Hydroxamic acid derivatives compounds

Abstract. The direct scale-up of a solid-phase synthesis has been demonstrated with 4-(2-amino-6-phenylpyrimidin-4-yl)benzamide and an arylsulfonamido-substituted hydroxamic acid derivative as examples. These compounds were obtained through combinatorial chemistry and solution-phase synthesis was used in parallel to provide a comparison. By applying highly loaded polystyrene-derived resins as the solid support, a good ratio between the product and the starting resin is achieved. We have demonstrated that the synthesis can be scaled up directly on the solid support, successfully providing the desired compounds easily and quickly in sufficient quantities for early development demands. 

Histone deacetylases are linked to the pathogenesis of malignancy from a mechanistic perspective. The capacity of HDAC inhibitors (HDACi) to interfere with the enzyme fimction has led to the observed prechnical and clinical activity in cancer therapy. Although the exact mechanism of anti-tumor activity is not fully elucidated, various cellular pathways have been shown to be involved. From the first chnical trials involving HDACi with short chain fatty acids to the newer generation hydroxamic acid derivatives and cychc tetrapeptides, a number of structurally diverse compounds have made the transition from the laboratory to the chnical arena. For purposes of this part of the discussion, HDACi are arbitrarily divided into the hydroxamates and nonhydroxamates. 

Multicomponent reactions have recently become one of the favored methods to prepare pharmacologically important compounds. Ugi condensations with O-protected hydroxylamines have been successfully performed in THE using ZnCl2 as activating agent (Scheme 56). This synthetic strategy opens up the route to a very convergent assembly of internal hydroxamic acid derivatives (A-acyl-A-hydroxypeptides 109)" . 

An interesting preparation of 128 involves the cycloaddition of carbon suboxide to the anil of cyclopentanone (129).87 Compound 129 also reacts with monosubstituted malonyl chlorides to give iV-aryl-2-oxo-3-alkyl-4-hydroxy-6,7-dihydro-5ff-1 -pyrindines (131) in fair yields.88 Similarly, the oxime ether of cyclopentanone (132) reacts to give the cyclic hydroxamic acid derivative (133),89 and benzylmalonyl chloride reacts with the A,A-dimethylhydrazone of cyclopentanone (134a) to give 134b in 90% yield.90... 

Synthesis. The synthesis of these new compounds are shown in Schemes 4-8. Condensation of -chloropivaloy1 chloride with tri-methylsilyl chloride-treated benzylhydroxylamine in methylene chloride in the presence of pyridine gave a hydroxamic acid derivative 9 in good yield. It is important to block the hydroxyl group of the hydroxylamine to ensure the desired N-acylation otherwise, a stable mixture of 40 60 N- and O-acylated products (9, 10) will be obtained. This isomeric mixture is not only difficult to separate but also reduces the efficiency of the synthesis. 

The nonsystemic miticide benzoximate was developed in Japan, in the research laboratories of the Nippon Soda Co. during the systematic investigation of hydroxamic acid derivatives. The herbicide alloxydim-sodium was prepared during the further development of compound with this skeleton. 

For this reason, we consider it hardly possible to cite all of the publications. Let us focus only on the following examples. Hydroxamic acids have already been for a long time subject of the classical analytical chemistry. In [71], the possibility of using these compounds in flotation of rare-earth minerals is shown. It has been concluded that on a mineral surface cerium chelates are formed. Besides, chemisorption is accompanied by a physical multilayer adsorption of hydroxamic acid derivatives formed by reaction with cations in the water phase. A number of chelate-forming compounds including hydroxamic acids has been tested in flotation of niobium ores [72]. The best results are obtained when using alkyl phosphonic acids. Chemisorption mechanism and the structure of the surface compounds are established by spectroscopic methods. 

Cycloadditions of chiral A -acylnitroso compounds have been widely studied. These heterodienophiles are accessible e.g. by oxidation of hydroxamic acid derivatives with periodate. C2-symmetric pyrrolidines lead to high selectivities. 1,2-Oxazines are useful precursors of amino alcohols and aza sugars. 

A series of hydroxamic acid derivatives with 4-hydroxy-l,4-benzoxazin-3-one structures occur in a number of cereal grain species (Poaceae or Gramineae) (Fig. 7.8) (Niemeyer, 1988). These compounds usually occur in plants as the 2-3-(9-D-glucosides enzymes that hydrolyze the compounds usually co-occur. DIBOA [2,4-dihydroxy-1,4(2H)-benzoxazin-3-one] (22) is the major compound in rye and DIMBOA [2,4-dihydroxy-7-methoxy-1,4(2H)-benzoaxa-... 

The hydroxamic acid derivative known as Desferrioxamine B methane sulphonate (DFOA), a selective chelator for iron which has been widely used for the treatment of iron overload in man, is effective, either alone or in combination with NajCaDTPA, for the removal of plutonium from rats. However, the compound is ineffective for the removal of americium and the effectiveness for the removal of plutonium was limited to very short times after injection [see Taylor 1991 for references]. 

The formula of the intermediate may be recognized as that of a thioester formed from lactic acid and GSH. Its ultraviolet absorption spectrum is characterized by a maximum at 235 m/i. This maximum absorption as well as its stability properties are characteristics manifested by other thioesters such as acetyl-CoA. The intermediate should also yield the hydroxamic acid derivative of lactic acid upon treatment with neutral hydroxylamine. The fact that it is a thioester suggests, by analogy with acetyl-CoA, that it is a high-energy compound. 

The efficiency of benzo-hydroxamic acid derivatives, which are effective copper inhibitors for pitting and general corrosion processes, increases with increasing hydro-phobicity. The adsorption model of these compounds can be described as follows The molecule is attached to the metal surface by the unpaired electrons of the nitrogen and oxygen atoms of the hydroxamic moiety and by the n electron cloud of the phenyl ring, which may interact with the empty d-orbital of iron. 

Taddei and coworkers [49] also reported an MW-promoted solid-phase synthesis of 3,6-disubstituted perhydro-diazepin-2,5-dione 70 (Scheme 10) involving a Mitsunobu cyclization of a hydroxamic acid derivative anchored to PS-DVB 2-chlorotrityl resin (69). The prepared compound was proved to be useful as constrained peptidomimetics. 

The name hydroxamic acid was first used by Losseii in 1869, in the case of oxalohj droxamic acid, obtained from diethyl oxalate and hydroxylamine. Where this grouping forms part of the main cyclic system, however, the compound is named as a derivative of this system. In this review, 2 and 3 would be named as 1-hydroxy-2-pyrrolidone and l-hydroxy-2-pyridone, respectively. 

The following discussion of hydroxamic acids includes saturated systems, e.g., 2, compounds such as 3, derived from aromatic systems, 7V-hydroxyimides such as 7V-hydroxyglutarimide (78), and certain of their derivatives including thiohydroxamic acids. Naturally occurring cyclic hydroxamic acids are discussed to show the range of structural types that has been found, hut macrocyclic polyhydroxamic acids are mentioned very briefly, because several comprehensive reviews of these compounds are already available. The main purpose of this review is to summarize the methods available for the synthesis of cyclic hydroxamic acids, to outline their characteristic reactions, and to present some useful physical data. Their synthesis and some biological properties have previously been reviewed by Coutts. ... 

Alicyclic hydroxamic acids undergo several specific oxidative cleavage reactions which may be of diagnostic or preparative value. In the pyrrolidine series compounds of type 66 have been oxidized with sodium hypobromite or with periodates to give y-nitroso acids (113). Ozonolysis gives the corresponding y-nitro acids. The related cyclic aldonitrone.s are also oxidized by periodate to nitroso acids, presumably via the hydroxamic acids.This periodate fission was used in the complex degradation of J -nitrones derived from aconitine. 

The hydroxamic acid function in most alicyclic and aromatic compounds is stable to hot dilute acid or alkali, and derivatives cannot undergo normal base-catalyzed Lessen rearrangement. Di Maio and Tardella," however, have shown that some alicyclic hydroxamic acids when treated with polyphosphoric acid (PPA) at 176°-195° undergo loss of CO, CO.2, or H2O, in a series of reactions which must involve earlj fission of the N—0 bond, presumably in a phosphoryl-ated intermediate. Thus, l-hydroxy-2- piperidone(108) gave carbon monoxide, 1-pyrroline (119), and the lactams (120 and 121). The saturated lactam is believed to be derived from disproportionation of the unsaturated lactam. 

Ring opening with subsequent recyclization to compound 15 occurred when 3,4-bis(hydroximinomethyl)furoxan 14 was heated in water prolonged heating afforded the nitromethyl derivative 16 (Scheme 5). Ring opening on attack by ammonia on the furoxan 14 led to the intermediate 17, which may be recyclized to hydroxamic acid 18 (75LA1029). 

The experimental conditions for the syntheses starting from acid chlorides of hydroxamic acids and from nitrile oxides are somewhat different. In the former case the other component of the reaction is organometallic, usually an organomagnesium derivative of an acetylene or, less frequently, a sodium enolate of a /8-diketone. Nitrile oxides condense directly with unsaturated compounds. 

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