Synthesis and Biological Activities of 4'-Thionucleosides branched at the Sugar Portion

When3，5-O-(Tetraisopropyldisiloxane-1，3-diyl)-4-thiofuranoid glycal(1)was lithiated with lithium diisopropylamide(LDA)and the resultingl-lithio species(2)was treated with carbon electmphile，1-carbon-substituted4-thiofuranoid glycal(3)could be obtained in good yield。Electaophilic glyoosidation between the glycal3 and silylated thymine was carried out in the presence of phenylselenenyl chloride(PhSeCI)or N-iodosuccinimide(NIS)to funish theβ-anomer of 4‘-thionudeoside(4)，stereoselectively。The glycosylated product 4was subjected to tin radical-mediated reduction to give the target1‘-carbon-substituted4’-thiothymidine(5).The reaction of1-lithio derivative 2 with benzenesulfonyl chloride gave1-chloro-glycal6.When6was treated with lithium2，2，6，6-tetramethylpiperidide(LTMP)，C-2lithiation proceeded to provide1-chloro-2-lithioglycal7.Reaction of 7with carbon electrophile gave the corresponding2-carbon-substituted1-chloroglycal8.The chloro-substituent of8could be removed by Birch reduction to furnish2-carbon-substituted glycal9.PbSeCl-mediated electrophilic glycosidation between9and silylated thymine gaveβ-anomer of the glycidal9.PbSeCl-mediated electrophilic glycrophile of 7with carbon removed by Birch reduction to furnish2-carbon-substituted glycal9.PbSeCl-mediated electrophilic glycidation between9and silylated。When 10was treated with tributyltin hydride in the presence of triethylborane under0_2atmosphere at-30°C，the target2‘-f3-carbon-substituted4’-thiothymidine derivative 11.Finally，5and11was desilylated with tetrabutylammonium fluoride to furnish1‘-and2’-β-carbon-substituted4‘-thiothymidine 12 and 13.Among the novel nucleide analogues synthesed in the presence-substituted4’-thiothymidine 12 and 13.Among the hydovel nucleide analogues synthized in the presence-sidietylborane under0_2atmosphere at-30°C

When 3,5-O-(Tetraisopropyldisiloxane-1,3-diyl)-4-thiofuranoid glycal (1) was lithiated with lithium diisopropylamide (LDA) and the resultingl-lithio species (2) was treated with carbon electmphile, 1-carbon-substituted 4-thiofuranoid glycal (3) could be obtained in good yield. Electaophilic glyoosidation between the glycal 3 and silylated thymine was carried out in the presence of phenylselenenyl chloride (PhSeCI) or N-iodosuccinimide (NIS) to funish the β-anomer of 4'-thionudeoside (4), stereoselectively. The glycosylated product 4 was subjected to tin radical-mediated reduction to give the target 1'-carbon-substituted 4'-thiothymidine (5).The reaction of 1-lithio derivative 2 with benzenesulfonyl chloride gave 1-chloro-glycal 6. When 6 was treated with lithium 2,2,6,6-tetramethylpiperidide (LTMP), C-2 lithiation proceeded to provide 1-chloro-2-lithioglycal 7. Reaction of 7 with carbon electrophile gave the corresponding 2-carbon-substituted 1-chloroglycal 8. The chloro-substituent of 8 could be removed by Birch reduction to furnish 2-carbon-substituted glycal 9. PbSeCl-mediated electrophilic glycosidation between 9 and silylated thymine gave β-anomer of the glycosidated product 10, stereoselectively. When 10 was treated with tributyltin hydride in the presence of triethylborane under 0_2 atmosphere at-30゜C, the target 2'-f3-carbon-substituted 4'-thiothymidine derivative 11.Finally, 5 and 11 was desilylated with tetrabutylammonium fluoride to furnish 1'- and 2'-β-carbon-substituted 4'-thiothymidine 12 and 13. Among the novel nucleoside analogues synthesized in this study, 1'-methyl-4'-thiothymidine 14 was found to showed anti-HSV-1 activity and anti-angiogenic activity.