| Research Abstract |
When 3,5-O-(1,1,3,3-tetralsopropyridene-1,3-diyl)-4-thiofuranoid glycal (1) was reacted with silylated thymine in the presence of N-iodosuccimide, β-anomer of 4'-thiothymine nucleoside (2) could be obtained stereoselectively. The glycosydated product 2 was subjected to tin-radical reduction and subsequent protecting group manipulation to give 4'-thiothymidine (3). Iodination of 5'-hydroxyl group of 3 with I_2/PPh_3/pyridine and acetylation of the secondary hydroxyl group furnished 3'-acetyl-5'-deoxy-5'-iodo-4'-thiothymidine (4). Compound 4 was converted to 4',5'-unsaturated nucleoside 5 by treatment of 4 with DBN. Acetyl group at the 3'-position of the resulting 5 was changed to TBDMS group to provide 6. 4'-Acetoxy 4'-thiothymidine derivative 7 could be synthesized by Pb(OAc)_4-mediated diacetoxylation of 6. When 7 was reacted with phenyltiotrimethylsilane (TMSSPh) in the presence of SnCl_4, nucleophilic substitution at the 4'-position of 7 proceeded smoothly to furnish 4'-α-phenyltio-
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4'-thiothymidine derivative (8). By using azidotrimethylsilane (TMSN_3) and methoxytrimethylsilane (TMSOMe), 4'-α-azido-(9) and 4'-α-methoxy-4'-thiothymidine derivative (10) could also be obtained. While 4'-α-C-allyl-4'-thiothymidine (11) was synthesized by the reaction of 7 with allyltrimethylsilane (TMSCH_2CH=CH_2), intramolecular cyclization occurred in the reaction with cyanotrimethylsilane (TMSCN). The target 4'-α-C-cyano nucleoside (12) could be obtained from 3',5'-bis-O-TBDMS-4'-acetoxy-4'-thiothymidine (13).4'-α-C-ethynyl-4'-thlothymidine derivative (14) was synthesized by Wittig-type reaction of 4'-α-formylnucleoside (15), which prepared by DIBAL-H reduction and acid hydrolysis of 12.
Oxidation of 3,5-O-(di-t-butylsilylene)-4-thiofuranoid glycal (16)with m-CPBA gave the corresponding S-oxide (17) as diastereomeric mixture. When the S-oxide 17 was reacted with Ac_2O/TMSOAc/BF_3OEt_2, "additive Pummerer reaction" has proceeded to furnish 1,2-di-O-acethyl-3,5-O-(di-t-butylsilylene)-4-thioribofuranose (18) stereoselectively. TMSOTf-mediated glycosidation between 18 and silylated pyrimidine nucleobase gave the β-amoner of 4'-thiopyrimidine ribonucleosides (19). Likewise, the corresponding purine nucleosides (20) could also be obtained stereoselective manner. The thio-glycosyl donor 18 could also be utilized for C-glycosidation. Thus, 3,5-O-(di-t-butylsilylene)-4-thioribofuranosyl thiophene (21) and furane (22). 3,5-O-(Dl-t-butylsilylene)-4-thiofuranosyl cyanide (23) was transformed into 4'-thiotiazofurin (24).
Among the novel nucleoside analogues synthesized in this study, 4'-azido-(25), 4'-α-C-cyano-(26) and 4'-α-C-ethynyl-4'-thlothymidine (27) were found to exhibit potent anti-HIV activity Less
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