Nucleosides, nitrone 1,3-dipolar cycloadditions

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... 

Isoxazole (as well as isoxazoline, and isoxazolidine) analogues of C-nucleosides related to pseudouridines 25 and 27 have been regioselectively synthesized by 1,3-dipolar cycloaddition (1,3-DC) of nitrile oxides (and nitrones) derived from uracyl-5-carbaldehyde 24 and 2,4-dimethoxypyrimidine-5-carbaldehyde 26 respectively <06T1494>. 

The reaction of 1,3-dipolar cycloaddition of enantiopure cyclic nitrones to protected allyl alcohol, is the basis of stereoselective syntheses of bicyclic N, O-iso-homonucleoside analogs (747), of isoxazolidine, to analogs of C-nucleosides related to pseudouridine (748) and to homocarbocyclic-2 -oxo-3 -azanucleosides (749) (Fig. 2.36). 

Dipolar cycloadditions of nitrones with vinyl acetate leads to 5-acetoxy-isoxazolidines, which can be easily transformed to isoxazolidinyl nucleosides by the Vorbriieggen methodology (803). 

Isoxazolidinyl nucleosides were also obtained through a less direct approach based on 1,3-dipolar cycloaddition of nitrones with vinyl acetate, followed by coupling of the isoxazolidin-5-yl acetates with silylated nucleobases (Vorbruggen nucleosidation) (Scheme 145, method B) <2003TA2717>. In the synthesis of 589, the first approach (method A) was more stereoselective whereas method B gave better yields. 

Abstract This review is devoted to the stereoselectivity of intermolecular (intramolecular cycloadditions are not included) 1,3-dipolar cycloadditions of sugar-derived nitrones. Stereoselective cycloaddition (transformation of isoxazolidine followed by reduction of the N O bond to produce both an amino and a hydroxy function) allows the synthesis of tailor-made products of possible biological interest such as pol>4iydroxylated pyrrolidines, pyrrolizidines, indolizidines, fi-aminocarbonyl compounds, and disaccharides. Attention is focused on the preparation of isoxazolidinyl nucleosides and to the catalysis of the cycloaddition by Lewis acids. This review has concentrated on the new developments achieved from 1999 to February 2007. 

With the goal of comparing the alternative synthesis of isoxazoHdinyl nucleosides, a two-step methodology based on the Vorbriiggen nucleosida-tion of the 5-substituted acetoxyisoxazolidines has also been studied [42] (also, H osova et al. unpublished results). The 1,3-dipolar cycloaddition of nitrones 86 and 87 with vinyl acetate leads to the 5-acetoxysubstituted isoxazoUdines as a mixtmre of diastereoisomers 93a-d and 94a-c, respectively (Fig. 21). In contrast to the cycloadditions with vinylated nudeobases. 

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