Hydroxamic special

There is some evidence that the iron-sulfur protein, FhuF, participates in the mobilization of iron from hydroxamate siderophores in E. coli (Muller et ah, 1998 Hantke, K. unpublished observations). However, a reductase activity of FhuF has not been demonstrated. Many siderophore-iron reductases have been shown to be active in vitro and some have been purified. The characterization of these reductases has revealed them to be flavin reductases which obtain the electrons for flavin reduction from NAD(P)H, and whose main functions are in areas other than reduction of ferric iron (e.g. flavin reductase Fre, sulfite reductase). To date, no specialized siderophore-iron reductases have been identified. It has been suggested that the reduced flavins from flavin oxidoreductases are the electron donors for ferric iron reduction (Fontecave et ah, 1994). Recently it has been shown, after a fruitless search for a reducing enzyme, that reduction of Co3+ in cobalamin is achieved by reduced flavin. Also in this case it was suggested that cobalamins and corrinoids are reduced in vivo by flavins which may be generated by the flavin... 

Although some of this early work was based on N nuclei which are of special interest for studies of hydroxylamines, oximes and hydroxamic acids, a variety of reasons led to a concentration of work on F and, particularly, H nuclei. These include the sensitivity of these nuclei to the method, the advent of commercially available instrumentation to allow exploitation of this sensitivity, the abundance of H compounds and the unfavorable spectral characteristics of N. ... 

Although several routes have been published for the preparation of hydroxamic acids on solid phase, these generally involve the preparation of a special linker to which hydrox-ylamine is attached. Dankwardt s approach obviates the need for special linkers or protecting groups, by displacing the desired hydroxamic acid from the resin directly using hydroxylamine, as illustrated in Scheme 86. CarboxyUc-acid-ester-linked, polymer-supported, Cbz-protected amino acids 195 (formed from 194) were displaced from the resin with aqueous hydroxylamine to provide the corresponding hydroxamic acids 196. 

The most common deviation is the exceptionally high reactivity of nucleophiles, such as hydroperoxide, hypochlorite and hydroxamate ions, with atoms bearing lone-pair electrons next to the nucleophilic centre. This phenomenon, known as the alpha-effect287, is found for aminolysis reactions of esters also285, and is commonly observed for attack at electrophilic centres where reactivity depends fairly strongly on the basicity of the nucleophile. Negative deviations may be evidence of steric hindrance, or in a few cases, in particular that of hydroxide ion, may reflect special solvation effects on the pKa or the nucleophilicity (or both) of the nucleophile. 

As the literature published up to 1976 on hydroxamates, with special reference to transition metals, has been well reviewed,37 this account will mainly concentrate on adding a few subsequent findings in this direction along with a brief account of the hydroxamic acid derivatives of main group elements. 

In an early report on peptide hydroxamic acids as metalloprotease inhibitors, the peptide acid (Z-Gly-L-Leu-OH) was converted into the V-hydroxysuccinimide ester using DCC, which was subsequently reacted with hydroxylamineJ10 More reactive condensing reagents such as BOP can form the hydroxamic acid directly from the carboxylic acid and hydroxylamine via an intermediate HOBt ester. A number of hydroxamic acids has been synthesized by the treatment of the corresponding methyl esters with hydroxylamine in the presence of KOH 122 this reaction requires careful choice of reagent concentrations and ratios. In addition, the precursor carboxylic acid is treated with diazomethane to make the methyl ester. The use of diazomethane makes the procedure hazardous, but should be useful in special cases that require a better cost performance. 

In contrast to the hydroxamate siderophores, little or nothing is known about the stability constant for the catechol siderophore, entero-bactin. Prior to determining the formation constant of enterobactin (for which hydrolysis of the ligand presents special problems), the reaction of catechol itself with ferric ion has been investigated (31). 

In any case, such values of electrochemical parameters for ligands relevant in biology almost from biopoiesis onwards allowed for broad and differentiated use of now essential elements much like in recent biomasses also >2.3 bio. years ago, without the necessity to have specialized transport systems at hand. Possibly, phosphate-containing regulating systems and transporters - besides the more advanced polyphenols, hydroxamates or proteins (chaperons) - involved in transportation of, e.g. Fe are relics of those days. Possible items of such transport include all of the more general essential elements except for Co and V. The edges to the central window of essentiality in the c/x... 

Nitrosocarbonyl compounds, prepared by the oxidation of hydroxamic acids with silver oxide, add to 2,5-dimethylfuran to give adducts (27) in the expected way, but these immediately rearrange to 1,4,2-dioxazoles (28). A special feature is that the reaction must be easily reversible since heating the adducts causes them to eliminate dimethylfuran, leaving the nitrosocarbonyl intermediate to be trapped by some other means.68... 

Siderophores as chemical entities can generally be classed as either hydroxamates or catechols. Ferrichrome and enterobactin are prototypical members of the two classes, respectively. The tri-catechol siderophore, enterobactin, is of special interest since it has been demonstrated repeatedly that it can sv5>ply iron to bacteria in the presence of certain ferric tri-hydroxamate type siderophores (Kj> = 103 ) not utilized by the organisms (IjJ. 

Primary peptide amides are prepared on the Rink linker 5. Although not covered in this chapter, secondary amides have been prepared on the linker described by Barany and co-workers (43). Peptide aldehydes have been prepared on the oxazolidine linker (44). The trityl linker (45) has also been used for the preparation of protected peptide fragments and other specialized C-terminal endings such as hydroxamic acids (46). 

In 1998, Dankwardt used for the first time ester linkers for the synthesis of hydroxamates [116]. The synthesis of hydroxamates and hydroxamic acids is a known synthesis on solid supports but former approaches used special hydroxamate linkers that had to be synthesized in previous reactions. The methodology published by Dankwardt is very simple because ArgoGel-OH resins can be used without further derivatization to bind protected amino acids 88 in the presence of coupling reagents. Hydroxamic acids 90 were cleaved by the addition of hydroxylamine in 21% (sterically hindered amino acids) to quantitative yields (glycin. Scheme 12). 

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