UBC Theses and Dissertations

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UBC Theses and Dissertations

Synthesis of nucleoside amino acids and glycosyl amino acids Dodd, Robert Hugh


The syntheses of glycos-3-yl and C-glycosyl α- and β-amino acid derivatives are described. The introduction of carbon-carbon linked substituents including β-alanine, at C-6 of uridine derivatives is also reported. Knoevenagel condensation of ethyl cyanoacetate (263) with 1,2:5,6-di-O-isopropylidene-α-D-ribo-hexofuranos-3-ulose (14) in N,N-dimethylformamide using ammonium acetate as the catalyst gave 3-C-[(R,S)-cyano(ethoxycarbonyl) methylene]-1,2:5,6-di-O-isopropylidene-α-D-allofuranose (264) in 26% yield as well as a chromatographically inseparable mixture of 3-C-[(R,S)-cyano(ethoxycarbonyl)methylene]-3-ieoxy-1,2: 5,6-di-O-isopropylidene-α-D-allofuranose (265) and 3,3-C-bis[(RS, SS, RR)-cyano (ethoxycarbonyl) methyl]-3-deoxy-1,2: 5,6-di-O-isopropylidene-α-D-allofuranose (266) in equal yields of 5%. Compound 264 was hydrogenated over platinum oxide in acetic anhydride to give in 96% yield 3-C-[(R,S)-acetamidomethyl (ethoxycarbonyl) methylene]-1,2:5,6-di-O- isopropylidene-α-D-allofuranose (270). Dehydration of 264 with thionyl chloride in pyridine afforded 3-C-[(R,S-cyano (ethoxycarbonyl) methylene]-3-deoxy-1,2:5,6-di-O-isopropylidene-α-D-erythro-hex-3-enofuranose (273). Compound 266 was isolated by reduction of 265 with sodium cyanoborohydride in methanol to give 3-deoxy-3-C-[(R,S-cyano (ethoxycarbonyl) methylene]-1,2:5,6-di-O-isopropylidene-α-D-allofuranose (268) followed by column chromatography on silica gel. Reaction of 3-C-formyl-1,2:5,6-di-O-isopropylidene-α-D-allofuranose (278) with sodium cyanide, ammonium carbonate and carbon dioxide gave in 53% yield 3-C-(2,4-diketo-tetrahydcoimidazol-5-(R, S)-yl)-1,2: 5,6-di-O-isopropylidene-α-D-allofuranose (280). Treatment of 280 with barium hydroxide gave a 2:1 mixture of D-2 and L-2-(1,2:5,6-di-O-isopropylidene-α-D-allofuranos-3-yl)glycine (281), respectively, in a combined yield of 74%. When ethyl cyanoacetate (263) was reacted with 2,5-anhydro-3,4,6-tri-O-benzoyl-D-allose (203) in N-N-dimethylformamide using ammonium acetate as catalyst, ethyl (E or Z)-4,7-anhydro-2-cyano-2,3,5-trideoxy-6,8-di-O-benzoyl-D-erythro-octon-2,4-dieneate (283) was produced in 31% yield. Hydrogenation of 283 over platinum oxide in acetic anhydride gave ethyl 4,7-anhydro-2-(R,S)-acetamidomethyl-6,8-di-O-benzoyl-2,3,5-trideoxy-4-(R,S)-D-erythro-D-octonate (284). Reaction of 2,3-0-isopropylidene-5-0-trityl-β -D-ribofuranosyl chloride (210) with diethyl sodium phthalimidomalonate in N,N-dimethylformamide at 90° provided in 46% overall yield a 1:1 mixture of the α and β anomars of diethyl 2,3-0-isopropylidane-5-0-trityl-D-ribofuranosyl phthalimidomalonate (287 and 288, respectively). An attempt to unblock 287 and 288 with hydrochloric acid was unsuccessful. Reaction of 2,4-di-t-butoxy-5-magnesiumbromopyrimidine (294) and acetone followed by treatment of the product with hydrochloric acid gave 5-(1-propen-2-yl)uracil (296) in 43% yield. The direct coupling of 294 with the glycosyl chloride 210 in the presence of catalytic iodo(phenyl)bis(triphanylphosphine) palladium (II) (298) was unsuccessful. Addition of 2,2'-anhydro-1-(3-0-acetyl-5-0-trityl-β-D-arabinofuranosyl)uracil (308) to excess 2-lithio-1,3-dithiane (126) in tetrahydrofuran at -78° gave 2-(1,3-dithian-2-yl)-1-(5-O-trityl-β-D-arabinofuranosyl)-4 (1H)-pyriiaidinone (309) and 2,2'-anhydro-5,6-dihydro-6-(S)-(1,3-dithiaa-2-yl)-1- (5-O-trityl-β-D-arabinofuranosyl)uracil (310) in yields of 15 and 30%, respectively. Treatment of 309 with Raney nickel gave 2-methyl-1-(5-G-trityl-β-D-arabinofuranosyl)-4(1H)-pyrimidinone (313) while hydrolysis of 309 in acid afforded 2-(1,3-dithian-2-yl)-4-pyrimidinone (314) and arabinose. Detritylation of 309 without glycosidic cleavage could only be effected by prior acetylation to 2-(1,3-dithian-2-yl)-1-(2,3-di-O-acetyl-5-O-trityl-β-D-arabinofuranosyl)-4(1H)-pyrimidinone (315) which, after treatment with acetic acid at room temperature followed by unblocking with sodium methoxide gave 2-(1,3-dithian-2-yl)-1-β-D-arabiaofuranosyl)-4(1H)-pyrimidinone (317) in 45% yield. Hydrolysis of the dithioacetal moiety of 315 always led to glycosidic cleavage. Treatment of compound 310 with Ranay nickel gave 41% of 2,2'-anhydro-5,6-dihydro-6-R-methyl-5'-O-trityluridine (318). Detritylation of 310 in refluxing acetic acid provided 10 and 90% yields of 5,6-dihydro-6-(S)-(1,3-dithian-2-yl)-1-β-D-arabinofuranosyluraci1 (319) and 3-[(S)-1-(1,3-dithian-2-yl)]propionamido-β-D-ar abinofurano-[1',2' :4,5]-2-oxazolidone (320), respectively. Acid hydrolysis of 319 afforded arabinose and 5,6-dihydro-6-(S)-(1,3-dithian-2-yl)uracil (321). Raney nickel treatment of 321 yielded the known 5,6-dihydro-6-methyluracil (322). When 319 was allowed to stand in water or methanol for 4 days, quantitative conversion to 320 occurred. Dehydration of 320 with trifluoroacetic anhydride and pyridine afforded 3-[(S)-1- (1,3-dithian-2-yl)] cyanoethyl-β-D- arabinofurano-[ 1',2':4,5]-2-oxazolidone (328) in 77% yield. Similarly, 3-(R)-1-methylpropionamido-β-D- arabinofurano-[1',2':4,5 ]-2-oxazolidone (329), obtained by Raney nickel treatment of 320, gave 3-(R) - 1-methylcyanoethyl-β-D-arabinofurano-[1'2':4,5]-2-oxazolidone (330). Treatment of 320 with excess p-nitrobenzoyl chloride in pyridine yielded 3-[(S)-1-(1,3-dithian-2-yl)]cyanoethyl-3',5'-di-O-p-nitrobenzoyl-β-D-arabinofurano-[1',2':4,5]-2-oxazolidone (333) which was converted by treatment with methyl iodide in dimethyl sulfoxide to 3-(S)-1-formylcyanoethyl-3',5'-di-O-p-nitrobenzoyl-β-D- arabinofurano-[1',2':4,5]-2-oxazolidone (335), characterized as its semicarbazone 336. An attempt to cyclize 328 with ammonia failed. Addition of 5-bromo-2',3'-0-isopropylidene-5'-O-trityl-uridine (340) in pyridine to excess anion 126 in tetrahydrofuran at -78° gave 5,6-dihydro-6-(R)-(1,3-dithian-2-yl)-2',3'-O-isopropylidene-5'-O-trityluridine (341), 5-(S)-bromo-5, 6- dihydro-6-(S) - (1,3-dithian-2-yl)-2',3'-O-isopropylidene-5'-O-trityluridine (342) and its 5-(R) isomer 343 in yields of 37, 35 and 10%, respectively. Desulfurization of 341 with Raney nickel afforded 5,6-dihydro-2',3'-O-isopropylidene-6-(S)-methyl-5'-O-trityluridine (346). Compound 341 was hydrolyzed in acid to give ribose and 5,6-dihydro-6-(R)-(1,3-dithian-2-yl)uracil (348). Treatment of 341 with methyl iodide in aqueous acetone gave a 30% yield of 5,6-dihydro-6-(R,S)-formyl-2',3'-O-isopropylidene-5'-O-trityluridiae (349), characterized as its semicarbazone 350. Both 342 and 343 gave 341 upon brief treatment with Raney nickel. Both 342 and 343 gave 6-formyl-2',3'-O-isopropylidene-5'-O-trityluridine (351) in approximately 41% yield when treated with methyl iodide in aqueous acetone containing 10% dimethyl sulfoxide. A by-product, identified as 6-formyl-2',3'-O-isopropylidene-3-methyl-5'-O-trityluridine (353) was also formed. Reduction of 351 with sodium borohydride in ethanol afforded, after unblocking, 6-hydroxymethyluridine (356), characterized by its hydrolysis in acid to the known 6-hydroxymethyluracil (357). Knoevenagel condensation of a mixture of 351 and 353 with ethyl cyanoacetate (263) yielded 38% of ∑-or z-6-[(2-carboethoxy-2-cyano)ethylidene]-2',3'-O- isopropylidene-5'-O-trityluridine (359)and 10% of its N-methyl derivative 360. Hydrogenation of 359 over platinum oxide in acetic anhydride followed by unblocking gave 6-[3-amino-2-(R or S)-carboxypropyl]uridine (363).

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