Synthesis and Biological Activities of Sugar Modified 4'-Thionucleosides

当3，5-O-(1，1，3，3-tetralsopropyridene-1，3-diyl)-4-thiofuranoid甘氨酸(1)在N-碘代蔗糖亚胺存在下与硅化胸腺嘧啶反应时，可以立体选择性地得到4‘-硫代胸腺嘧啶核苷(2)的β异构体。糖基化产物2经锡自由基还原，再经保护基团处理，得到4‘-硫代胸苷(3)。用I_2/PPh_3/吡啶对3的5‘-羟基进行碘化和乙酰化反应，得到3’-乙酰基-5‘-脱氧-5’-碘-4‘-硫代胸苷(4)。化合物4与DBN反应生成4‘，5’-不饱和核苷5。4‘-乙酰氧基-4’-硫代硫代亚胺衍生物7可通过乙酸铅催化的二乙酰氧基化反应合成。当7在SnCl4存在下与苯硫基三甲基硅烷反应时，7的4‘-α上的亲核取代反应顺利进行，得到4’-TbDMS-…更多4‘-硫代胸苷衍生物(8)。利用叠氮三甲基硅烷(TSMN3)和甲氧基三甲基硅烷(TMSOMe)合成了4‘-α-叠氮基-(9)和4’-α-甲氧基-4‘-硫代嘧啶衍生物(10)。4‘-α-C-烯丙基-4’-硫代胸苷(11)是由7与烯丙基三甲基硅烷(TMSCH2CH=CH2)反应合成的，与氰基三甲基硅烷(TMSCN)反应发生了分子内环化反应。目标化合物4‘-α-C-氰基核苷(12)可由3’，5‘-二-O-叔丁基二甲基-4’-硫代胸苷(13)合成。4‘-α-C-乙炔基-4’-硫代胸苷衍生物(14)由4‘-α-甲酰基核苷(15)经Dibal-H还原和酸水解得到4’-TdN-C-氰基核苷(14)。3，5-O-(二叔丁基硅烯)-4-硫代呋喃甘醇(16)与间-CPBA反应得到相应的S氧化物(17)。当S氧化物17与Ac_2O/TMSOAc/BF_3OEt_2反应时，“加成Pummerer反应”进行了立体选择性地提供1，2-di-O-acethyl-3，5-O-(di-t-butylsilylene)-4-thioribofuranose(18)。TMSOTf介导的18和硅基嘧啶核苷酸碱基之间的糖苷反应得到了4‘-硫代嘧啶核糖核苷的β-氨基化合物(19)。同样，相应的嘌呤核苷(20)也可以以立体选择性的方式获得。硫代糖基供体18也可用于C-糖苷化。因此，3，5-O-(di-t-butylsilylene)-4-thioribofuranosyl噻吩环(21)和呋喃(22)。3，5-O-(DL-叔丁基硅烯)-4-硫代呋喃糖基氰化物(23)被转化为4‘-硫代唑呋喃(24)。在本研究合成的新型核苷类似物中，4’-叠氮基-(25)，4‘-α-C-氰基-(26)和4’-α-C-乙炔基-4‘-硫代胸苷(27)具有较弱的抗艾滋病毒活性

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- … More 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