Isoxazoline compounds intramolecular cycloadditions

Intramolecular cycloadditions of alkenyl-substituted nitrile oxides produce bicyclic isoxazolines. When monocyclic olehns are used, tricyclic structures are obtained. This approach was pioneered by both Kozikowski s and Curran s groups. A typical case involves the cycloaddition of nitro compound 191 [mixture of diastereomers derived from pentenose pyranoside 190], which produced a diaster-eomeric mixture of isoxazolines that contain cis-fused rings (i.e., 192) in near quantitative yield (326) (Scheme 6.85). Further elaboration of this mixture led to epoxycyclopentano-isoxazoline 193, which was then converted to the aldol product in the usual manner. The hydrogenation proceeded well only when rhodium on alumina was used as the catalyst, giving the required p-hydroxyketone 194. This... 

An intramolecular cycloaddition of the tetradecatrienyl nitroethyl ether 263 was used in the synthesis of the 14-membered bicyclic precursor 265 of crassin acetate 266, a cembrane lactone possessing antibiotic and antineoplastic activity (332). Nitro compound 263 was obtained from farnesyl acetate (262) in several steps and was then treated with phenyl isocyanate and triethylamine to give the tricyclic isoxazoline 264 (Scheme 6.98). Conversion to ketone 265 was accomplished by hydrogenation of the cycloadduct with Raney Ni and boric acid followed by acetylation (332). In this case, the isoxazoline derived from a 3-butenyl nitroethyl ether moiety served to produce a 3-methylenetetrahydropyran moiety (332). 

In the great major tiy of applications that use the intramolecular nitrile oxide-alkene cycloaddition, the intention is to prepare intermediates for the synthesis of natural products or related compounds. The most popular transformations of these isoxazolines are the following ring cleavage modes ... 

The sesquiterpene skeleton has also been assembled by the intramolecular nitrile oxide cycloaddition sequence. Oxime 238 (obtained from epoxy silyl ether 237), on treatment with sodium hypochlorite gave isoxazoline 239, which was sequentially hydrolyzed and then subjected to the reductive hydrolysis conditions-cyclization sequence to give the furan derivative 240 (330) (Scheme 6.93). In three additional steps, compound 240 was converted to 241. This structure contains the C11-C21 segment of the furanoterpene ent-242, that could be obtained after several more steps (330). 

One of the very first uses of the intramolecular nitrile oxide cycloaddition involved the synthesis of macrocyclic lactones. Asaoka et al. (238) conceived this approach to the 16-membered ring antibiotic A26771B (277). Nitro compound 274 [obtained from 11-acetoxydodecanal (273)] was dehydrated with 4-chlorophenyl isocyanate-triethylamine and this was followed by dipolar cycloaddition, which gave isoxazoline 275 as a 4 1 mixture of diastereomers (Scheme 6.100). 

Scheme 10.7 gives some other examples of 1,3-DPCA reactions. Entries 1 to 3 are typical intermolecular 1,3-DPCA. The 1,3-dipoles in each instance are isolatable compounds. Entries 4 and 5 are intramolecular nitrone cycloadditions. The product from Entry 5 was used in the synthesis of the alkaloid pseudotropine. The proper stereochemical orientation of the hydroxyl group is ensured by the structure of the isoxazoline from which it is formed. 

Intramolecular 1,3-dipolar cycloaddition has been employed for the synthesis of various natural products as well. For instance, Mateos et al. reported a diastereoselective synthesis of the model insect antifeedant 281 related to 12-hydroxyazadiradione utihzing the intramolecular nitrile oxide cycloaddition (Scheme 65) [167]. The nitro compound 279 was synthesized from a-cyclocitral 278 in four steps. The cleavage of isoxazoline 280 was performed under three different conditions Raney Ni-mediated cleavage in methanol-water-acetic acid provided the epimeric ketoalcohol 282 in 5 3 ratio. While there was 100% selectivity in favor of the axial alcohol 282a in the presence of Pd/C and boric acid, the selectivity was in favor of the equatorial alcohol 282b when boric acid was replaced by acetic acid. 

Kinetic profiles of several base-catalyzed cycloaddition—condensation reactions of activated primary nitro compounds with dipolarophiles to isoxa-zolines (Machetti-De Sarlo reaction) were studied in both H2O and CHCI3 (13CEJ665). The copper-catalyzed intramolecular version of the same reaction was applied to the synthesis of tricyclic isoxazoline 39 starting from nitro derivative 38. Nucleophilic fragmentation of 39 afrbrded clean 40 that is a key intermediate for the synthesis of racemic tetrodotoxin (13JOC11901). 

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