A general and efficient synthesis of pyridin-2-yl C-ribonucleosides bearing diverse alkyl, aryl, amino, and carbamoyl groups in position 6.
An efficient and practical methodology of preparation of 6-substituted pyridin-2-yl C-ribonucleosides was developed. A one-pot two-step addition of 2-lithio-6-bromopyridine to TBS-protected ribonolactone followed by acetylation gave 1beta-(6-bromopyridin-2-yl)-1-O-acetyl-2,3,5-tri-O-(tert-butyldimethylsilyl)-D-ribofuranose in high yield. Its reduction with Et(3)SiH and BF(3) x Et(2)O afforded the desired TBS-protected 6-bromopyridine C-ribonucleoside as pure beta-anomer in good overall yield of 63%. This intermediate was then subjected to a series of palladium catalyzed cross-coupling reactions, aminations and aminocarbonylations to give a series of protected 1beta-(6-alkyl-, 6-aryl-, 6-amino-, and 6-carbamoylpyridin-2-yl)-C-ribonucleosides. Deprotection of silylated nucleosides by Et(3)N x 3HF gave a series of title free C-ribonucleosides (12 examples).
Stefko
Martin
M
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead & IOCB Research Center, Flemingovo nam. 2, CZ-16610 Prague 6, Czech Republic.
Slavetínská
Lenka
L
Klepetárová
Blanka
B
Hocek
Michal
M
D000473:Alkanes / Q000138:chemical synthesis* / Q000737:chemistry; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009005:Monosaccharides / Q000138:chemical synthesis* / Q000737:chemistry; D010165:Palladium / Q000737:chemistry; D012265:Ribonucleotides / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
C548181:1beta-(6-bromopyridin-2-yl)-1-O-acetyl-2,3,5-tri-O-(tert-butyldimethylsilyl)-D-ribofuranose; D000473:Alkanes; D002219:Carbamates; D009005:Monosaccharides; D012265:Ribonucleotides; D010165:Palladium