Cycloaddition reactions hydroxylamine synthesis

The general method, that has been widely used for the synthesis of perhydropyrrolo[1,2-6]isoxazoles, is based on a cycloaddition reaction of cyclic nitrones with dipolarophiles. The nitrone is easily available by oxidation of the corresponding hydroxylamine with mercuric chloride. The cycloaddition of nitrone to dipolarophiles is highly regioselective and stereoselective and have been often applied in the total synthesis of natural products <20010L1367, 2004BML3967, 2005JOC3157>. As one representative example of dipolar cycloaddition, reaction... 

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. 

As part of an extensive study of the 1,3-dipolar cycloadditions of cyclic nitrones, Ali et al. (392-397) found that the reaction of the 1,4-oxazine 349 with various dipolarophiles afforded the expected isoxazolidinyloxazine adducts (Scheme 1.78) (398). In line with earlier results (399,400), oxidation of styrene-derived adduct 350 with m-CPBA facilitated N—O cleavage and further oxidation as above to afford a mixture of three compounds, an inseparable mixture of ketonitrone 351 and bicyclic hydroxylamine 352, along with aldonitrone 353 with a solvent-dependent ratio (401). These workers have prepared the analogous nitrones based on the 1,3-oxazine ring by oxidative cleavage of isoxazolidines to afford the hydroxylamine followed by a second oxidation with benzoquinone or Hg(ll) oxide (402-404). These dipoles, along with a more recently reported pyrazine nitrone (405), were aU used in successful cycloaddition reactions with alkenes. Elsewhere, the synthesis and cycloaddition reactions of related pyrazine-3-one nitrone 354 (406,407) or a benzoxazine-3-one dipolarophile 355 (408) have been reported. These workers have also reported the use of isoxazoles with an exocychc alkene in the preparation of spiro[isoxazolidine-5,4 -isoxazolines] (409). 

Sneider et al. (27,28) applied a familiar nitrone for the synthesis the immunosuppressant (—)-FR901483 (14) in a recent study (Scheme 12.7). The nitrone 12 is generated in situ from ketone 10 and the optically pure hydroxylamine 11 at 25 °C. The resultant nitrone 12 underwent a 1,3-dipolar cycloaddition reaction with ethyl acrylate in refluxing toluene to give the diastereomer 13 with 71 % diastereomeric excess (de). In 22 synthetic steps including the 1,3-dipolar cycloaddition, the target molecule 14 was obtained. 

Intramolecular cycloaddition reactions of nitrones have been used widely in synthesis. The required unsaturated nitrones can be obtained by oxidation of N-alkenyl-hydroxylamines or by condensation of an aldehyde with an A -substituted hydroxylamine. Thus the cis bicyclic isoxazolidine 212 was obtained by reaction of 5-heptenal with AT-methylbydroxylamine, by way of the intermediate ititrone 211 (3.139). 

Tethering the alkene to the carbon atom of the nitrone allows the preparation of cw-l,2-disubstituted cycloalkanes such as 212. Examples in which the alkene is tethered to the nitrogen atom of the nitrone are also common. Thus, addition of formaldehyde to the hydroxylamine 213 promoted formation of the intermediate nitrone and hence the cycloadduct 214 (3.140). " Subsequent transformations led to the alkaloid luciduline. This synthesis illustrates a useful feature of the 1,3-dipolar cycloaddition reaction of nitrones, in that it provides an alternative to the Mannich reaction as a route to (3-amino-ketones, via reductive cleavage of the N-0 bond in the isoxazolidine and oxidation of the 1,3-amino-alcohol product. In another example of such an intramolecular cycloaddition reaction, the bridged bicyclic product 217, used in a synthesis of indolizidine 209B, was formed by addition of an aldehyde to the hydroxylamine 215, followed by heating the intermediate nitrone 216 (3.141).142... 

The two main routes for the synthesis of isoxazoles are (a) the attack of hydroxylamine (NH2OH) on diketones and (b) a reaction of nitrile oxides called a 1,3-dipolar cycloaddition. They thus form a link between the strategy we have been discussing (cyclization of a nucleophile with two heteroatoms and a compound with two electrophilic carbon atoms) and the next strategy—cycloaddition reactions. 

Kerr and coworkers developed an elegant access to optically active 3,6-cis disubstituted oxazine ring system via a homo-l,3-dipolar cycloaddition reaction of an aldehyde, a hydroxylamine, and a cyclopropane in the presence of a Lewis acid (Scheme 16). To emphasize the usefulness of this reactivity, it was first applied to the synthesis of phyllanthidine (7) (vide infra. Scheme 33). A modified version of this reaction provided access to 2,5-disubstituted pyrroloisoxazohdines, which upon N—O bond cleavage efficiently furnished the corresponding 2,5-cis pyrrofidine ring system (Scheme 16). 

The nitroso functionality is a powerful dienophile and N-alkyl- and N-acylnitroso compounds give inter- and intrahetero Diels-Alder reactions easily. The cycloadditions also occur in aqueous medium although some nitroso compounds (i.e. N-acylnitroso derivative) are short-lived in the presence of water. The NO functionality is generated in situ by periodate oxidation of the hydroxylamine group and the cycloaddition with butadienes gives a 1,2-oxazine ring. Scheme 5.16 illustrates the utility of the nitroso Diels-Alder cycloaddition for the synthesis of (—l-swainsonine/ (—)-pumiliotoxin and BCX-1812... 

In theory, three isoxazolines are capable of existence 2-isoxazoline (2), 3-isoxazoline and 4-isoxazoline. The position of the double bond may also be designated by the use of the prefix A with an appropriate numerical superscript. Of these only the 2-isoxazolines have been investigated in any detail. The preparation of the first isoxazoline, 3,5-diphenyl-2-isoxazoline, from the reaction of )3-chloro-)3-phenylpropiophenone with hydroxylamine was reported in 1895 (1895CB957). Two major syntheses of 2-isoxazolines are the cycloaddition of nitrile A-oxides to alkenes and the reaction of a,/3-unsaturated ketones with hydroxylamine. Since 2-isoxazolines are readily oxidized to isoxazoles and possess some of the unique properties of isoxazoles, they also serve as key intermediates for the synthesis of other heterocycles and natural products. 

The well-known Robinson-Schbpf reaction has been applied to the synthesis of JZ-adaline (107) from ketoglutaric acid (457), ammonium chloride, and keto-aldehyde (458) (Scheme 58) 338). The second synthesis of starts with nitrone 459 462). Reaction of 459 with pentylmagnesium bromide gave a hydroxylamine (460) which was oxidized to yield a mixture of nitrones 461 and 462. Without separation of the nitrones (461 and 462), successive treatments with allylmagnesium bromide and then mercuric oxide gave a mixture of desired nitrones 466 and 467 and by-product 468. Nitrones 466 and 467 are capable of 1,3-dipolar cycloaddition and, on heating in chloroform, 466 and 467... 

Alkenyl nitrones, having the alkene connected to the nitrone nitrogen atom, have been used in another approach to intramolecular reactions (231-235). Holmes and co-workers have this method for the synthesis of the alkaloid (—)-indolizidine 209B 137 (210,231). The alkenyl nitrone 134, was obtained from the chiral hydroxylamine 133 and an aldehyde. In the intramolecular 1,3-dipolar cycloaddition, 135 was formed as the only isomer (Scheme 12.45). The diastereofacial selectivity was controlled by the favored conformation of the cyclohexane-like transition state in which the pentyl group was in a pseudoequatorial position, as indicated by 134. Further transformation of 135 led to the desired product 137. 

Taking this into account, Meijere and Brandi [117] together explored the effect of microwave heating during the 1,3-dipolar cycloaddition of nitrones, generated in situ and bicyclopropylidene 182 for the synthesis of these spiro-p-lactams 184 (Scheme 43). The reaction of Ai-substituted hydroxylamine hydrochlorides 185,... 

Methods for the reductive cleavage of the N—O bond in hydroxylamines have assumed increasing importance in synthesis because it is a key step in routes based on cycloaddition of nitrones and nitroso compounds. Inter- and intra-molecular cycloadditions of nitrones lead to the formation of tetrahydroisox-azoles (Scheme 25) these compounds are then converted into amino alcohols by reductive cleavage of the N—-O bonds. This type of reaction sequence has been exploited in the synthesis of a number of alkaloids.Nitroso compounds, particularly those activated by electron-withdrawing substituents, act as dienophiles in the Diels-Alder reaction (Scheme 26) and the cycloadducts can be used as synthetic intermediates by cleaving the N—O bonds. 

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