Nitrile isoxazoline moieties

An efficient synthetic route to (10Z)- and (10 )-19-lluoro-la,25-dihydroxy vitamin D3 has been developed (488). The key feature of this pathway is the introduction of a 19-fluoromethylene group to a (5 )-19-nor-10-oxo-vitamin D derivative. The 10-oxo compound 445 has been obtained via a 1,3-dipolar cycloaddition reaction of (5 )-la,25-dihydroxyvitamin D with in situ generated nitrile oxide, followed by ring cleavage of the formed isoxazoline moiety with molybdenum hexacarbonyl. Conversion of the keto group of (5 )-19-nor-10-oxo-vitamin D to the E and Z fluoromethylene group has been achieved via a two-step sequence, involving a reaction of lithiofluoromethyl phenyl sulfone, followed by the reductive de-sulfonylation of the u-lluoro-j3-hydroxysulfone. The dye-sensitized photoisomerization of the (5 )-19-fluorovitamin D affords the desired (5Z)-19-fluorovitamin D derivatives, (10Z)- and (10 )-19-fluoro-la,25-dihydroxy-vitamin D3. 

The cycloaddition of a nitrile oxide with a chiral allylic ether affords an isoxazoline with selectivity for the pre/-isomer. This selectivity increases with the size of the alkyl substituent and is insensitive to the size of the allyl oxygen substituent. However, allyl alcohols tend to form the / ar/ isomcr preferentially, although the selectivity is often low.427"434 The product of dipolar cycloadditions based on nitrile oxides, the isoxazoline moiety, can be converted into a large variety of functional groups under relatively mild conditions.3 Among other products, the addition can be used to prepare P-hydroxy ketones (Scheme 26.17).435 The isoxazoline moiety can be used to control the relative stereochemistry through chelation control.436,437... 

Macrocycles containing isoxazoline or isoxazole ring systems, potential receptors in host—guest chemistry, have been prepared by multiple (double, triple or quadruple) 1,3-dipolar cycloadditions of nitrile oxides, (prepared in situ from hydroxamoyl chlorides) to bifunctional calixarenes, ethylene glycols, or silanes containing unsaturated ester or alkene moieties (453). This one-pot synthetic method has been readily extended to the preparation of different types of macrocycles such as cyclophanes, bis-calix[4]arenes and sila-macrocycles. The ring size of macrocycles can be controlled by appropriate choices of the nitrile oxide precursors and the bifunctional dipolarophiles. Multiple cycloadditive macrocy-clization is a potentially useful method for the synthesis of macrocycles. 

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. 

Electroactive 3-(N-phenylpyrazolyl)fullereno[l,2-r/]isoxazolines have been synthesized by using 1,3-dipolar cycloaddition of pyrazole nitrile oxides, generated in situ, to Cgo at elevated temperature or microwave irradiation. The cyclic voltammetry measurements show a strong donor pyrazole ring, and a better acceptor ability of the fullerene moiety than the parent C60 (538). Treating fullerene Cgo with mesitonitrile oxide in toluene gives fullerene-nitrile oxide adduct, which is supposed to be useful for electrical and optical components (539). 

Talaromycin B is a spiro-acetal produced by the fungus Talaromyces stipitatus, the toxicity of which may be due to its ability to block outward potassium fluxes. In an elegant synthesis, the requisite open-chain polyol with hydroxy groups in the y-and y -positions was assembled from nitrile oxide and olefin building blocks 50 and 51, both of which carry a f>w(hydroxyethyl) moiety protected as a cyclohexanone acetal (284). Hydrogenolysis of the N O bond of isoxazoline 52 using Raney nickel, followed by treatment with aqueous acid, gave the spiroketal 53, which was further transformed into racemic talaromycin B (54) (Scheme 6.54) (284). 

The direct cycloaddition adduct was oxidized, resulting in the hydroxylated isoxazoline product (316). Better selectivities were obtained in 1,3-dipolar cycloadditions of 204 with nitrile oxides (317,318). The 1,3-dipolar cycloadditions proceeded with concomitant loss of the boron group to give the isoxazoline products in up to 74% ee (318). The alkene 204 was also tested in reactions with nitrones. The reactions proceeded with poor yields, but high selectivities were observed in two cases (318). Gilbertson et al. (319) investigated the use of chiral ot,p-unsaturated hexacarbonyldiiron acyl complexes 205 as dipolarophiles in reactions with nitrones. Selectivities of up to >92% de were observed. The iron moiety was removed oxidatively after the cycloaddition and the thioester was hydrolyzed. 

Triptycene cyclopentenedione 47 underwent 1,3-DC with nitrile oxides affording polycyclic isoxazolines 48 bearing the triptycene moiety. The adducts 48 exist in solution in their two enolic forms 49 and 50, in equimolecular amounts <02JOC4612>. 

An intramolecular double nitrile oxide cycloaddition with alkyne and olefin moieties was exploited in the synthesis of novel unsymmetrical hybrid spiro (isoxazole-isoxazoline) ligands 14 which were effective in promoting a Pd-catalyzed tandem cyclization <07TA919>. 

Isoxazolines 54, prepared by stereoselective 1,3-DC of nitrile oxides and enantiopure allylic alcohols, were converted into p-amino acids 56 eind 58 by nucleophilic addition to the C=N bond followed by reductive cleavage of the N-0 bond and oxidative cleavage of the diol moiety. The facial selectivity in the nucleophilic addition was dictated by the C-5 substituent in either a directed (hydride addition) or a sterically (Grignard reagents addition) controlled manner <03JA6846>. 

Other cascade sequences have also been observed to occur from the thermolysis of isoxazolines, thereby increasing the utility of the nitrile oxide cycloaddition reaction. For example, in the context of synthesizing testosterone derivatives, Guarna and coworkers reported that the reaction of a nitrile oxide derived from oxime 89 with 76 gave isoxazoline 90 (Scheme 15) (91TL6395). Hydrolysis of the ketal moiety provided cycloadduct 91, which was heated at reflux in DMF to furnish 92 in 30% yield. 

Isoxazole-isoxazoline polyheterocyclic systems have been synthesized for applications as ionophores using resin boimd alkenes/alkynes as dipo-larophiles. For instance, the isoxazole possessing an alkene moiety 41 was reacted with a nitrile oxide, generated from nitroalkane 13d imder Mukaiyama conditions, to afford isoxazoline 42 in high yield (Scheme 12) [ 104]. 

As part of their solid- and solution-phase synthesis of novel hydantoin-isoxazoline containing hetero cycles, Kurth and co-workers reacted solid supported urea intermediates 48, possessing an alkene moiety with nitrile oxides derived from nitroalkanes 13a and 13d to afford isoxazolines 49 as a 1 1 mixture of diastereomers (Scheme 15) [109]. The urea fimctionality in 49 was then cyclized to obtain hydantoin 50. 

This result prompted us to first apply the strategy to the asymmetric 1,3-dipolar cycloaddition of nitrile oxides, which had not been developed when our research project started. The idea was presented as follows when nitrile oxide is generated in situ from hydroximoyl chloride by treatment with ethylzinc moiety as abase, the stereochemical course of nitrile oxide coordinated to the chiral zinc species 5 was anticipated to be controlled efficiently. In accordance with this hypothesis, the asymmetric 1,3-dipolar cycloaddition of nitrile oxides to allylic alcohols was realized to afford the corresponding 2-isoxazolines 6 with excellent enantioselectivity (Eq. 11.3). Even when a catalytic amount (0.2 equiv) of diisopropyl (R,/f)-tartrate [(R,/ )-DlPT] was employed, the 2-isoxazolines 6 were obtained with the selectivity of up to 93% ee by the addition of a small amount of 1,4-dioxane (Eq. 11.4). This method was the first catalytic enantioselec-tive 1,3-dipolar cycloaddition of nitrile oxides with alkenes. The method was efficiently applied to the total synthesis of (—)-Lasubine 11 (Scheme 11.2) [11]. 

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