Isoxazolines 5,9-fused bicyclic

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. 

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. 

The cu-dioxane (97) underwent cyclization to afford a single tricyclic isoxazoline in which the new 5,5-fused bicyclic system formed rapidly at 0 C (Scheme 27).45 The isomeric tranr-dioxane also gave a single tricyclic isoxazoline (96) as product but only at 20 C. The results were rationalized as follows cyclization of the nitrile oxide derived from (96) occurred with the vinyl group equatorial, while the cis isomer required an axial vinyl group in the transition state. The isoxazoline (96) was converted in several steps to a known PGF2a precursor. 

Other reactions. Microwave irradiation of 3-phenyl-2-isoxazolin-5-one (159) in the presence of KF on alumina, without any solvent, reacted with aromatic aldehydes (160) to afford 4-(arylmethylene) derivatives (161) (Equation (31)) <93SC16>. The fused bicyclic-isoxazoline (162) underwent a thermal retro-Diels-Alder reaction and resulted in a mixture of 3-phenyl isoxazole (163) and norborn-eneadduct (164) (Equation (32)) <90MRC1023>. 

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

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... 

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. 

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