Isoxazoline-bridged

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. 

Confalone and Ko have reported formation of the macrocyclic INOC product (104) in 30% yield from cyclization of an aryl-bridged nitrotriene containing a 17-atom intervening bridge.48 Cyclization to the conjugated diene system did not occur, presumably because of geometric constraints and the fact that the more accessible double bond is trisubstituted. Isoxazoline (104) is a potential maytansine precursor. 

Allylic stannanes condense with nitro dienes in the presence of titanium tetrachloride to give alkenyl a-chlorooximes treatment of the a-chlorooximes with base then affords bicyclic isoxazolines.50 Thus, cyclization of the intermediates (107a-c), obtained from appropriate 1 -nitro- 1,5-hexadienes and (3-propenyl)trimethyltin, gave bicyclic isoxazolines (Scheme 31). Cyclization occurred exclusively on the double bond with the longer (three-atom vs. two-atom) intervening bridge, even when that double bond was trisubstituted. 

The 1,3-dipolar cycloaddition of exocyclic methylenes with nitrile oxides has already been addressed in section 2.13.10 This work, shown in Scheme 8.4.2, is notable in that high stereoselectivity in the resulting isoxazoline can be obtained. This is presumably the consequence of the bulk of the nitrile oxide directing approach to the a face of the sugar methylene. Through the use of these reactions, C-disaccharides, bridged by isoxazoline rings have been made accessible. 

Dawson, etal.,17 demonstrated the formation and conversion of bridging isoxazolines to p-hydroxy ketones. A particular example, shown in Scheme... 

Both nitrile oxide (eq 3) and silyl nitronate (eq 4) cycloadditions are highly diastereoselective processes. The use of either approach enables access to A -isoxazolines in good yield. Unfortunately, the corresponding nitrone cycloadditions are only slightly selective (dr = 78 22) The enantiomeric sultam was implemented effectively in azomethine ylide cycloadditions to gain access to bridged p)rrolidines with high levels of diastereos-election (eq 5). ... 

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