Retro-hydroxamates

The problem of antibiotic-resistant bacteria has created a pressing demand for new antibacterial agents with novel mechanisms of action. Af-Formylhydroxylamines, also known as reverse- or retro-hydroxamates, are one of the few novel targets that are currently being pursued against a variety of metalloenzyme targets, including carboxy... 

Since the hydroxamate group —N(OH)—CO is intrinsically unsymmetrical, its coordination characteristics do not change when positioned in the reverse direction —CO—N(OH) (in which the positions of the hydroxamate nitrogen and carbon are interchanged). The relationship between these different structures is referred to as retro-hydroxamate isomers. The retro prefix is generally preserved for structures that are reversed to that of the naturally occurring structure. 

On the other hand, desmethyl-retro-hydroxamate ferrichrome 15, where the terminal methyl groups were replaced by hydrogen, showed no signihcant growth promotion activity toward Arthrobacter flavescence, and only one third of the iron(III) transport efficiency toward U. sphaerogena, which confirms the importance of the methyl groups... 

In accordance with Emery s retro-hydroxamate ferrichrome, mentioned above, two retro analogs of the linear ferrioxamine G and cyclic desferrioxamine E (129 and 130, respectively) were prepared. The iron-chelating properties were compared to DFO, showing that the linear retro-desferrioxamine G (131) binds iron faster and the cyclic retro desferrioxamine E (132) has improved affinity to iron, compared to the linear DFO. Based on these resnlts, many retro-hydroxamate ferrioxamines were prepared. In a later paper, Akiyama and coworkers reported the attachment of -cyclodextrin, a cyclic oligosaccharide, composed of seven a-D-glucopyranoside units, linked from position 1 to position 4, to linear retro-hydroxamate ferrioxamines (133 and 134), which formed 1 1 iron(III) complexes. Influenced by the chiral -cyclodextrin gronp, 133 and 134 formed A-selective coordination around the metal ion. In addition, Akiyama proposed that the... 

In general, C-acyl nitroso compounds-9,10-dimethylanthracene cycloadducts derived from hydroxamic acids (-R = alkyl, aryl, ti/2 = 4.1 h for -R = -Ph at 60°C) decompose more slowly than those derived from N-hydroxycarbamates or N-hydroxyureas [11, 13, 14]. Further addition of alkyl groups to the N atom of N-hydroxyurea-derived cycloadducts produces a further increase in the rate of the retro-Diels-Alder reaction of these cycloadducts [36]. These general trends suggest the possibility of the development of acyl nitroso compound-9, 10-dimethylanthracene cycloadducts as a general class of HNO or NO donors with varied release profiles. 

In these reactions the acylnitroso species is formed by oxidation of a hydroxamic acid and trapped by cycloaddition with 9,10-dimethylanthracene and then this adduct is separately heated to effect retro [4+2] cycloaddition. In this way exposure of the product to the oxidant is avoided. 

The use of acyl nitroso compounds as dienophiles was first described by Kirby. The primary method for generating these highly reactive, unstable species is by periodate oxidation of hydroxamic acids. The acyl nitroso compounds can be trapped in a Diels-Alder reaction with 9,10-dimethylanthracene to give adduct (95) (equation 36) which can act as an alternative source of the dienophile, since retro [4 + 2] cycloaddition occurs under mild thermal conditions. 

By retro synthetic analysis collagenase inhibitor RO0319790 (1) can be assembled from two chiral building blocks, (R) -succinate 2 and (S)-tert-leucine N-methyla-mide 13. As the latter can be prepared from commercially available (S)-tert-leucine 8 our work concentrated in particular on the construction of the first building block 2. In order to assemble the carbon skeleton of 2 in the most efficient way, extremely cheap maleic anhydride 4 was converted in a known ene reaction with isobutylene to provide the cyclic anhydride 6. Hydrogenation of the double bond followed by the addition of EtOH/p-TsOH yielded the racemic diethyl ester substrate 9 for the enzyme reaction. The enzymatic monohydrolysis of 9 afforded the monoacid (R)-2a. (R)-2 a was coupled via its acid chloride with leucine amide 13 to ester 14, which finally was converted into the hydroxamic acid 1. 

Retro-inversion of hydroxamate enkephalinase inhibitors [89] leads to a 5-fold difference in potency between the (/ ) and (5) isomer compared with the 100-fold difference obtained with retrothiorphan. This difference between the thiol and hydroxamate inhibitors may be explained in terms of the geometrical parameters existing in their inhibitor-zinc complexes since in the thermolysin-thiol inhibitor complex, the zinc is tetra-coordinated [87], whereas in the thermolysin-hydroxamic acid inhibitor complex it is penta-coordinated [88]. The conformational space accessible to the thiol function is less than that accessible to the hydroxamate function, as there is only one degree of freedom in retrothiorphan (a rotation around the alpha... 

The presence of the ortho-riiXro group allowed nucleophilic cleavage to liberate the desired amine [6]. An amidine linker [7,8] provided a resin bound amine that was stable to oxidative, reductive, and alkylative conditions. The use of 2-chlorotrityl resin proved to be useful for the preparation of a secondary amine library [9] as well as hydroxamic acids [10]. Tertiary amines were prepared by 1,4 addition to a resin bound acrylate followed quatemization and a retro-Michael reaction [11]. The p-nitrophenyl carbonate linker has been shown to be useful for the inunobilization of ben-zamidines [12] and for the synthesis of sulfonamides [13]. Sulfonamides and amides were also prepared using a halogenated Wang resin [14]. 

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