seems assured, l us-arinine, for instance, is both a constituent of ferrirhodin and is produced at high levels in iron deficiency. Although the structures are quite varied they are, for the most part -- like the di- and tri- hydroxamates — derived from the N-hydroxyamino acids. 

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... 

Bis(silyl)ketene acetals undergo silatropic ene reaction with nitrosobenzene to give N-hydroxyamino acid derivatives. When allylmagnesium chloride is reacted with nitroarenes, unstable adducts result. Reduction of these adducts with LAH in the presence of palladium on charcoal leads to A -allyl-W -aryl-hydroxylamines (73 Scheme 15). With alkyl Grignard reagents this reaction is negligible. ... 

The reaction of nitrones with various nucleophiles provides a powerful strategy for the introduction of a substituent at the a-position of secondary amines.9 The reaction of nitrones with Grignard reagents or organolithium compounds affords various a-substituted hydroxylamines, which can be converted into a-substituted secondary amines by catalytic hydrogenation. The nucleophilic reaction with potassium cyanide gives a-cyanohydroxylamines which are useful precursors for amino acids and N-hydroxyamino acids.10... 

N-Hydroxyamino acids, and in particular hadacidin (113) can be prepared by reaction of a-halogenocarboxy1ic acid derivatives (115)... 

II. N-Hydroxyamino Acid Residues as Fragments of Natural Products. 206... 

VIII. Synthesis of N-Hydroxyamino Acids and Their Derivatives.224... 

N-Hydroxyamino acids should, at present, be treated as a new, separate, characteristic group of amino acids. This is necessitated by the particular biological action of these compounds and their derivatives. Although a-N-hydroxyamino acids were first discovered by Miller and Plochl 1) as early as 1893, they have aroused particular interest mainly in the last twenty years. 

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). 

A description of physical and chemical properties of N-hydroxyamino acids and methods of their analysis will be included and brief mention will be made of the more important natural products containing N-hydroxyamino acid residues as well as the main aspects of their biogenesis. 

The first brief review devoted strictly to N-hydroxyamino acids was written by Chimiak (S) in 1965. Moller (4) in Cyanide Biology briefly reviewed the title compounds (1) as intermediates in metabolic transformations of cyanide. A recent review in Japanese by Akiyama (5) devoted only two pages to this subject. The small number of articles describing the chemistry of N-hydroxyamino acids was the reason for writing this review. 

Free N-hydroxyamino acids (1) or (2) have never been isolated from living organisms, probably because of their instability. As already mentioned, N-hydroxyamino acid residues occur only as fragments of many natural products containing the N-hydroxyamide bond. The isolation of free N -hydroxy-L-arginine from the fermentation medium of Bacillus cereus (6, 7) may be considered as an exception however, this compound contains an N-hydroxyguanidine rather than an N-hydroxyamine group. 

Derivatives of phosphonic N-hydroxyamino acid analogues (22-25) (Scheme 38, page 236) are also known as naturally occurring compounds. 

N-Hydroxyamino acids are colourless, solid, crystalline compounds only stable in the solid state. When heated they melt above 200 °C with decomposition (79). However the melting point is not a good criterion of purity (80). They are usually purified by recrystallization from hot water in which they are less soluble than amino acids. However, recrystallization in this case is accompanied by great losses due to decomposition (80). N-Hydroxyamino acids are slightly soluble in alcohol and sparingly soluble in ether, acetone and other organic solvents (f, 79, 82, 31). They are soluble in both acid and basic aqueous solution and form the corresponding salts (79, 81). Stable solid hydrochlorides are obtained in this way (1, 82). 

A molecule of an a-N-hydroxyamino acid is a dipolar ion (27) (79, 81) as confirmed by the IR spectra which contain characteristic COO and -NHJ -OH group bands. The isoelectric point of these compounds lies within the 6-7 pH range. pKi constants have values between 2.1 and 2.3, while pK2 lies between 5.7 and 5.9 (81). 

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). 

N-Hydroxyamino acids readily undergo catalytic reduction, being transformed into the corresponding amino acids (32). Amino acids are also the main products formed when N-hydroxyamino acids are heated with hydrochloric acid (82) at elevated pressure (Scheme 6). 

Spenser and Ahmad (81, 92) found that disproportionation of N-hydroxyamino acids (27) occurs in aqueous solution. The keto acid oxime (31) decompose further to give the corresponding nitrile (33) (93) (Scheme 6). The above results are questionable as Steiger (94) and Moller et al. (95) obtained amino acids and the corresponding aldoximes (36) from aromatic N-hydroxyamino acids (34) and (35) (Scheme 7). 

In view of these unfavourable chemical properties it is evident why no underivatized free N-hydroxyamino acid has been isolated from biological material so far. 

N-Hydroxyamino acids have been, until now, rarely used as substrates for syntheses. However a general synthesis of 3-oxazolin-5-ones (38) from such substrates (1) and from carbonyl compounds (37) 96) has been described (Scheme 8). 

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