Isoxazolines dienes

Likewise, addition of enol silyl ethers such as 980 to the intermediate 977 a furnish the 5-trimethylsilylmethylisoxazolidine 981 in 61% yield and 15% isoxazoline 982 [73, 74] whereas addition of 2-trimethylsilyloxyfuran 827 to 977 a affords, via the intermediates 983, on work-up with CF3CO2H, 96% yield of a mixture of lactones 984 and 985 [75] (Scheme 7.23). More recently it has also been reported that Danishefsky (trimethylsilyloxy)dienes add to intermediates such as 977 to give the corresponding products [76]. 

The diolefin 1064 gives rise to the isoxazoline 1065, which cannot eliminate tri-methylsilanol 4 [122]. Cychzation of the co-nitroolefin 1066 with trimethylchloro-silane (TCS) 14/triethylamine at -35 °C then HCl-induced removal of trimethyl-silanol 4 leads, in 85% yield, to the dimer 1067, which is converted in two more steps into racemic pyrenophorin 1068 [112] (Scheme 7.39). Further cyclizations of co-nitroolefins [109] to monomeric or dimeric isoxazolines have been described. Conjugated dienes such as butadiene afford a mixture of the mono or bis adducts [115-117]. 

Intramolecular 1,3-dipolar cycloaddition of cyclo-1,3-diene- and -1,3,5-triene-tethered nitrile oxides give tricyclic isoxazolines, for example, 353, as a single stereoisomer. 

A variety of cyclic ethers, 410, have been obtained via both, solution-phase and polymer-supported methods in the [3 + 2] cycloadditions of nitrile oxides to alkenes and dienes to give isoxazolines (Scheme 1.50). Both simple and substituted dienes have been found suitable for polymer-supported formation of cyclic ethers of ring sizes five through seven (449). 

Diastereoselective intermolecular nitrile oxide—olefin cycloaddition has been used in an enantioselective synthesis of the C(7)-C(24) segment 433 of the 24-membered natural lactone, macrolactin A 434 (471, 472). Two (carbonyl)iron moieties are instrumental for the stereoselective preparation of the C(8)-C(ii) E,Z-diene and the C(i5) and C(24) sp3 stereocenters. Also it is important to note that the (carbonyl)iron complexation serves to protect the C(8)-C(ii) and C(i6)-C(i9) diene groups during the reductive hydrolysis of an isoxazoline ring. 

With an ot, y-ketodiol, cyclization to produce a 3-furanone derivative is feasible, as is shown for the synthesis of ascofuranone (71) and geiparvarin (72) (Scheme 6.57) (286). The precursor for 71 was prepared by the cycloaddition of diene 66 to nitroalcohol 67. In this case, regioselective attack occurred only on the terminal double bond. Reductive cleavage-hydrolysis of the isoxazoline adduct 68 with Mo(CO)6 followed by acid-induced cyclization led to the furanone intermediate (286). A similar strategy was used for the synthesis of geiparvarin (72) (Scheme 6.58) (286). 

Intramolecular cycloaddition of the nitrile oxide intermediate generated from the unsaturated oxime 221 was used for an evenmal synthesis of la,2p,25-trihydroxy-vitamin D3 (262) (Scheme 6.90). Oxime 221, prepared from tri-O-isopropyhdene-d-mannitol (220), was processed as usual to give isoxazoline 222 in good yield and with excellent stereoselectivity. Conversion of 222 to the aldol 223 proceeded in the normal manner and further elaboration gave the desired diene intermediate 224 (262). 

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. 

Cheletropic reactions, dimethylgermylene to 1-azabuta-1,3-dienes. 57, 5 Chemotherapeutic agents isoxazolines. 60, 297 thiopyrylium salts, 60, 172 Chiral auxiliaries, in diastereoselective cycloadditions of nitrile oxides, 60, 286-94... 

The formation of pyrylium salts from methyl(ene) ketones and 1,3-diketones, e.g., of 2,4,6-triphenylpyrylium from acetophenone and dibenzoylmethane, has an interesting counterpart in several reactions of pyrylium salts. With nucleophiles like phenylhydrazine,353 hydroxylamine,353 or benzylmagnesium chloride,178-180 2,4,6-triphenylpyrylium forms unstable 2,4-dien-l-ones or 4 -pyrans, which rearrange easily to more stable pyrazolines, isoxazolines, or 2H-pyrans on treatment with strong acids, both types of product split off acetophenone, yielding 1,3,5-triphenylpyrazole, 3,5-diphenyl-isoxazole, and 1,3-diphenylnaphthalene, respectively. These same products can be obtained directly from the above nucleophiles and dibenzoylmethane.63,354-357 The condensation of methyl(ene) ketones with 1,3-diketones yielding pyrylium salts can, therefore, be considered reversible in a certain sense. 

Swem oxidation of isoxazolines 795 yields p-ketoesters 796 in moderate yields. By treatment with hydrazines, p-ketoesters 796 can be condensed to give the corresponding hydrazones 797, which concomitantly undergo elimination to give novel spiro-fused isoxazolinopyrazolones 798 (3,7,9-substituted-l-oxa-2,7,8-tri-azaspiro[4.4]nona-2,8-dien-6-one) in moderate to good yields (Scheme 4.231). ... 

A number of D,L-aminodeoxysugars were synthesised by reduction of 2-isoxazolines. The overall process required three steps involving addition of hydroxamic acid chlorides (generated from aldoximes, NCS and triethylamine using basic alumina or florisil as a solid-phase base) to dienes, followed by stereospecific hydroxy-... 

Cobalt(II)-bis((Z)-2-hydroxy-5,5-dimethyl-1 -(4-methylpiperazin-l -yl)hex-2-ene-1,4-dione) efficiently catalyses the aerobic oxidative 5-exo cyclization of )5,) -unsaturated oximes to give isoxazolines. Carbon-centred radicals are generated in the basic cyclization step. The predominant oxidative products of the reaction carried out in the presence of i-PrOH and TBHP are (16), whereas reductive products (17) are selectively obtained when the reaction is carried out in toluene in the presence of cyclohexa-1, 4-diene. " ... 

Traceless cleavage with a sulfone linker has also been utiUzed in the solid-phase synthesis of isoxazolines and isoxazoles. Nitrile oxides generated in situ reacted regioselectively to the solid-supported diene (Scheme 11.46). Subsequent formation of pyrroles released the cycloadducts from the resin in a traceless manner. 

---