A-Benzyl nitrone

Transformation of chiral nitrones into enantiomer enriched a-chiral N -hydroxylamines and their derivatives, has been successfully employed in the enantioselective synthesis of (+ )-(R)- and (—)-(S)-zileuton (216). An expeditious synthesis of thymine polyoxin C (347), based on the stereocontrolled addition of 2-lithiofuran (a masked carboxylate group) to the A-benzyl nitrone derived from methyl 2,3-O-isopropylidene-dialdo-D-ribofuranoside, is described (Scheme 2.151) (194). 

The stereoselectivity of these cycloaddition reactions is influenced by the steric hindrance of both, the IV- and C -substituent of the nitrone, that is, the selectivity increases as the nitrogen substituent of the nitrone becomes bulkier. As shown in Table 2.17, the highest diastereoselectivity in these reactions was observed with A-benzyl nitrones (479b) and (480). 

Bis(oxazolinyl)pyridine-Ce(IV) triflate complex 78 catalyzed the enantioselective 1,3-DC of acyclic nitrones with a,p-unsaturated 2-acyl imidazoles. For example, C-phenyl A -benzyl nitrone reacted with 77 in the presence of 78 to give the adduct 79 with excellent diastereo-and enantioselectivity. Isoxazolidine 79 was then converted into P -hydroxy-P-amino acid derivatives by hydrogenation of the N-0 bond in the presence of Pd(OH)2/C and cleavage of the 2-acyl imidazole with MeOTf in MeCN <06OL3351>. 

Various kinds of chiral acyclic nitrones have been devised, and they have been used extensively in 1,3-dipolar cycloaddition reactions, which are documented in recent reviews.63 Typical chiral acyclic nitrones that have been used in asymmetric cycloadditions are illustrated in Scheme 8.15. Several recent applications of these chiral nitrones to organic synthesis are presented here. For example, the addition of the sodium enolate of methyl acetate to IV-benzyl nitrone derived from D-glyceraldehyde affords the 3-substituted isoxazolin-5-one with a high syn selectivity. Further elaboration leads to the preparation of the isoxazolidine nucleoside analog in enantiomerically pure form (Eq. 8.52).78... 

Dipolar cycloaddition reactions between three A-benzyl-C-glycosyl nitrones and methyl acrylate afforded key intermediates for the synthesis of glyco-syl pyrrolidines. It was found that furanosyl nitrones (574) and (575) reacted with methyl acrylate to give mixtures of all possible 3,5-disubstituted isoxazolidines (577) and (578). On the other hand, the reaction with pyranosyl nitrone (576) was much more selective and cycloaddition at ambient temperatures afforded only one of the possible Re-endo adducts (579a). The obtained isoxazolidines were transformed into the corresponding (V-benzyl-3-hydroxy-2-pyrrolidinones (580—582) on treatment with Zn in acetic acid (Scheme 2.264) (773). 

Reaction of a disubstituted nitronate anion with an allylic or benzylic halide leads not to the expected C-alkylated nitro compound, but rather to the carbonyl product. Presumably this reaction, known by fte names of its discoverers, proceeds by the displacement of the halide ion by nitronate oxygen followed by loss of the oxime (equation 15). 

A -Benzyl-C-glycosyl nitrones reacted with acrylate to give glycosyl isoxazolidines which were easily converted to glycosyl pyrrolidines by reduction of the N-0 bond with Zn in acetic acid. The best result was obtained with pyranosyl nitrone 88 which quantitatively afforded the cycloadduct 89 with complete regio- and stereoselectivity <03TA3731>. 

The benzylic anion (175) generated from (174) reacted with N-a-diphenyl-nitrone (176) to give the phosphorate (177), characterized by P NMR, and subsequent protonolysis products. A similar reaction of the O-trans isomer of... 

A. Dondoni, S. Franco, F. Junquera, F. L. Merchan, P. Merino, and T. Tejero, Synthesis of V-benzyl nitrones, Synth. Common. 24 2537 (1994). 

In the Krohnke reaction a benzyl halide or a-haloketone is converted into the pyridinium salt, which reacts with p-nitrosodimethylaniline to give a nitrone this. 

The Stereoselectivity of 1,3-Dipolar Cycloadditions. The exo or endo stereochemistry of 1,3-dipolar cycloadditions is not as straightforward as it is for Diels-Alder reactions. Stereoselectivity, more often than not, is low, as shown by the nitrone reactions that we saw on p. 335 when we were looking only at regiochemistry. We now see that the major regioisomer 6.344 from the reaction of CVV-diphcnylnitronc with methyl acrylate is a mixture of exo and endo isomers, exo- and endo-6.344. Similarly, the only regioisomer 6.346 from the reaction of A-benzyl-C-ethylnitrone with methyl crotonate is a mixture of exo-6.346 and endo-6.346. In both cases, the reaction is a little in favour of the exo product.867... 

When the cycloadditions arc conducted with unsaturated esters a similar trend is observed63. The reaction of the TV-benzyl nitrone 5a with ( )-methyl 2-butenoate is poorly selective (d.r. 74 26), but with 5 b the same ester gives a 90 10 mixture of products in favor of the 3,4-trans-4,5-fraHi-cycloadduct63. 

A solution of 1.08 g (7.73 mmol) of ( )-rra s-6-ethyl-5,6-dihydro-5-melhyl-2//-pyran-2-one and 3.26 g (18.0 mmol) of A-benzyl-C-phenyl nitrone in 8 mL of toluene is refluxed for 33 h. Concentration under reduced pressure gives a residue which is chromatographed on silica gel using diethyl ether/light petroleum 1 1 as eluant. The higher R, isomer is 1,9-Irons, yield 37% and the lower Rf isomer is 1,9-cis yield 44% d.r. 54 46. 

A stirred solution of 0.451 g (1 mmol) of A-benzyl C-[l-(l-oxo-3-phenyl-3-phenylsulfonylpropoxy)ethyl] nitrone and 0.152 g (1 mmol) of l,8-diazabicyclo[5.4.0]undec-7-ene in 10 mL of CC14 is refluxed under argon for 15 h. The mixture is cooled, and the red oil formed is decanted from the solution. The solvent is evaporated and the residue is purified by flash chromatography yield 0.195 g (63%) mp 118-119 C. 

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