Isoxazoline, formation

Since isoxazoline formation, subsequent modification at the ring or adjacent centers and reductive cleavage can be carried out in a highly diastereoselective manner, a scheme was devised to synthesize various iminopolyols by this strategy. 

Reaction of hydroxylamine with tri- and tetrasubstituted pyrylium salts yields pyridine iV-oxides and/or 2-isoxazo-lines via the intermediacy of keto-ketoximes <1998T9747>. The regiochemistry of 2-isoxazoline formation from unsymmetrical pyryliums, and the Beckman rearrangement of the intermediate keto ketoximes have also been explored C1998T9747, 1999T15011>. 

Fig. 15.43. Isoxazoline formation by way of a 1,3-dipolar addition of an in situ generated nitrile oxide to trans-butene.

Phase-transfer addition (c/. Vol. 6, p. 31) of dibromocarbene to carvone and reduction to a monobromo-ketone by tributyltin hydride, or to a dibromo-alcohol with lithium aluminium hydride, is reported/ 1,3-Dipolar cycloaddition of acetonitrile oxide occurs exclusively at the exocyclic double bond in limonene to give (155 R = Me, X = Hi), whereas isoxazoline formation with carvone yields (155 R = Me, X —O) and the isomeric product from attack at the C-6 double bond benzonitrile oxide, however, only yields (155 R = Ph, X = 0 or NOH). A re-investigation of aqueous chlorination of a -terpineol indicates that the diequator-ial chlorohydrin (156) and the corresponding diaxial chlorohydrin are the major... 

The oxygen-nitrogen bond of isoxazolines can be cleaved by reduction and a number of imaginative syntheses have employed isoxazoline formation and cleavage... 

Treatment of 2-isoxazolines with acid usually leads to ring rupture and formation of chalcone products 62HC(l7)l), although 5-methyl-3-phenyl-2-isoxazoline forms a quaternary salt with dimethyl sulfate in the presence of perchloric acid (Scheme 51) (73BSF1390). 

It was also found that bromonitrophenylmethane (375) reacted with sodium aryl-methanenitronate (374) in DMSO to give the isoxazoline iV-oxide (369) in 60% yield. Both reactions probably involved the formation of a vicinal dinitroethane derivative (376), which lost nitrous acid to give cfs-a-nitrostilbene (368). As mentioned, the reaction of (368) with (374) gave the isoxazoline iV-oxide (369). 

In a number of cases the intermediate oxime has been isolated in the reaction of hydroxylamine and /3-keto esters. The reaction of ethyl acetoacetate with hydroxylamine generated an oxime which cyclized on base treatment (Scheme 144) (70MI41600). Likewise, treatment of an analogous amide with hydroxylamine generated a ring opened material which cyclized on treatment with HCl (Scheme 144) (67T831). The presence of a minor contaminant in the standard reaction of ethyl acetoacetate with hydroxylamine was discovered and identified as an isomeric isoxazolin-3-one. The mechanism of product formation has been discussed (70BSF2685). 

One of the most important routes to isoxazole and isoxazoline rings involving the formation of the 1—5 and 2—3 bonds involves the condensation of hydroxylamine with a,/8-unsaturated carbonyl compounds. This method was previously widely used, but it is now of no preparative value, though it has been recently applied to determine the configuration of oximes. " The only new modification of this synthesis is the use of the acetals (27) of a,/8-acetylenic aldehydes for preparation of 5-substituted isoxazoles (28)... 

Accordingly, cyclic nitronates can be a useful synthetic equivalent of functionalized nitrile oxides, while reaction examples are quite limited. Thus, 2-isoxazoline N-oxide and 5,6-dihydro-4H-l,2-oxazine N-oxide, as five- and six-membered cyclic nitronates, were generated in-situ by dehydroiodination of 3-iodo-l-nitropropane and 4-iodo-l-nitrobutane with triethylamine and trapped with monosubstituted alkenes to give 5-substituted 3-(2-hydroxyethyl)isoxazolines and 2-phenylperhydro-l,2-oxazino[2,3-fe]isoxazole, respectively (Scheme 7.26) [72b]. Upon treatment with a catalytic amount of trifluoroacetic acid, the perhydro-l,2-oxazino[2,3-fe]isoxazole was quantitatively converted into the corresponding 2-isoxazoline. Since a method for catalyzed enantioselective nitrone cycloadditions was established and cyclic nitronates should behave like cyclic nitrones in reactivity, there would be a good chance to attain catalyzed enantioselective formation of 2-isoxazolines via nitronate cycloadditions. 

Nitrile oxides are usually prepared via halogenation and dehydrohalogenation of aldoximes [11] or via dehydration of primary nitro alkanes (Scheme 1) [12]. However, it is important to note that nitrile oxides are relatively unstable and are prone to dimerization or polymerization, especially upon heating. 1,3-Dipolar cycioaddition of a nitrile oxide with a suitable olefin generates an isoxazoline ring which is a versatile synthetic intermediate in that it provides easy access to y-amino alcohols, )5-hydroxy ketones, -hydroxy nitriles, unsaturated oximes, and a host of other multifunctional molecules (Scheme 1) [5a]. Particularly for the formation of )5-hydroxy ketones, nitrile oxide-olefin cycioaddition serve as an alternative to the Aldol reaction. 

The above methodology has been extremely useful for the synthesis of a variety of INOC precursors. For instance, treatment of 0-trimethylsilyl a-bro-moaldoximes 52b, e, f with F ion in presence of unsaturated alcohols 57 produces oximino ethers 58 which can be readily oxidized using NaOCl (Scheme 8) [29]. The transient nitrile oxide intermediates formed undergo spontaneous cyclization to fused isoxazolines 59. The preferred stereoisomer in the formation of the five-membered ring ethers is trans whereas in the six-membered ring ethers the cis isomer predominates (see Table 5). MM2 calculations helped rationalize the experimentally observed stereoselectivites (see Table 5). 

Monoalkylation of Af-tosylallylamine 10 with dibromoalkane 101 proceeded in 60-90% yield (Eq. 10 see also Scheme 3 and Eq. 2) [17]. The bromoalkyl-amines 102 were converted to nitro compounds 103. In situ transformation of 103 into nitrile oxides led to spontaneous cycloaddition with formation of isox-azolines fused to 5-, 6-, and 7-membered ring heterocycles 104 a-c. Under very high dilution conditions, 103 d was converted to 104 d, an isoxazoline fused to an 8-membered azocine, in low (10%) yield. 

The reduction of the isoxazoline ring after the cycloaddition was not successful with the usual reagents (see p. 532), but Sml2 accomplished the reaction. In contrast to the epoxidation used as the final step in most of the other epothilone A syntheses, the epoxide was introduced through a sulfite intermediate. Deprotection of C(15) leads to intramolecular displacement at the sulfite with formation of the epoxide (Steps E-3 and E-4). 

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