Bicyclic isoxazolines

The photolysis of 3-( p-cyanophenyl)-2-isoxazoline in benzene produced a tricyclic product along with six other materials (Scheme 46) (B-79MI41616). Irradiation of the bicyclic 2-isoxazoline (155) produced benzonitrile, /3-cyanonaphthalene and polymer via a proposed biradical intermediate (156) (Scheme 47) (B-79MI41615). 

The reaction of benzonitrile oxide with the bicyclic isoxazoline (451) produced the three fused diisoxazoles shown in Scheme 105 (77JCS(Pi)2222). 

Scheme 17). A priori, both bicyclic isoxazoline epi-mers could be utilized in this synthesis because the newly formed stereocenter is eventually destroyed. Nevertheless, the two isoxazoline diastereomers were separated, and the subsequent stages of the synthesis were defined using the major isomer 30. 

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]. 

Halide substituted isoxazolines 371a-f gave bicyclic dihydropyridones 374 after rearrangement. Methoxycarbonyl substituted isoxazolines 371g-k gave the lactams 375, whereas carbonyl substituted isoxazolines 373a-e gave pyrroles 376 (Scheme 51). 

Reactions with participation of the C=C bond are the most studied of INOCs. Normal products of such reactions are annulated isoxazolines. A synthesis of bicyclic isoxazolines via sequential Michael and intramolecular 1,3-dipolar additions (403) are mentioned as an example. Michael addition of 1-nitroalkadiene, R1R2C=CH(CH2) CH=CHN02 to allylic stannane R3R4C=C(R5)CH2SnR63... 

Spiro-isoxazoline 57 (Scheme 16) undergoes thermolytic rearrangement followed immediately by cyclization of the intermediate enaminone to bicyclic 58 (89J(P1)1253). Imine 59 when heated gives iminium salt 60, hence providing a new and efficient route to parent substance 2 (03T3099). 

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. 

Many aspects of intramolecular nitrile oxide cycloadditions are similar to those of the intermolecular ones. Due to the proximity of the reacting groups, however, there are also several items that differ significantly. While HOMO-LUMO interactions and steric effects direct the intermolecular nitrile oxide cycloaddition to 1-alkenes to produce 5-substituted isoxazolines, the intramolecular cases often show a different behavior. With most of them, regioselectivity is determined by geometric constraints and cycloadditions occur in the exo mode to furnish the annulated bicycle (Scheme 6.42). 

Uses of Nitrile Oxide Cycloadditions in the Isoxazoline Route Toward Mono- and Bicyclic Imino Acids and Imino Polyols... 

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... 

In a similar approach, Shishido et al. (241) used oxime 215 [derived from the monoterpene (+)-citronellal (214)] for the synthesis of (—)-mintlactone (218) and (+)-isomintlactone (219), sweet compounds isolated from some Mentha species (Scheme 6.89). Bicyclic isoxazoline 216 was obtained in good yield from the cycloaddition. As expected, the product possessing tra i-l,4-substimtion prevailed. Reductive hydrolysis of the major isomer of 216 using hydrogen-Raney Ni-trimethyl borate provided p-hydroxyketone 217. This compound was dehydrated to give an enone and this was followed by carbonyl reduction-lactonization to complete the synthesis of both lactones 218 and 219 (241). 

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). 

Photolysis of the bicyclic isoxazoline 31 is believed to involve the intermediacy of the (Z)-azirine 33 (R1 = R2 = R3 = R4 = H), which subsequently ring-opens to the corresponding nitrile ylide 34.1,7-Electrocycliza-tion of the nitrile ylide 34 onto the enone system then leads to the 1,3-oxazepine 35 (Scheme 13) [73TL1835 74JCS(CC)373], Thermolysis of the closely related (Z)-azirines 33 (R1 = R3 = R4 = Ph), generated... 

Cyclizations of the nitrile oxide derived from nitroalkene (71) also led to bicyclic isoxazoline (72) as one stereoisomer, presumably through a transition state that minimized A1 -strain (Scheme 20).3S Re-... 

Cyclization of nitrile oxides with a four-atom intervening chain to the alkene always leads to 5,6-fused bicylic isoxazolines possessing a bridgehead C—N double bond. This is in contrast to nitrone cycliza-tions where competition to form bridged bicyclic isoxazolidines is observed. The alkenyl oximes (73) and (74) cyclize in typical fashion via nitrile oxide intermediates (Scheme 21).33a>36 The stereochemistry of cyclization here was studied both experimentally and by calculation. The higher stereoselectivity observed with the (Z)-alkene is typical. (Z)-Alkenes cycloadd much slower than ( >alkenes in intermole-cular reactions this is attributed to greater crowding in the transition state. Thus, intramolecular cycloaddition of (Z)-alkenes depends on a transition state that is heavily controlled by steric factors. 

Macro carbocyclic rings can be constructed by cyclization of nitrile oxides derived from oj-nitro-l-al-kenes (Scheme 22). If the intervening bridge is not longer than seven atoms, only fused bicyclic products are obtained. Thus, the nitrile oxide derived from nitro compound (75a) is cyclized in 44% yield to the 5,9-fused bicyclic isoxazoline (76a).38 10-Nitro-l-decene (75b) also cyclized to (76b) in unspecified yield.39 It should be noted that these results go counter to the usual regiochemistry of an intermolecular nitrile oxide cycloaddition where the five-substituted isoxazoline is usually,27 although not always,40 heavily preferred from reaction of a terminal alkene. Thus, geometric constraints have won out over the normal electronic control. 

---