Isoxazolidines nucleosides

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... 

The reaction of silyl ketene acetal addition to nitrones has been used for the synthesis of optically active (2S,3S)-benzoyl- and /V- oc-phenyl isoserine (636a) of isoxazolidine nucleoside-analog of thymine polyoxine C(636b) and of... 

Chiacchio et al. (2007) have also demonstrated the synthesis of methylene-isoxazolidine nucleoside analogs by microwave-assisted nitrone cycloaddition. The insertion of a methylene isoxazolidine spacer unit between the nucleobase and the hydroxyl-methyl group in the N, O nucleoside analogs could control the conformational mobility of the system. The cycloaddition between a proper N-methylated nitrone and a suitably functionahzed allene, (often thymallene) in CCl or EtOH at 70°C for 10 min generated the methylene-isoxazolidine nucleoside ankogs with good yields (45-72%) and purity. The reaction rate was enhanced, when the reactions were ran under microwave irradiation, in comparison to conventional reaction conditions. 

Gotkowska et al. reported the synthesis of novel isoxazolidine analogues of homonucleosides (29 and 30). The facile synthesis and the potential biological activity of isoxazolidine nucleoside analogues may open a new window to optimise lead molecules in this series. 

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 O-methyl-O-tert-butyldimethylsilyl ketene acetal with N-benzyl- and A-methyl-2,3-O-Mopropylidene D-glyceraldehyde nitrones (292), in the presence of boron trifluoride etherate, affords the corresponding isoxazolidine-5-ones in high yields. These compounds were successfully applied as key intermediates in the synthesis of isoxazolidinyl nucleosides of the L-series (Scheme 2.177) (638). 

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). 

Among a number of other homochiral furanosyl- and isoxazolidinylthymine targets, these workers also applied an achiral cycloaddition approach with vinyl acetate to successfully prepare the antiviral agent d4T (11) and its 2-methyl analogue (Fig. 1.1) (45). In more recent work, similar nitrones [9, R = Me or benzyl (Bn)] were used to prepare hydroxymethyl substituted isoxazolidines [3-(46) and 3,5-substituted (47)] for the preparation of further nucleoside analogues. 

A variety of N- and C-nucleoside derivatives in which the sugar unit has been replaced by a functionalised isoxazolidine have been synthesized. The synthetic approaches to different classes of nucleoside analogues such as 115 were all based on 1,3-DC of nitrones <03TA2717, 03TA2419, 03T4733, 03T5231, 03JMC3696>. 

The nucleoside analogues, l-(isoxazolidin-5yl)thymine and -uracil, were characterized by fast atom bombardment tandem mass spectrometry (EAB-MS/MS), and their spectra compared to those of dideoxyribose nucleosides and 5-phenyl- and 5-naphthylisoxazolidine <2001JMP1220>. 

Similarly, isoxazolidinyl nucleosides were prepared by Lewis acid-catalyzed coupling of isoxazolidin-5-yl acetate derivatives with nucleoside bases (see Section 4.03.11). 

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. 

Addition of hydroxylamines on the double bond of the unsaturated aldonic acid lactones 497 gave the isoxazolidin-3-yl acyclo C-nucleosides 499 (92T10363) (Scheme 127). 

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. 

The fused isoxazolidine 108 was made by regioselective and diastereoselective [3+2] cycloaddition, and has been converted to the nucleosides 109. ... 

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