42-Isoxazoline ring

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)... 

The isoxazoline ring is also readily cleaved by such reducing agents as do not affect the isoxazole ring. Thus, for example, the treatment of isoxazolines (186) with LiAlHj proceeds with a smooth cleavage of the heterocyclic ring to form substituted 3-amino-propan->l-ols... 

Boiling hydriodic acid also degrades the isoxazoline ring - but does not affect that of isoxazole. ... 

A formal total synthesis of the prostaglandin involved unmasking of an isoxazoline ring by hydrogenation over W-2 Raney Ni/BCl3/MeOH, H2O to reveal a -hydroxyketone. It was necessary in this case to deactivate the Raney... 

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 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). 

Hydrogenolysis of the isoxazoline ring with Ra-Ni in the presence of hydrogen results in conversion to a hydroxymethyl ketone (Scheme 4.142).540... 

New applications of nitrile oxide 1,3-DC have been reported. Soluble, single-wall carbon nanotubes (SWNT) 32 functionalized with pentyl esters at the tips and pyridyl isoxazoline rings along the walls were prepared using pentyl ester-SWNT as dipolarophile. The complex... 

A rapid access to carbocyclic nucleosides, containing a fused isoxazoline ring has been proposed, starting from cyclopentadiene. The route involves a het-ero Diels-Alder cycloaddition reaction of nitrosocarbonylbenzene followed by a 1,3-dipolar cycloaddition of nitrile oxides, cleavage of the N-0 tether and transformation of the heterocyclic aminols into nucleosides via construction of purine and pyrimidine heterocycles (457). 

Diastereoselective intermolecular nitrile oxide—olefin cycloaddition has been used in an enantioselective synthesis of the C(7)-C(24) segment 433 of the 24-membered natural lactone, macrolactin A 434 (471, 472). Two (carbonyl)iron moieties are instrumental for the stereoselective preparation of the C(8)-C(ii) E,Z-diene and the C(i5) and C(24) sp3 stereocenters. Also it is important to note that the (carbonyl)iron complexation serves to protect the C(8)-C(ii) and C(i6)-C(i9) diene groups during the reductive hydrolysis of an isoxazoline ring. 

Novel polycyclic heterocyclic systems including the isoxazoline ring were described. Thus, oximes 191 and 193 in the presence of sodium hypochlorite afforded heterocycles 192 or 194, respectively (equations 83 and 84). Intramolecular cycloaddition of nitrile oxide was used in the synthesis of the A-ring fragments of la,25-dihydrovitamin D3 and taxane diterpenoids, sulphur-containing isoxazoles, fluoro-substituted aminocyclopentanols and aminocyclopentitols . New gem- and vic-disubstituted effects in such cyclization reactions have been reviewed by Jung. ... 

As noted previously, the use of chiral sultam auxiliaries provides access to ena-ntiomerically enriched isoxazolines. These products can be elaborated to provide nonactic acid and 8-ep/-nonactic acid, the subunits of nonactin (Scheme 2.15) (141-143). Subsequent cleavage of the isoxazoline ring in the presence of Raney... 

Isoxazoline Ring Cleavage Reactions of the Aldol Type... 

Cozzi and co-workers (243,263) studied the influence of the double-bond configuration on the stereochemical course of the intramolecular cycloaddition of chiral alkenes, where the stereocenter is located outside the isoxazoline ring (Table 6.15). On the basis of experimental results as well as theoretical calculations, two models were proposed for the reaction with (Z)- and ( )-aIkenes, in accord with the model proposed for a-X-substituted alkenes (see Section 6.2.3.1). 

Reduction of the isoxazoline ring can lead to different mixtures of amino alcohols depending on the reducing reagent used. Catalytic hydrogenation as well... 

The category Id cyclization has also been applied to 4-aminoindoles of the type found in the indolelactam tumour promoters such as lyngbyatoxin A and pendolmycin. In a synthesis of analogues of lyngbyatoxin A the isoxazoline 8.4A was constructed as a key intermediate ]. Reductive cleavage of the isoxazoline ring generated 8.4B which was cyclized by reaction with terf-butyldimethylsilyl triflate (Entry 6, Table 8.1). The cyclization of a thioamide was a key step in the synthesis of pendolmycin[5] (Entry 7, Table 8.1). 

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