Branched-chain nucleosides : synthesis of structural analogs of the polyoxin complex and of puromycin
Creators: name: Richards, Colin Maxwell
Publisher: name: University of British Columbia
Year: 2011

description: The synthesis of a number of 3-C-cyanomethyl-2,3-dideoxy-hexo-pyranosides, pentofuranosides and pentopyranosides and the conversion of these compounds to their respective purine nucleosides are reported. Methyl 4,6-0-benzylidene-2-deoxy-α-D-erythro-hexopyranosid-3-ulose (127) was condensed with the carbanion formed from diethylcyano-methylphosphonate and sodium hydride to afford the unsaturated compounds methyl 4,6-0-benzylidene-E-(and Z)-3-C-cyanomethylene-2, 3-dideoxy-α-D-erythro-hexopyranoside (128 and 129). Acid hydrolysis of 128 gave the unblocked α,β-unsaturated nitrile 141. Hydrogenation of 128 afforded methyl 4,6-0-benzylidene-3-C-cyanomethyl-2, 3-dideoxy-α-D-ribo-hexo-pyranoside (140) which was subsequently debenzylidenated, p-chlorobenzoylated, and fused directly with 2,6-dichloropurine to afford 4,6-di-0-p-chlorobenzoyl-3-C-cyanomethyl-2,3-dideoxy-D-ribo-hex-l-eno-pyranose (149) and 2,6-dichloro-9-(4’,6'-di-0-p-chlorobenzoyl-3'-C-cyanomethyl-2',3'-dideoxy-α- and β-D-ribo-hexopyranosyl)purine (150 and 151). Debenzyli-denation of 128 also yielded methyl 1,6-anhydro-3-C-cyanomethyl-2,3-dideoxy-α-D-ribo-hexopyranoside which was characterized as its p-chloro-benzoyl derivative 148. Treatment of the blocked α-nucleoside 150 with aqueous dimethylamine in methanol resulted in replacement of the 6-chloro group by N,N-dimethylamine and hydrolysis of the cyanomethyl group to yield 2-chloro-6-N,N-dimethylamino-9-(3'-C-N,N-dimethylamino-carbamoylmethyl-2' ,3'-dideoxy-α-D-ribo-hexopyranosyl)purine (152). However identical treatment of the blocked β-nucleoside gave 2-chloro-6-N,N-dimethylamino-9-(3'-C-cyanomethyl-2',3'-dideoxy-β-D-ribo-hexopyranosyl)-purine (153). Reaction of 150 with anhydrous dimethylamine at -5° afforded 2,6-di-N,N-dimethylamino-9-(3'-C-cyanomethyl-2',3' -dideoxy-α-D-ribo-hexopyranosyl)purine (158). Hydrogenation of 158 followed by acetylation yielded 2,6-di-N,N-dimethylamino-9-(3'-C-[2"-acetamidoethyl]-2’,3’-dideoxy-α-D-ribo-hexopyranosyl)purine (170). 2-Deoxy-g-erythro-pentose (171) was treated with 0.05% methanolic hydrogen chloride followed by reaction with chlorotriphenylmethane in pyridine to afford methyl 2-deoxy-5-0-trityl-α-(and β)-D-erythro-pentofuranosides (175) and (176) respectively. Ruthenium tetroxide oxidation, followed by condensation with the carbanion formed from diethylcyanomethylphosphonate and sodium hydride and subsequent hydrogenation gave methyl 3-C-cyanomethyl-2,3-dideoxy-5-0-trityl-α-D-erythro-(and threo)-pentofuranoside (186 and 187), and methyl 3-C-cyanomethyl-2,3-dideoxy-5-0-trityl-β-D-threo-pentofuranoside (188). Attempted selective removal of the 5-0-trityl group was unsuccessful. Compounds 187 and 188 were converted to the same pentopyranoside to aid in structural proof. Methyl 4-0-p-bromobenzoyl-3-C-cyanomethyl-2,3-dideoxy-α-D-threo-pentopyranoside (191), derived from 187 and 188, was utilized in nucleoside synthesis by direct fusion to yield 2,6-dichloro-9-(4'-0-p-bromobenzoyl-3'-C-cyanomethyl-2’,3'-dideoxy-β-(and α)-D-threo-pentopyranosyl)purine (195 and 196), and 4-0-p-bromobenzoyl-3-C-cyanomethyl-2,3-dideoxy-D-threo-pent-l-eno-pyranose (197). Treatment of 195 and 196 with aqueous dimethylamine in methanol gave 2-chloro-6-N,N-dimethylamino-9-(3'-C-cyanomethyl-2', 3’-dideoxy-β-(and α)-D-threo-pentopyranosyl)-purine (198 and 199). Reduction of 198 over platinum oxide in acetic anhydride and ethanol gave 2-chloro-6-N-N-dimethylamino-9-(3'-C-[2"-acetamidoethyl]-2',3'-dideoxy-β-D-threo-pentopyranosyl)purine (200). The ketose, 1,2:5,6-di-0-isopropylidene-α-D-ribo-hexof uranos-3-ulose (9) was reacted with phosphonoacetic acid trimethyl ester and potassium t-butoxide to afford E-(and Z,)-3-C-(methoxycarbonyl)methylene-3-deoxy-1,2:5,6-di-0-isopropylidene-α-D-ribo-hexofuranose (11 and 10) and E-(and Z)-3-C-(methoxycarbonyl)methylene-3-deoxy-1,2 :5 ,6-di-0-isopropylidene-α-D-xylo-hexofuranose (205 and 204). Stereospecific hydroxylation of 10 and 11 afforded 3-C-[S-and R-hydroxy(methoxycarbonyl)methyl]-1,2:5,6-di-0-isopropylidene-α-D-glucofuranose, (211) and (212), respectively in a combined yield of 43% after chromatography. Selective formation of the monomesylates, 215 and 216, followed by treatment with sodium azide and reduction afforded the methyl D-2-(and L-2)-1,2:5,6-di-0-isopropylidene-α-D-glucofuranos-3-yl)glycinate 218 and 217. Base hydrolysis of the latter compounds yielded D-2- and L-2-(1,2:5,6-di-0-isopropylidene-α-D-glucofuranos-3-yl)-glycine, 221 and 220, respectively. The structures of the glycosyl amino acids were correlated with that of L-alanine by circular dichroism. In addition the glycosyl α-amino esters were derivatized as acetamido, 222 and 223, and as benzamido derivatives 224 and 225. Similarly stereospecific hydroxylation of pure E-3-C-(methoxy-carbonyl)methylene-3-deoxy-1,2:5,6-di-0-isopropylidene-α-D-xylo-hexofuranose (205) afforded crystalline 3-C-[R-hydroxy(methoxycarbonyl)-methyl]-1,2:5,6-di-0-isopropylidene-α-D-galactofuranose (226) in 55% yield. Treatment of 226 with methanesulfonyl chloride in pyridine afforded 3-C-[R-methanesulfonyloxy(methoxycarbonyl)methyl]-1,2:5,6-di-0-isopropylidene-α-D-galactofuranose (229) and the unusual 3-C-[methanesulf onyloxy(methoxycarbonyl)methylene]-3-deoxy-l,2:5,6-di-0-isopropylidene-α-D-xylo-hexofuranose (230), in 60 and 30% yields, respectively. Treatment of 229 with sodium azide, followed by reduction, afforded the α-amino esters, methyl-L-2-(1,2:5,6-di-0-isopropylidene-α-D-galactofuranos-3-yl)-glycinate (232) and methyl D-2-(1,2:5,6-di-0-isopropylidene-α-D-galactofuranos-3-yl)glycinate (234). Base hydrolysis of 232 and 234 yielded L-2-(and D-2)-(1,2:5,6-di-0-isopropylidene-α-D-galactofuranos-3-yl)glycine 233 and 235, respectively. The dihydroxy compound 212 was selectively monoacetylated then stereospecifically dehydrated to give 3-C-[Z-1'-0-acetyl-1’-(methoxy-carbonyl) methylene]-3-deoxy-1,2:5,6-di-0-isopropylidene-α-D-ribo-hexofuranose (237). Hydrogenation of 237 yielded the saturated acetoxy compound 238, which was catalytically deacetylated in 100% yield to afford 3-C- [S-hydroxy (methoxycarbonyl) methyl]-3-deoxy-1,2:5,6-di-0-isopropylidene-α-D-allofuranose (239). Treatment of 239 with methane-sulfonyl chloride and p-toluenesulfonyl chloride gave the methanesulfonate and p-toluenesulfonate, 240 and 241, respectively. Treatment of either 240 or 241 with sodium azide in anhydrous dimethylformamide, followed by hydrogenation resulted in methyl D-2-(and L-2)-(3-deoxy-1,2:5,6-di-0-isopropylidene-α-D-allofuranos-3-yl)glycinate, 243 and 245, respectively. Base hydrolysis of 243 gave D-2-(3-deoxy-1,2:5,6-di-0-isopropylidene-α-D-allofuranos-3-yl)glycine. In addition to correlating the above glycosyl amino acids with L-alanine by means of circular dichroism, the glycosyl methyl glycinate 243 was converted to a compound of known absolute configuration as determined by X-ray crystallography. Treatment of all six glycosyl amino acids with L-amino acid oxidase from Crotalus Adamanteus failed to afford additional proof of amino acid configuration.