Isoxazolidines bridged

Many intramolecular nitrone cycloadditions have been carried out on substrates containing a cyclic intervening bridge. Perhaps the simplest possibility here is an o-disubstituted aromatic substrate, as, for example, the nitrone derived from aldehyde (42), which cyclizes to the 5,6-fused isoxazolidine (43 Scheme 10).19 There are many additional possibilities the nitrones derived from biphenyl aldehyde... 

Cyclic nitrone (52) has a cyclic bridge and cyclic enol ether dipolarophile thus all three elements are present in rings (Scheme 13).24 Models show that direct cyclization of (52) is not possible because of the relative positions of the dipole and dipolarophile. However, a pentacyclic cage isoxazolidine was formed by heating (52) presumably epimerization at the phenyl-bearing bridgehead carbon preceded cycloaddition. 

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. 

When 3,4-disubstituted /3-lactam 457 was treated with methylhydroxylamine hydrochloride in the presence of sodium carbonate in methanol, a quantitative yield of an isomeric mixture of fused adduct 458 and bridged isoxazolidine 459 in a 15 1 ratio, respectively, was obtained (Equation 72) via a nitrone intermediate <1999TL5391>. 

The intramolecular nitrone-alkene cycloaddition (INAC) of hept-6-enoses 110 can proceed either via the exo-mode to give fused isoxazolidines 111 or the endo-mode to give the bridged 1,2-oxazocines 112 (Scheme 23). 

Intramolecular nitrone-alkene cycloaddition. Reaction of cycloalkanones substituted by a 3-(2-propenyl) or a 3-(3-butenyl) side chain with alkylhydroxylamines with azeotropic removal of water results in a bridged bicycloalkane fused to an isoxazolidine ring. The transformation involves formation of a nitrone that undergoes intramolecular cycloaddition with the unsaturated side chain. 

The reaction of 3-methyl-6-heptenal with jV-methylhydroxylamine is more complex it gives two cis-isomers (38c and 38d), one trans isomer (39c), and one bridged isoxazolidine (40b), in a 19.4 15.4 60.1 5.0 ratio.134... 

When heated, some isoxazolidines isomerize to the more stable isomers. 5-Ethoxycarbonylisoxazolidine obtained from the nitrone 18a and ethyl acrylate gives the more stable 4-substituted isomer.96 An extensive study of the thermal isomerization of fused isoxazolidines was carried out by LeBel et a/..139,141,184 Thus, the trans-fused isoxazolidine 39b isomerizes into a mixture of two cis-fused isomers, 38b and 38f. Starting from one of the last two compounds, the same equilibrium mixture is obtained.139,184 Thermal equilibration of frans-isoxazolidine (39d)139 with the cis-fused isomer (38c) is also described, and the isomerization of the bridged isoxazolidine (40a) to the fused isoxazolidine (38a).139,184 The time required for attaining equilibrium depends on the temperature. At 180° the trans-isomer 39c disappears after about 200 hours at 200° and 235°, it takes only 2 hours and 45 minutes, respectively. In almost all cases the cis-fused isomer is more stable and predominates in the mixture. 

Tethering the alkene to the carbon atom of the nitrone allows the preparation of cw-l,2-disubstituted cycloalkanes such as 212. Examples in which the alkene is tethered to the nitrogen atom of the nitrone are also common. Thus, addition of formaldehyde to the hydroxylamine 213 promoted formation of the intermediate nitrone and hence the cycloadduct 214 (3.140). " Subsequent transformations led to the alkaloid luciduline. This synthesis illustrates a useful feature of the 1,3-dipolar cycloaddition reaction of nitrones, in that it provides an alternative to the Mannich reaction as a route to (3-amino-ketones, via reductive cleavage of the N-0 bond in the isoxazolidine and oxidation of the 1,3-amino-alcohol product. In another example of such an intramolecular cycloaddition reaction, the bridged bicyclic product 217, used in a synthesis of indolizidine 209B, was formed by addition of an aldehyde to the hydroxylamine 215, followed by heating the intermediate nitrone 216 (3.141).142... 

Nitrone cycloaddition chemistry continues to dominate the literature on the synthesis of isoxazolidines. More attention is now being paid to the stereochemical outcome of the reaction of both the intra- and inter-molecular varieties of the reaction. For example the preference for fused or bridged products from the intramolecular reaction of nitrones (II6) depends on the substitution... 

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