A-N-Hydroxyamino acids

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. 

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). 

After completion of this review another independent review appeared covering only a part of the subject discussed here, i.e, a-N-hydroxyamino acids and their chemistry 220). In addition a few papers... 

Chimiak, A. N-Hydroxyamino Acids and Their Derivatives. Wiad. Chem. 19, 803 (1965) Chem. Abstr. 64, 4881 (1966). 

Ahmad, A. The Chemistry of a-N-Hydroxyamino Acids. Bull. Chem. Soc. Japan 47, 2583 (1974). 

Oppolzer has documented a method for the asymmetric synthesis of a-amino and a-N-hydroxyamino acids using 1-chloro-l-nitrosocyclohexane... 

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)... 

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. 

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). 

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 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). 

Only a few N-hydroxyamino acids have been analysed using a standard Durrum D-500 (99) amino acid analyser. The retention times for all compounds investigated so far (with norleudne as a standard), are given in Table 2 and are always lower than those of the corresponding amino acids. 

N-Hydroxyamino acids, similar in action to N-hydroxyurea, some N-hydroxyamides and some aromatic hydroxy acids, are inhibitors of ribonucleotide reductases 112), a unique group of metalloenzymes, essential for cell proliferation. Inhibition of substrate reduction in vitro (l5o = 2.3-10 ) is accompanied by decay of the tyrosyl radical but not the iron atom from the E. coli subunit B2 of this enzyme. Inhibitors of the above type donate an electron to the enzyme s free radical, producing an inactive protein-enzyme with a still intact binuclear iron complex and a new more stable free radical of the nitroxide type (52)... 

It is thought that N-hydroxyamino acids are intermediates in the biosynthesis of cyanoglucosides and glucosinolates (4,122,123) (Scheme 15). However, the assumption 124) that 6-(a-aminoadipoyl)-cysteinyl-N-hydroxyvaline (53) is an intermediate in the biosynthesis of the P-lactam ring of the penicillins has not yet been confirmed 125). 

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 hydrolysis of nitriles (58) formed in this way is usually difficult (Scheme 19). In the presence of cone, sulfuric acid mainly amides of a-keto acid oximes (59) were obtained (1), Concentrated hydrochloric acid yields amides of N-hydroxyamino acids (60) (130) while in dilute acid the desired products (1) are formed (1, 79). Taking into account the instability of N-hydroxyamino nitrile (58) and the possibility of its polymerization, the first stage of hydrolysis is carried out at lower temperature (79). The Strecker method has also been applied to the synthesis of several cyclic N-hydroxyamino acids (70, 71) (134). 

The fact that substitution of bromine in compounds of type (127) with hydroxylamine is accompanied by Walden inversion led Noce et al. (158) to the first synthesis of optically active N-hydroxyamino acids L- and D-N-hydroxyleucine (66). The same method was later used to synthesize the aromatic D-amino acids N-hydroxytyrosine (35) and N-hydroxyphenylalanine (34) (159). Reaction of hydroxylamine with a,a -dibromopimelic acid gave l-hydroxy-2,6-piperidine dicarbox-ylic acid (134) (158). Shin (160) studied the reaction of esters (128) and (129) with hydroxylamine in the presence of triethylamine and obtained the ethyl (77) and tert miy (130) esters of N-hydroxyamino acids as oils. 

As described in section 6 the reaction of hydroxylamine with bromo derivatives (127) is complex. Therefore it is better to use stable alkoxy-amines for the substitution reaction. In a second step which used acids or boron trifluoroacetate the protecting O-alkyl group is removed to form the N-hydroxyamino acid (163) (Scheme 31). 

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