Cyclization of hydroxamates

The cyclizations of hydroxamic acids (204) (Y = O or S), with various reagents capable of undergoing nucleophilic attack twice at the same carbon atom, are very important routes for the synthesis of the ring systems in this chapter (Scheme 39). 

As it has been shown, there are many ways to assemble the 1,4-(oxa/thia)-2-azole ring. Most of them are performed by inter- or intramolecular cyclization of suitable acyclic precursors. Some of them are found to be suitable for the synthesis of various ring systems, by using readily available, and properly modified reactants. Of particular importance are the following (a) the cyclizations of sulfenamides leading to (oxa/thia)azolium salts (Scheme 33) (b) the cyclization of hydroxamic acids (Scheme 39) (c) the dipolar cycloaddition methodology (Scheme 40) (d) the cyclizations of chlorosulfenyl chlorides (Scheme 46) and (e) the cyclizations of chloromethane sulfonamides (Schemes 47 and 48). Other cyclizations reported are preparative ways used mainly for the synthesis of specific compounds and the scope of these reactions has not been widely studied. 

Fragments Intramolecular Cyclizations of Hydroxamic Acids and Aminophenylthiocarbamides... 

Cyclization of Hydroxamates i-Cysteine-derived thiazolidine hydroxamate ester 71 is cyclized to the thiazolidine-fused fS-lactams 72 using methyl sulfonyl chloride [63]. The cleavage of the thiazolidine ring with methoxycarbonylsulfenyl chloride afforded the monocyclic fS-lactam 74 (Scheme 3.28). An Sml2-mediated scission of the N-O bond in 72 followed by cleavage of the thiazolidine ring afforded the NH monocyclic -lactam 73 in reasonable yield (Scheme 3.28). 

A variety of condensation processes can lead to cyclic hydroxamic acids. These involve either the condensation of two molecules or the intramolecular cyclization of a single compound. In some cases, a primary hydroxamic acid function is already present and formation of a cyclic compound can arise by suitable reaction on nitrogen. These processes will be dealt with first. 

Shaw and McDowellhave prepared imidazolone derivatives by cyclization of a-acylamino amides. In a variation of this reaction the azlactone (30) was gradually converted to the hydroxamic acid (31) by methanolic hydroxylamine. Sodium methoxide and hydroxylamine readily gave the acyclic hydroxamic acid (32) which could be cyclized to 31 by dilute acid. Benzyloxyurea has been used in the sjrnthesis of pyrimidine hydroxamic acids (33) by reaction with /S-diketones followed by catalytic hydrogenation of the benzyl group. Protection... 

Other zinc reductions have been used extensively. Zinc dust in aqueous ammonium chloride is a standard reagent for the reductive cyclization of nitro esters to hydroxamic acids. These reactions are usually carried out at low temperatures (0°-10°) to avoid further reduction. Despite the fact that good yields can often be obtained, these reductions are highly capricious, depending on the quality of the zinc (impurities seem to improve the reaction) and other unknown factors. 

Perhaps the most reliable method for the reductive cyclization of a nitro ester to a hydroxamic acid is that which involves treatment with sodium horohydride in the presence of palladium on charcoal. Although under these conditions aromatic nitro compounds are reduced to amines, o-nitro esters such as 53, in which the ester group is suitably oriented with respect to the nitro group, give good yields of cyclic hydroxamic acids (54). Coutts and his co-... 

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. 

An alternative procedure for the synthesis of aliphatic 2-substituted oxazoline hydroxamates was described by Pirrung and colleagues in the context of preparing inhibitors of E. coli LpxC zinc amidase [378], As shown in Scheme 6.210 a, the protocol involved the cyclization of suitable amides, formed in situ by acylation of a serine-derived 0-2,4-dimethoxybenzyl (DMB)-protected hydroxamate. The cyclization... 

An alternative procedure that generates stable, storable nitrone intermediates 175 from 170, mediated by dry m-CPBA as oxidating reagent, is shown in Scheme 77 ". Conversion of the nitrone 175 to the hydroxylamine by an exchange reaction with hydroxylamine hydrochloride was followed by EDC/HOAt-mediated cyclization to hydroxamic acid 174 (HOAt l-hydroxy-7-azabenzotriazole). 

The formation of numerous ring-substituted spirolactams (53b) employed this methodology, which to date has also found application in a number of natural product syntheses. For example, the critical spirane junction-forming step in the synthesis of the muscarinic Mj receptor antagonist (—)-TAN1251A (58) from L-tyrosine involves PIFA-induced cyclization of the hydroxamic ester 56 to 57 according to Scheme 12 °. 

Intramolecular Cyclization of 0-, W-Alkylhydroxylamines and Hydroxamates. 9.4 Cycloaddition of Nitrones to Unsaturated Compounds. 9.5 Hetero-Diels-Alder [4+2]-Reactions... 

A previous review has highlighted the following methods of ring synthesis intramolecular cyclization of oximes, nitro alkenes, and nitrones, and [4+2] cycloaddition reactions <1996CHEC-II(6)279>. In addition to that, this review includes the intramolecular cyclization of hydroxylamines, hydroxamates, hetero-Diels-Alder [4+2], 1,3-dipolar cycloaddition of nitrile oxides to alkenes, and [3+3] cycloaddition reactions. This review does not cover cycloaddition reactions of the [4+2] [3+2] and [4+2] [3+2] [3+2] types which primarily led to heterocycle-fused oxazine ring systems. 

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

Carboxylic acid derivatives of thiazepine were obtained by cyclization of D-penicillamine. The ester derivative 107a was transformed to the carboxylic acid 107b and hydroxamic acid 107c. The latter compound is a matrix metalloproteinase (MMP) inhibitor (Figure 13) <1999JME4547>. 

Aziridinones (z-lactums).3 The hydroxamic acid (1) is converted in almost quantitative yield to the a-lactam 2 when treated with triflic anhydride and triethylamine in CH2C12 at — 70°. This cyclization of a hydroxamic acid was first encountered in a thebaine derivative. 

A2-Oxazolines. The intramolecular cyclization of /1-hydroxy hydroxamates to /1-lactams by P(C6H5)3-CC14 (10,447-448) can be used for cyclization of a carboxylic acid and a /1-amino alcohol to form a d2-oxazoline (equation I).1... 

The cyclohexene 121, which was readily accessible from the Diels-Alder reaction of methyl hexa-3,5-dienoate and 3,4-methylenedioxy-(3-nitrostyrene (108), served as the starting point for another formal total synthesis of ( )-lycorine (1) (Scheme 11) (113). In the event dissolving metal reduction of 121 with zinc followed by reduction of the intermediate cyclic hydroxamic acid with lithium diethoxyaluminum hydride provided the secondary amine 122. Transformation of 122 to the tetracyclic lactam 123 was achieved by sequential treatment with ethyl chloroformate and Bischler-Napieralski cyclization of the resulting carbamate with phosphorus oxychloride. Since attempts to effect cleanly the direct allylic oxidation of 123 to provide an intermediate suitable for subsequent elaboration to ( )-lycorine (1) were unsuccessful, a stepwise protocol was devised. Namely, addition of phenylselenyl bromide to 123 in acetic acid followed by hydrolysis of the intermediate acetates gave a mixture of two hydroxy se-lenides. Oxidative elimination of phenylselenous acid from the minor product afforded the allylic alcohol 124, whereas the major hydroxy selenide was resistant to oxidation and elimination. When 124 was treated with a small amount of acetic anhydride and sulfuric acid in acetic acid, the main product was the rearranged acetate 67, which had been previously converted to ( )-lycorine (108). 

Ferrioxamines B and E are prime examples of the linear and cyclic species, respectively. Several members of the series have been prepared by total synthesis, thus establishing the sequence of the contained units (For example, four isomers could be constructed from the hydrolytic products of ferrioxamine B). The three hydroxamate functions must be spatially located so as to form a stable, intramolecular hexa-dentate ferric chelate. Acetylation of ferrioxamine B affords ferrioxa-mine Di ferrioxamine G corresponds to component B with succinic replacing acetic acid cyclization of G yields ferrioxamine E components Ai and D2 carry l-amino-4-hydroxyaminobutane in place of a residue of the next higher homologue. 

H)-Oxazolones are formed by the spontaneous cyclization of /3-oxo isocyanates (equation 134). Similarly, o-hydroxyphenyl isocyanate, produced by the Curtius rearrangement of the azide of salicylic acid or by the action of sodium hypochlorite on salicylamide, forms benzoxazolone (equation 135). An analogous reaction is the formation of IV-phenyl-benzoxazolone by the action of thionyl chloride on the hydroxamic acid shown in equation (136) (78TL2325). Pyrolysis of aryl azidoformates affords benzoxazolones by nitrene insertion (equation 137) (81CC241). 

Other intramolecular cyclizations accompanied by elimination are the preparation of the l,2,4-dioxazolin-3-ones (190) by HC02H dehydrative cyclization of a precursor percar-bamic acid (72JPR145) formation of the l,3,4-dioxazol-5-ones (191) from the hydroxamic ester (192) (78JAP78127479) and preparation of the 1,3,2-dioxazolidine (57) by base treatment of the precursor A-methoxy-A-hydroxyethoxy compound (80IZV2181). 

In a similar fashion, 1-acetylisatin, when reacted with hydroxylamine hydrochloride furnishes quinazoline-3-oxide through cyclization of the intermediate hydroxamic acid234. This intermediate hydroxamic acid can be isolated by treatment of the quinazoline oxide with alkali235 (Scheme 54). 

The cyclophosphonamide hydroxamic acids 217 were prepared by cyclization of the iV-hydroxyalkyl amino acid esters 214 with phosphonyl dichlorides 215, and by subsequent conversion of the ester group to a hydroxamic acid upon treatment with hydroxylamine and NaOMe in MeOH <2003BMC5461>. 

The phenylselenyl sulfate promoted cyclization of alkenyl hydroxamic acids reported by Tiecco [98], illustrates the interesting case in which the change of the experimental conditions has a substantial influence on the nature of the... 

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