Hydroxamic acids periodate

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 intramolecular /zetero-Diels-Alder reactions of 4-O-protected acyl-nitroso compounds 81, generated in situ from hydroxamic acids 80 by periodate oxidation, were investigated under various conditions in order to obtain the best endo/exo ratio of adducts 82 and 83 [65h] (Table 4.15). The endo adducts are key intermediates for the synthesis of optically active swainsonine [66a] and pumiliotoxin [66b]. The use of CDs in aqueous medium improves the reaction yield and selectivity with respect to organic solvents. 

N-Acylnitroso compounds 4 are generated in situ by periodate oxidation of hydroxamic acids 3 and react with 1,3-dienes (e.g. butadiene) to give 1,2-oxazines 5 (Scheme 6.3). The periodate oxidation of 4-O-protected homo-chiral hydroxamic acid 6 occurs in water in heterogeneous phase at 0°C, and the N-acylnitroso compound 7 that is generated immediately cyclizes to cis and tranx-l,2-oxazinolactams (Scheme 6.4) [17a, b]. When the cycloaddition is carried out in CHCI3 solution, the reaction is poorly diastereo-selective. In water, a considerable enhancement in favor of the trans adduct is observed. 

The hetero-Diels-Alder reaction has also utilized dienophiles in which both reactive centers are heteroatoms. Kibayashi reported that the intramolecular hetero-Diels-Alder cycloaddition of chiral acylnitroso compounds, generated in situ from periodate oxidation of the precursor hydroxamic acid, showed a marked enhancement of the trans-selectivity in an aqueous medium compared with the selectivity in nonaqueous conditions (Eq. 12.55).125 The reaction was readily applied to the total synthesis of (—)-pumiliotoxin C (Figure 12.5).126... 

Acyl nitroso compounds (3, Scheme 7.2) contain a nitroso group (-N=0) directly attached to a carbonyl carbon. Oxidation of an N-acyl hydroxylamine derivative provides the most direct method for the preparation of acyl C-nitroso compounds [10]. Treatment of hydroxamic acids, N-hydroxy carbamates or N-hydroxyureas with sodium periodate or tetra-alkyl ammonium periodate salts results in the formation of the corresponding acyl nitroso species (Scheme 7.2) [11-14]. Other oxidants including the Dess-Martin periodinane and both ruthenium (II) and iridium (I) based species efficiently convert N-acyl hydroxylamines to the corresponding acyl nitroso compounds [15-18]. The Swern oxidation also provides a useful alternative procedure for the oxidative preparation of acyl nitroso species [19]. Horseradish peroxidase (HRP) catalyzed oxidation of N-hydroxyurea with hydrogen peroxide forms an acyl nitroso species, which can be trapped with 1, 3-cyclohexanone, giving evidence of the formation of these species with enzymatic oxidants [20]. 

C-Nitrosocarbonyl compounds RCONO (R = Me or Ph), generated from hydroxamic acids and tetraethylammonium periodate, readily react with dienes such as butadiene and... 

Acylnitroso compounds 197 (R = Me, Ph or Bn) react in situ with 1-methoxycarbonyl-1,2-dihydropyridine to yield solely the bridged adducts 198 quantitatively. On the other hand, 1 1 mixtures of the regioisomers 199 and 200 were formed from the nitroso-formates 187 (R = Me or Bn) (equation 110)103. The chiral acylnitroso compounds 201 and 202, which are of opposite helicity, add to cyclohexadiene to give optically active dihydrooxazines in greater than 98% diastereomeric excess (equations 111 and 112)104. Similarly, periodate oxidation of the optically active hydroxamic acid 203 in the presence of cyclopentadiene, cyclohexa-1,3-diene and cyclohepta-1,3-diene affords chiral products 204 (n = 1, 2 and 3, respectively) in 70-88% yields and 87-98% de (equation 113)105. 

Tetra-rt-propylammonium periodate oxidation of the hydroxamic acids 215 (R = CH2OH, CH20Me, CH2NHPI1 or CC Me), derived from L-proline, generates nitroso compounds 216, which, in the presence of cyclohexadiene, give mixtures of diastereomeric cycloadducts 217 in 79-89% yields and 26-68% de values (equation 115)109. 

NMR data on hydroxylamines, oximes and hydroxamic acids appeared at roughly the same periods as those of other types of compounds with a small delay for N relative... 

Tables S1-S6 show a wide diversity of the elements determined within an individual group of reagents. For the purpose of having a better idea on the apphcabUity of these reagents, we decided to now present the number of reagents for the determination of each element in a set of periodic tables (Tables 2 and 3) that show the vast majority of metallic elements of the periodic table can be determined either by the use of oximes and/or hydroxamic acids.

TABLE 3. Periodic system showing the number of reagents from the group of hydroxamic acids with which a certain element can be determined. Superscripts denote the number of reagents considered as hydroxamic acids and subscripts denote the number of elements considered as thiohydroxamic acids... 

Oxidation of secondary hydroxamic acids with performic acid affords the N-alkyl residue as a carboxylic acid (136). A most useful oxidative reaction is that obtained by action of periodate on hydroxamic acids and hydroxylamines (41, 43, 121, 122). Primary hydroxamic acids give ni-... 

The facile oxidation of hydroxylamine and its derivatives with periodate has led to the suggestion that the method be used as a sensitive diagnostic test for the presence of the secondary hydroxamic acid link (43). The amM of the alkane dimers at 2670 A is close to 10, i. e., about ten times the absorbancy of ferric monohydroxamate at 5100 A. It should be noted that other attempts to increase the sensitivity of hy-droxamate determination have taken advantage of the relative alkali... 

Aliphatic nitroso compounds can be prepared from IV-alkylhydioxylamines oxidation widi bromine, chlorine or sodium hypochlorite in weakly acidic solution, reaction with potassium dichromate in acetic or sulfuric acid, and by oxidation widi yellow mercury(II) oxide in suspension in an organic solvent. Silver carbonate on Celite has also been used to prepare aliphatic nitroso compounds, such as ni-trosocyclohexane, in high yield from the corresponding hydroxylamines." Aqueous sodium periodate and tetraalkylanunonium periodates, which are soluble in organic solvents, are the reagents most commonly used for the oxidation of hydroxamic acids and IV-acylhydroxylamines to acylnitroso compounds... 

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. 

Recently, Kibayashi s group (85JA5534) elegantly carried out the stereo-controlled total synthesis of gephyrotoxin (skin extracts of neopropical poison dart frog) based upon an intramolecular nitroso Diels-Alder reaction. The hydroxamic acid 365 was treated with tetrapropylammonium periodate... 

Oxidations of hydroxamic acids by periodate (assumed to involve a nitrosylacyl intermediate) and of hydrazides by potassium ferrocyanide, followed by quenching with amines, are of limited preparative value. 

Oxidation of diene-containing hydroxamic acids has been reported to give acylnitroso species which undergo spontaneous hetero-IMDA reactions to give heterobicyclic ketones. (E,E)-N-Hydroxy-5,7-dodecadienamide, upon treatment with tetrapropylammonium periodate, gave the pyrido[l,2-b][l,2]oxazine structure in high yield88. 

The pioneering studies of Kirby et al. have established that acylnitroso compounds are useful heterodienophiles in [4 -I- 2] cycloadditions. These species, which can best be generated by periodate oxidation of a hydroxamic acid, are unstable and may undergo rapid solvolysis or dimerization. However, in the presence of a diene such as 9,10-dimethylan-thracene an isolable adduct such as 14 is produced [Eq. (18)]. 

Despite the overall similarities between the effects of hydroxamic acid and depsipeptide HDAC inhibitors on cancer cells, we have identified some important class-specific effects (in addition to the selective induction of a-tubulin acetylation). Importantly, the kinetics of inhibition of cellular HDACs by these inhibitors varies widely. While hydroxamic acids induce rapid histone acetylation in intact cells, the onset of action of the depsipeptide inhibitors is much slower (Fig. 12-10). Also, following removal of compound by extensive washing, histone acetylation is rapidly lost in hydroxamic acid treated cells, but is maintained for protracted periods in cells treated with depsipeptide inhibitors. 

DFP is stable and in the absence of moisture can be stored for considerable periods without decomposition. Hydrolysis in neutral aqueous solution occurs slowly. The reaction is catalyzed by both acid and base. At pH>7, hydrolysis is proportional to the hydroxide ion concentration and at high pH is extremely rapid. The product is always diisopropyl phosphoric acid (equation 38), except under more forcing conditions which eventually produce phosphate (and propan-2-ol). The hydrolysis is strongly catalyzed by the addition of a-effect nucleophiles such as hypochlorite, peroxide, hydroxylamine, hydroxamic acid and their substituted derivatives . Under basic conditions, such nucleophiles (HOX) are present as the anion and are responsible for the rapid initial displacement of fluoride ion from DFP to give intermediate 36 shown in equation 39. Displacement of OX by hydroxide ion regenerates the catalytic OX anion. The reaction with hydrogen... 

C.iii. Nitroso-Type Compounds. Nitroso compounds (R—N=0) show reactivity as dienophiles in Diels-Alder reactions, giving heterocyclic rings. In Kibayashi s synthesis of fasicularin, " for example, hydroxamic acid 180 was treated with tetrapropylammonium periodate in the presence of 9,10-dimethyl-anthracene to give transient acylnitroso compound 181, and the resultant Diels Alder product 182 was formed in 84% yield. In this particular example, the Diels-Alder adduct essentially "protected" the acyl nitroso unit, which was used in a subsequent reaction. 

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