Branched-chain carbohydrates and nucleosides
Creators: name: Cliff, Brian Leonard
Publisher: name: University of British Columbia
Year: 2010

description: The syntheses of a number of branched-chain carbohydrates and nucleosides are reported. The application of the Kiliani-Fischer cyanohydrin synthesis to 1,2:5,6-di-0-isopropylidene-α-g-ribo-hexofuranos-3-ulose (25) yielded either the 3-C-cyano-1,2 : 5 , 6-di-0-isopropylidene-α -D-gluco or allofuranose, (26 and 27, respectively) predominantly, depending upon the conditions employed. The stereoselectivity of the reaction was examined. Reduction of the cyaho group and acetylation of the resulting amine afforded 3-C-acetamido-methyl-1, 2 : 5 ,6-di-0-isopropylidene-α-g-allo and gluco-furanose (53 and 54, respectively) and provided an unequivocal proof of structure for the original cyanohydrins. The ylid generated by the reaction of potassium t-butoxide and carbomethoxymethyldimethyl phosphonate was condensed with 1,2:5,6-di-0-isopropylidene-α-D-ribo-hexofuranos-3-ulose (25) to afford, after reduction of the α,β-unsaturated esters (135 and 136), 3-C-(carbomethoxy-methyl) -3-deoxy-l ,2 :5 ,6-di-0_-isopropylidene- α -D-allofuranose (35) . The 5,6-0-isopropylidene group of 35 was hydrolyzed, the resulting diol was oxidatively cleaved and reduced, and the resulting alcohol was benzoylated to give 5-0-benzoyl- 3-C- (carbomethoxymethyl) -3-deoxy-l, 2-0-isopropylidene- α -D- ribofuranose (172) . The 1,2-0-isopropylidene group of 172 was hydrolyzed to yield the 5-0-benzoyl-3-C-carboxymethyl- 3-deoxy-α, β-D-ribofuranose-2,3-γ-lactone (173) which was acetylated to afford 1-0-acetyl-5-0-benzoyl-3-C-carboxy- methyl-3-deoxy-β-D-ribofuranose-2,3-γ-lactone (169). Compound 169 was fused directly with 2,6-dichloropurine to give 2,6-dichloro-9-[3'-C-(carboxymethyl-2',3'-γ- lactone)-31-deoxy-β and a-D-ribofuranosyl]purine (174 and 175, respectively) and reacted with N⁶ -benzoyl-N⁶ , 9-bis(trimethylsilyl)adenine, in the presence of stannous chloride, to afford N⁶ -benzoyl-9-(31-C-carboxymethyl-21,31 -γ-lactone-3'-deoxy-β-D-ribofuranosyl)adenine (176) and the α-anomer 177. De-benzoylation of the β-nucleoside 176 yielded 9-[3'-C-(carboxymethyl-2',3'-γ-lactone)-3'-deoxy-β-D-ribofuranosyl]adenine (17 8) while the α-nucleoside 177 afforded 9 -[3'-C-carboxymethyl-3'-deoxy-α-D-ribofuranosyl] adenine (181). Condensation of methyl nitroacetate with 5-0-benzoyl-1,2-0-isopropylidene-α-D-erythro-pentofuranos-3-ulose (182) and 5-0-benzyl-l,2-0-isopropylidene-α-D-erythro-pentofuranos-3-ulose (194) in the presence of ammonium acetate, followed by immediate treatment with p-toluenesulphonic acid mono-hydrate in acetic anhydride, yielded (E) and (Z) 5-0- benzoyl and 5-0-benzyl-3-deoxy-l, 2-0-isopropylidene-3-C-nitro (methoxycarbonyl) methylene- α -D-erythro-pentof uranose , respectively (189 and 198). In a similar set of reactions with 1,2:5,6-di-0-isopropylidene- α -D-ribo-hexofuranos-3-ulose (25) , the major product, obtained in good yield, was 3-0 - acetyl-1,2:5, 6-di-0-isopropylidene-3-C- [(R, S) nitro-(methoxycarbonyl)methyl]- α -D-allofuranose (165). The 5,6-0_-isopropy lidene group of compound 165 was hydrolyzed and the resulting diol was treated with p-toluenesulphonic acid monohydrate in acetic anhydride at elevated temperature to afford, after reduction with sodium cyanoborohydride , 5 , 6-di-0-acetyl-3-deoxy-l,2-0-isopropylidene-3-C-[(R,S)-nitro(methoxycarbonyl)methyl]- α -D-allofuranose (241) . Acetolysis of compound 241 gave 1,2 ,5 , 6-tetra-0-acetyl-3-deoxy-3-C-[(R,S)-nitro(methoxycarbonyl)methyl]- α,β-D-allofuranose (243) which was used in an unsuccessful nucleoside synthesis with bis(trimethylsilyl)thymine. Reduction of the nitro group of 3-0-acetyl-l, 2 :5 , 6-di-0-isopropy lidene-3-C-[(R, S)-nitro (methoxycarbonyl) methyl] - α -D-allofuranose by hydrogenation over Raney nickel afford methyl L- and D-2-(1, 2 : 5 ,6-di-O-isopropylidene- α -D-allofuranos-3-yl)glycinate (205 and 206, respectively). The major product, methyl L-glycinate 205, was acetylated and the 0-acetate and 5,6-0-isopropylidene groups were hydrolyzed to yield a compound which was successively treated with sodium periodate and sodium borohydride to give, after acetylation, methyl N-acetyl-L-2-(1,2-0- isopropylidene- α -D-ribofuranos-3-yl)glycinate (232) and its 5-0-acetyl derivative (233). Trifluoroacetylation of methyl L-2-(1, 2 : 5 ,6-di-0-isopropylidene- α -D-allofuranos-3-yl)glycinate (205), followed by successive replacement of the 5,6 and 1,2-0-isopropylidene acetals with 0-acetate blocking groups, afforded methyl L-2- (1,2,3,5, 6-penta-0-acetyl- α , β-D-allofuranos-3-yl) -N-trifluoroacetyl glycinate (250). The attempted fusion of the bromo-sugar derivative of compound 250 with N⁶-benzoyl-N⁶-9-bis-(trimethylsilyl)adenine yielded 1,1'-anhydro-2,3,5,6-tetra-0-acetyl-3-C-(R)-methoxycarbonyl-1(R),1'(S)-N-trifluoroacetoepimo- α -g-allofuranose (252) whereas the silver trifluoromethylsulfonate catalyzed condensation of the same bromo-sugar with bis(trimethyl-silyl)thymine afforded 1-[2',3',5',6'-tetra-0-acetyl-3'-C-((S)-N-trifluoroacetyl-carbomethoxy(amino)methyl)-β-D-allofuranosyl]thymine (257).