Modular and practical synthesis of 6-substituted pyridin-3-yl C-nucleosides.
A novel modular and practical methodology for preparation of 6-substituted pyridin-3-yl C-nucleosides was developed. The Heck reaction of 2-chloro-5-iodopyridine with a 3'-TBDMS-protected glycal gave a 6-chloropyridin-3-yl nucleoside analogue, which was then desilylated, selectively reduced, and reprotected to give the TBDMS-protected 6-chloropyridin-3-yl C-2'-deoxyribonucleoside as a pure beta-anomer in a total yield of 39% over four steps. This key intermediate was then subjected to a series of palladium-catalyzed cross-coupling reactions, aminations, and alkoxylations to give a series of protected 1beta-(6-alkyl-, 6-aryl-, 6-hetaryl, 6-amino-, and 6-tert-butoxypyridin-3-yl)-2'-deoxyribonucleosides. 6-Unsubstituted pyridin-3-yl C-nucleoside was prepared by catalytic hydrogenation of the chloro derivative and 6-oxopyridine C-nucleoside by treatment of the 6-tert-butoxy derivative with TFA. Deprotection of all the silylated nucleosides by Et3N.3HF gave a series of free C-nucleosides (10 examples).
Joubert
Nicolas
N
Gilead Sciences & IOCB Research Center, Institute of Organic Chemistry and Biochemistry, v.v.i., Academy of Sciences of the Czech Republic, CZ-16610, Prague 6, Czech Republic.
Pohl
Radek
R
Klepetérová
Blanka
B
Hocek
Michal
M
D000586:Amination; D008958:Models, Molecular; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry*; D010084:Oxidation-Reduction; D011725:Pyridines / Q000737:chemistry*; D013696:Temperature
D009705:Nucleosides; D011725:Pyridines