Hydroxamic derivs

Synthesis of VRC3375, a Proline-3-alkylsuccinyl Hydroxamate Derivative. 186... 

Namely, the reaction of 2-thioxothiazolidin-4-one N-hexanoic acid (116) with 2,5-dimethyl-l-phenylpyrrol-3-carboxaldehyde (117) in methanol under the catalytic action of ethylenediamine diacetate (EDDA) yields 5-[(2,5-dimethyl-l-phenylpyrrol-3-yl)methylidene]-2-thioxothiazolidin-4-one N-hexanoic acid (118) in 79% yield. The hydroxamate derivative of 118 is prepared by reacting this compound with 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine followed by treatment with p-toluenesulfonic acid in methanol to afford compound 121 in 60% yield. Esterification of compound 118 is carried out by using methyl iodide in acetonitrile in the presence of sodium carbonate to give compound 120. The 5-(cyclohexyl)methylidene analogue (119) is obtained in 42% yield by direct reaction of compound 116 with cyclohexanecar-boxaldehyde in methanol under the catalytic action of EDDA. 

Zanda and colleagues" have developed an alternative one-step method for the synthesis of hydroxamate derivatives 114 directly from a broad range of inactivated esters 113 and the anion of O-benzylhydroxylamine generated in situ (Scheme 59). 

Cyclization of the hydroxamic derivative 127 with ethyl orthoformate gives the pyrazolo[3,4-d] pyrimidines 128 (74GEP2356690). 

P,y-Diamino analogues 49 of statine are prepared stereoselectively starting from the O-methyl hydroxamate derivative of N-protected statine. The reaction sequence involves the formation of a p-lactam intermediate obtained by internal cyclization under Mitsunobu conditions.184 Alternatively, direct amination of either a p-oxo ester 31 followed by reduction of the resulting enamine 50, 85 or by reduction of the corresponding ,p-unsaturated ester, 88 gives an enantiomeric mixture of the corresponding unprotected p-amine, which is protected by a carbamate prior to chromatographic separation (Scheme 20). 

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. 

A series of benzothiadiazepines, for example 95 (R = (CH2)4NHS02Me, X = OCH2, Ar = 3,5-dimethoxyphenyl) have been reported by Chemey and co-workers <03JMC1811>. These hydroxamate derivatives were designed and evaluated as selective tumour necrosis factor-a converting enz3nne inhibitors. 

Analysis of Material Following Lessen Rearrangement of the Dinitrophenyl Hydroxamate Derivative of Oelalin from Ichthyocol as Compared with the Analysis of a Suitable... 

Angelini described the preparation of dihydro- 1,4-benzothiazine and related compounds from analogous esters by a two-stage reduction using tin and HC1 or lithium aluminum hydride.129 It is interesting to compare the reaction of 2-nitrophenol with similar reagents to produce benzooxazine derivatives. 2-Nitrophenol reacts with a-bromoethyl acetate, and the adduct is cyclized with zinc and ammonium chloride to the hydroxamic derivative 85.130 The adduct with phenacyl chloride has been similarly cyclized under a variety of conditions.131,132... 

Esters, ethers and hydroxamates derived from these linkers can be cleaved with mild acids such as TFA or HC1 in dioxane (Table 14.4). If TFA is used for release of alcohols, trifluoroacetates can be formed [2], but these can be easily hydrolyzed later with aqueous base. Simple amines cannot be cleaved from this type of linker by acidolysis. Thiols may be cleaved with HF. 

Other methods, among which thermolysis or photolysis of tetrazene [59], photolysis of nitrosoamines in acidic solution [60], photolysis of nitrosoamides in neutral medium [61], anodic oxidation of lithium amides [62], tributylstannane-mediated homolysis of O-benzoyl hydroxamic derivatives [63, 64], and spontaneous homolysis of a transient hydroxamic acid sulfinate ester [65] could have specific advantages. The redox reaction of hydroxylamine with titanium trichloride in aqueous acidic solution results in the formation of the simplest protonated aminyl radical [66] similarly, oxaziridines react with various metals, notably iron and copper, to generate a nitrogen-centered radical/oxygen-centered anion pair [67, 68]. The development of thiocarbazone derivatives by Zard [5, 69] has provided complementary useful method able to sustain, under favorable conditions, a chain reaction where stannyl radicals act simply as initiators and allow transfer of a sulfur-containing... 

Bromonaphthalene (9).3 In the same manner the acyl chloride 6 was reacted with hydroxamic derivative 7 to give the mixed ester 8, which heated in BrCCl3/PhCI in the presence of azoisobutyromtnle (AIBN) at 130°C afforded 9 in 85% yield. 

The most obvious common feature of all ribonucleotide reductase inhibitors except for the least effective chelators desferrioxamine, EDTA, and EGTA is that all are aromatic or heterocyclic. The superior activity of aromatic compounds became evident in comparative studies with hydroxamate derivatives, too A corresponding hy-... 

The hydroxamate derivative is readily complexed with acidified ferric chloride to form a dark brown coloration which may be easily measured in a spectrophotometer. Unfortunately the assay system can also be used to measure two other enzymes—aspartate kinase and aspartyl-tRNA synthetase (although the latter catalyzes the formation of the a-aspartyl hydroxamate). There are two possible ways to distinguish between aspartate kinase and AS. 

Using the EQCM technique, unambiguous evidence was provided for the corrosion inhibition actions of benzo-hydroxamic derivatives on copper in 0.5 M NaCl solutions. The /7-CI-BHA formed a stable film on the surface which provided excellent protection against corrosion. 

The unreacted acetylcholine can be estimated colori-metrically as its hydroxamate derivative. 

Intramolecular amidopalladation has also been used in the construction of isoin-dolinones (110) from hydroxamic derivatives (109). In the presence of ligand (111), the product was obtained in <99% ee. The use of MeCN as a highly coordinating solvent (ff) proved to be essential. ... 

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