N-Hydroxyamino acid derivatives

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

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. ... 

Ottenheijm s group has recently improved procedure VIII.7 (164) (Scheme 33) for the preparation of optically active N-hydroxyamino acid derivatives by a substitution reaction. N-Benzyloxyamino acid esters were obtained from triflates of a-hydroxy esters and O-benzylhy-droxylamine (222). The optical purity of the products was very high. 

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. 

Nitrono) or t i[CH=N+(0 )] 1 peptides were introduced in 1987 by Grundke et al. [11 This pioneering work on simple model (nitrono) peptides has not been continued, and no (nitrono) analogue of a bioactive peptide has been reported so far. However, model (nitrono) dipeptides (e.g., 12) have been prepared in good yield (Scheme 2) by coupling an N-pro-tected a-amino aldehyde12 with the hydroxyamide terminus of an a-hydroxyamino acid derivative, 3 the synthesis of which is presented in Section 10.8.3.1. 

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. 

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

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. 

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

The specific activities and biological roles of naturally-occurring peptide derivatives of N-hydroxyamino acids of the siderophore class and their analogues are now well understood. The matter has been and still is being discussed in numerous reviews of which the latest have been cited in Section I. Therefore only the most important aspects of this topic will be summarized here. 

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). 

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). 

Testa et al. (187) added benzaldehyde oxime (187) to a,P-unsatur-ated esters (121) and diethylamides (229) obtaining nitrones (191,192,194) and from them esters of p-N-hydroxyamino acids (230) and their derivatives (231) (Schema 46). 

Alkylation of hydroxamic acids as a method of co-N-hydroxyamino acids (2) synthesis was introduced by Maurer and Miller 196), When N- r -butoxycarbonyl-6-hydroxynorleucine benzylhydroxamate (248) or a homologue was treated with triphenylphosphine and diethylazodi-carboxylate (DEAD) under Mitsunobu conditions 197), intramolecular alkylation took place leading to N-hydroxylactams (249) or (250) as well as lesser amounts of hydroximates Z-(251) and -(252) (Scheme 50). The products were separated and distinguished by NMR spectrometry 196,198,199). Derivatives of the seven-membered N-hydroxylactam (253) were applied for the total synthesis of mycobactin S2 (254) 199) (Scheme 51). 

Apart from the synthetic methods for esters described in sections VIII.3-VIIL7 and VIIL9-VIIL11, N-hydroxyamino acid esters (76, 77,130, 213) may also be obtained by acid-catalysed esterification of N-hydroxyamino acidb (80,100,160) although the best reagent for quantitative esterification is diazomethane (80) (Scheme 55). When this reagent is used N-methyl derivatives are not formed although this had been suspected previously (100). 

---