Diastereoselective synthesis of a collection of new homonucleoside mimetics containing pyrrolo[1,2-b]isoxazoline and pyrrolidine rings

The 1,3-dipolar cycloaddition of enantiopure cyclic hydroxylated nitrones and allyl nucleobases has been exploited for the preparation of a novel class of homonucleoside mimetics, where the furanose ring is replaced by a pyrrolo[1,2-b]isoxazolidine system. The nitrones were easily prepared starting from l-malic and l-tartaric acids and gave cycloadducts in a diastereoselective manner, which were deprotected to give good yields of the homo-N,O-nucleoside mimetics. The reduction of the isoxazolidine ring, a 1,3-aminoalcohol equivalent, allows easy access to other new pyrrolidine nucleoside mimetics.

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1-{[(2S,3aS,4S,5S)-4,5-Dihydroxyhexahydropyrrolo[1,2-b]isoxazol-2-yl]methyl}-5-methylpyrimidine-2,4(1H,3H)-dioneC12H17N3O5[α]D25=+70 (c 0.5, DMSO)Source of chirality:l-tartaric acid

1-{[(2S,3aS,4S,5S)-4,5-Dihydroxyhexahydropyrrolo[1,2-b]isoxazol-2-yl]methyl}-5-fluoropyrimidine-2,4(1H,3H)-dioneC11H14FN3O5[α]D25=+42 (c 0.71, DMSO)Source of chirality:l-tartaric acid

1-{[(2R,3aR,4S)-4-Hydroxyhexahydropyrrolo[1,2-b]isoxazol-2-yl]methyl}-5-methylpyrimidine-2,4(1H,3H)-dioneC12H17N3O4[α]D25=-122 (c 0.635, CH3OH)Source of chirality:l-malic acid

1-{[(2R,3aR,4S)-4-Hydroxyhexahydropyrrolo[1,2-b]isoxazol-2-yl]methyl}-5-fluoropyrimidine-2,4(1H,3H)-dioneC11H14FN3O4[α]D25=-93 (c 1.36, CH3OH)Source of chirality:l-malic acid

(2R,3S)-3-Hydroxy-2-[(2R)-2-hydroxy-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl]pyrrolidinium trifluoroacetateC14H20F3N3O6[α]D25=-12 (c 0.565, CH3OH)Source of chirality:l-malic acid

(2R,3S)-3-Hydroxy-2-[(2R)-2-hydroxy-3-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl]pyrrolidinium trifluoroacetateC13H17F4N3O6[α]D25=+11 (c 2.595, CH3OH)Source of chirality: l-malic acid

(2S,3S,4S)-3,4-Dihydroxy-2-[(2S)-2-hydroxy-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl]pyrrolidinium trifluoroacetateC14H20F3N3O7[α]D25=-4 (c 0.435, DMSO)Source of chirality: l-tartaric acid

(2S,3S,4S)-3,4-Dihydroxy-2-[(2S)-2-hydroxy-3-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propyl]pyrrolidinium trifluoroacetateC13H17F4N3O7[α]D25=+4 (c 0.595, CH3OH)Source of chirality: l-tartaric acid