Isoxazolidinyl nucleosides

Syntheses of isoxazolinyl and isoxazolidinyl nucleoside analogs 98T6587. 

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). 

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). 

In contrast to the installation of the nucleobase via nucleophilic substimtion of a suitable leaving group on the isoxazolidinyl cycloadduct, Colacino et al. (51) and Sindona and co-workers (52,53) prepared isoxazolidinyl nucleosides using vinyl nucleobases as the dipolarophile (Scheme 1.5). In Sindona s work, while a three-component reaction of hydroxylamine, formaldehyde, and 20 afforded a complex mixture of cycloadducts and byproducts, the known dipole 21 reacted with N-9-vinyladenine (20) in benzene at reflux to afford a racemic mixture of adduct 22 and its enantiomer (45%). The ester function was then used to effect a resolution by pig... 

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. 

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. 

Cycloaddition of W-methylnitrone to 2,3-dideoxy-6-0-Tbdps-D-erjrAro-pent-2-enono-1,4-lactone afforded derivative 17 as a useful intermediate for making [3.3.0]bicyclic isoxazolidinyl nucleosides. ... 

The thiazolidinyl analogue 202 of pseudouridine, and its enantiomer, have been made, with chirality originating in d- or L-cysteine, ° whilst thiazolidinones 203 (B=Cyt, Thy, 5-fluoro-Cyt) have been prepared, using Pummerer-type chemistry. 4 -Azathymidine derivatives such as 204 have been prepared by cycloadditions of nitrones with vinyl acetate, followed by base- sugar condensation, and the isoxazolidinyl nucleoside 205, and its trans-isomer, have been made as racemates. The N-in-ring analogue 206 of 3 -deoxythymidine has... 

---