| The syntheses of glycos-3-yl and C-glycosyl (alpha)- and (beta)-amino acid derivatives are described. The introduction of carbon-carbon linked substituents including (beta)-alanine at C-6 of uridine derivatives is also reported.;Knoevenagel condensation of 1 with 2,5-anhydro-3,4,6-tri-O-benzoyl-D-allose followed by hydrogenation of the product gave 4,7-anhydro-2-(R,S)-acetamidomethyl-6,8-di-O-benzoyl-2,3,5-trideoxy-4-(R,S)-D-glycero-D-octonate (4). Reaction of 2,3-O-isopropylidene-5-O-trityl-(beta)-D-ribofuranosyl chloride with diethyl sodium phthalimidomalonate yielded the (alpha) and (beta) anomers of diethyl 2,3-O-isopropylidene-5-O-trityl-D-ribofuranosyl phthalimidomalonate (5). Compounds 4 and 5 are functionalized precursors to the medically-important C-nucleosides.;An attempt to form a C-nucleoside directly by the palladium-catalyzed coupling of a glycosyl halide with a pyrimidine base failed. However, a new method of attaching carbon-carbon linked substituents at C-5 of uracil was developed in the course of this study.;Reaction of 2-lithio-1,3-dithiane (6) with 2,2'-anhydro-1-(3-O-acetyl-5-O-trityl-(beta)-D-arabinofuranosyl)-uracil gave 2-(1,3-dithian-2-yl)-1-(5-O-trityl-(beta)-D-arabinofuranosyl)-4(1H)-pyrimidinone and 2,2'-anhydro-5,6-dihydro-6-(S)-(1,3-dithian-2-yl)-1-(5-O-trityl-(beta)-D-arabinofuranosyl)uracil (7). Treatment of 7 with acid led to an unusual cleavage of the 2,3-bond of the pyrimidine ring.;Knoevenagel condensation of ethyl cyanoacetate (1) with 1,2:5,6-di-O-isopropylidene-(alpha)-D-ribo-hexofuranos-3-ulose followed by catalytic reduction of the nitrile group of the main product obtained gave 3-C-{(R,S)-acetamido-methyl (ethoxycarbonyl)methylene}-1,2:5,6-di-O-isopropylidene-(alpha)-D-allofuranose (2). Application of the Bucherer hydantoin synthesis to 3-C-formyl-1,2:5,6-di-O-isopropylidene-(alpha)-D-allofuranose gave the 3-C-hydantoin analogue which was hydrolyzed to give D-2 and L-2-(1,2:5,6-di-O-isopropylidene-(alpha)-D-allofuranos-3-yl)glycine (3), previously obtained by another route in our laboratory. Both 2 and 3 are analogues of the sugar moiety of the polyoxins.;Reaction of 6 with 5-bromo-2',3'-O-isopropylidene-5'-O-trityluridine gave 5,6-dihydro-6-(R)-(1,3-dithian-2-yl)-2',3'-O-isopropylidene-5'-O-trityluridine and the 5-S and 5R isomers of 5-bromo-5,6-dihydro-6-(S)-(1,3-dithian-2-yl)-2',3'-O-isopropylidene-5'-O-trityluridine (8). Hydrolysis of the dithioacetal of 8 gave the 6-formyl analogue (9) which was converted to the 6-semicarbazone and 6-hydroxymethyluridine. Knoevenagel condensation of 1 with 9, hydrogenation of the product and removal of the blocking groups gave 6-{3-amino-2-(R or S)-carboxypropyl}uridine (10). Compound 10 is an isomer of an unusual nucleoside found in the t RNA of E. coli.;Several of the novel dithianyl nucleosides synthesized exhibited moderate activity against Leukemia 1210 in vitro. |
