3.4.5- Trisubstituted 2-isoxazolines

The use of silylketals derived from allylic alcohols and 1-substituted nitroethanols for the stereocontrolled synthesis of 3,4,5-trisubstituted 2-isoxazolines via intramolecular 1,3-dipolar cycloaddition has been demonstrated. Here again, the use of silyl nitronates (ISOC) increases the level of selectivity compared to INOC (Eq. 8.92).145... 

Breau and co-workers reported diastereoselective INOC and ISOC reactions of silaketals 205 derived from allyUc alcohols and nitroethanols for the synthesis of 3,4,5-trisubstituted 2-isoxazolines 206 (Scheme 50) [152,153]. 

Dipolar cycloadditions of ( -phenyl-/V-methylnitrone (585) to Baylis-Hillman adducts such as ( 3-hydroxy-a-methylene esters) (608-610) proceed with complete regioselectivity in good yields to afford the corresponding diastere-omeric 3,5,5-trisubstituted isoxazolines (611-613) (Scheme 2.269). Attack by the dipole in (585) from the less sterically hindered side of dipolarophiles (608-610) affords C-3/C-5 cis isoxazolidines (611a,b-613a,b) as the major products (780). 

In another variation, the intermediate aldol product 64, with an extra hydroxy group in the y-position, was used to construct the furan ring of rosefuran (65), a trace component of rose oil (Scheme 6.56) (285). Here, the reaction of the nitropentene derivative 61 with crotyl acetate (62) afforded the 3,4,5-trisubstituted isoxazoline (63) in moderate yield. Removal of the acetyl group by saponification of the cycloadduct, subsequent demasking of the aldol moiety using Mo(CO)6, and exposure of the ketodiol (64) to acid gave the target compound 65 (285). 

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. 

Nitrile oxide cycloaddition with mono- and trisubstituted alkenes affords almost exclusively 5-mono- and 4,5,5-trisubstituted isoxazolines, respectively, the regioselectivity being determined by steric effects. Reverse regioselectivity in nitrile oxide cycloaddition to terminal alkenes has been reported <1997CC1517> for example, 4-A t/-butylbenzoni-trile oxide was forced to reverse alignment for the cycloaddition by formation of the inclusion complex 470 with /3-cyclodextrin. Under these conditions, 90% of the 3,4-disubstituted cycloadducts were obtained, whereas in the absence of cyclodextrin the aromatic nitrile oxide afforded only the 5-substituted isoxazoline. 

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 same patent and publication (07W0106818,15JFC121) mentioned the preparation of 4-SF5-2,3,5-trisubstituted-4-isoxazolines 171a—d in case when nitrones 170a—c were used as 1,3-dipoles in cycloaddition reactions with SFs-alkynes 129a,c,d (Scheme 53). 

The formal 3 + 2-cycloadditions of nitrone ylides with c-poor alkenes yielded all-ax-5-aryl-2,3,5-trisubstituted Af-hydroxypyrrolidines in a stepwise process. The 3 + 2-cycloaddition of 77-aryl-5-methylenehydantoin (55) with benzonitrile oxide produced 5-spiro isoxazoline adducts (56) and (57) with complete regio-selectivity. Facial selectivity resulted from atroisomerism around the A -aryl bond (Scheme 17). ... 

Propargylic N-aUcylhydroxylamines 9 can be efficiently cyclized to the isomeric 2,3,5-trisubstituted 4-isoxazolines 10 in the presence of Znh and DMAP [335] ... 

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