Bicyclic isoxazolidines

Asymmetric 1,3-dipolar cycloaddition of cyclic nitrones to crotonic acid derivatives bearing chiral auxiliaries in the presence of zinc iodide gives bicyclic isoxazolidines with high stereoselectivity (Eq. 8.51). The products are good precursors of (3-amino acids such as (+)sedridine.73 Many papers concerning 1,3-dipolar cycloaddition of nitrones to chiral alkenes have been reported, and they are well documented (see Ref. 63). 

The impulse to the study of these cycloadditions came from the discovery that 5-spirocyclopropane isoxazolidines (or isoxazolines) undergo a thermal rearrangement resulting in the production of selectively substituted tetrahydro-(or dihydro) pyrid-4-ones (Scheme 42) [64], In particular, cyclic nitrones gave ultimately N-bridgehead bicyclic ketones, molecular skeleton of many alkaloid families [65]. 

Oxidative ring opening of isoxazolidines leads to nitrones. Thus, bicyclic isox-azolidines (50) and (51), treated with m-CPBA, afford nitrones (52), (53), (54), and (55) (Scheme 2.19). Conformational analysis has confirmed the key role of the nitrogen lone pair with respect to regioselectivity of the reaction and of the intramolecular kinetic deprotonation of the intermediate oxoammonium derivative (125). 

The reaction of 1,3-dipolar cycloaddition of enantiopure cyclic nitrones to protected allyl alcohol, is the basis of stereoselective syntheses of bicyclic N, O-iso-homonucleoside analogs (747), of isoxazolidine, to analogs of C-nucleosides related to pseudouridine (748) and to homocarbocyclic-2 -oxo-3 -azanucleosides (749) (Fig. 2.36). 

Cycloadditions of pyrroline-derived nitrones (525) to 3-buten-l-ol (526) afford bicyclic isoxazolidines (527) which were transformed into indolizidines (528) (Scheme 2.249) (82, 111, 116, 750). 

These studies were carried out for hve-membered monocyclic TV-alkoxy-(406-408) and /V-siloxyisoxazolidines (178) (A), for iV-siloxytetrahydro-4// -oxazines (274), and bicyclic fused derivatives containing the isoxazolidine ring (B) (99, 157, 337). 

The intramolecular dipolar cycloaddition of a nitrone with an unactivated allene was also studied [76], Treatment of 5,6-heptadien-2-one with N-methylhydroxyl-amine in refluxing ethanol yielded allenyl nitrone 78, which cyclized with the terminal allenic C=C bond to give an unsaturated bicyclic isoxazolidine. On the other hand, the site selectivity decreased with an allenic ketone having a trimethylene tether. 

This work has since been extended to cyclobutyl isoxazolidine adducts (e.g., 86) from the cycloaddition of 87 to methylenecyclopropane (88) (Scheme 1.18) (124— 127). Thermolysis afforded a mixture of products, of which the bicyclic azepinone (89) predominated. Spirocyclic adducts were also prepared from an intramolecular reaction in the synthesis of cyclic amines (Scheme 1.72, Section 1.11.3). 

There have been simultaneous reports of the intramolecular cycloaddition of alkenyl nitrones bearing alkenylsulfide (202,203) or alkenylsulfone substitutents (Scheme 1.40) (203). In both cases, the isolated products were the corresponding fused bicyclic isoxazolidine adducts 178 and 179, respectively. 

Saito et al. (351a) reported the previously unprecedented formation of a 4,5-fused bicyclic isoxazolidine by an intramolecular cycloaddition reaction (Scheme 1.68). 

Cyclopentyl isoxazolidine cycloadduct 324 was prepared by intramolecular nitrone cycloaddition by Baldwin et al. (280,281,352,353) as part of studies toward a total synthesis of pretazettine (Scheme 1.69). Related adducts have been prepared elsewhere (354—356) including fluorine-substituted carbocycles (357) and the adducts prepared by lOAC by Shipman and co-workers (333,334) who demonstrated their potential as a route to aminocyclopentitols (Scheme 1.66, Section 1.11.2). Such bicyclic structures have been prepared in rather unique intermolecular fashion by Chandrasekhar and co-workers (357a) from the cycloaddition of C,N-diphenyl nitrone to fulvene (325). 

The intermolecular cycloaddition route to spirocyclopropyl isoxazolidines and their subsequent rearrangement, used so widely by Brandi and co-workers (372-375) (Schemes 1.16 and 1.17, Section 1.5), has also been achieved in an intramolecular sense (Scheme 1.72). Cycloaddition of the alkenyl nitrone reagents (333a-c) afforded bicyclic isoxazolidinyl adducts 334, which rearranged under thermolysis in analogous fashion to the earlier work to give piperidinones (335) via... 

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). 

The intramolecular cycloaddition of a silyl nitronate bearing a dipolarophilic appendage provides easy access to fused, bicyclic isoxazolidines (22). This process, in general, is very facile, and has allowed the use of unfunctionalized alkenes as dipolarophiles (Table 2.39) (106,124). Thus, a silyl nitronate bearing an allyl group will undergo the [3 + 2] cycloaddition at room temperature over 15 h to provide the corresponding isoxazoline upon acidic workup in moderate yield. 

Interestingly, furoxanes (274) have also been shown to be competent dipoles for the [3 + 2] cycloaddition. These compounds result from a dimerization of the corresponding nitrile oxide (Eq. 2.26) (237-241). Under elevated temperatures, the addition of a dipolarophile results in the cycloadduct 275. This intermediate is unstable under the reaction conditions and undergoes a retro-[3 + 2] cycloaddition to reveal a nitronate. In the presence of excess dipolarophile, the reaction proceeds to provide bicyclic isoxazolidines in moderate yield. 

A further rearrangement route to bicyclic aminoketones has been investigated by Padwa et al. (128-134) (Scheme 1.19). Building on the allene-nitrone cycloadditions reported by Tufariello, the alkenyl isoxazolidine adducts 90 and 91 were... 

Intramolecular 1,3-dipolar additions of nitrones and nitrile oxides to carbohydrate alkene groups have met with success. Thus, treatment of the unsaturated heptose ether 68 (Scheme 17), which can be made following 1,3-dithianyl anion addition to C-l of 2,3,4-tri-0-benzyl-5,6-dideoxy-D-xy/o-hex-5-enose, with IV-methylhydroxylamine in refluxing methanol, affords the nitrone 69 that cyclizes to give the bicyclic isoxazolidine 70 (60% isolated) together with the epimer at the new asymmetric center carrying the methylene carbon atom (16% isolated) [35]. 

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