Synthesis and Biological Activities of Sugar Modified 4'-Thionucleosides

当3,5- o -（1,1,3,3-四还丙基-1,3-二基）-4-硫代核苷(1)与硅基化胸腺胺在n -碘亚胺存在下反应时，可以立体选择性地得到4'-硫代胸腺核苷(2)的β-异位物。糖基化产物2经过锡自由基还原和随后的保护基团操作得到4'-硫代胸苷(3)。用I_2/PPh_3/吡啶碘化3的5′-羟基，次羟基乙酰化得到3′-乙酰基-5′-脱氧-5′-碘-4′-硫代胸腺嘧啶(4)。化合物4经DBN处理后转化为4′，5′-不饱和核苷5。将得到的3'位置的乙酰基5改为TBDMS基团，以提供6。4′-乙酰氧基4′-硫代胸腺嘧啶衍生物7可由Pb(OAc)_4介导的6二乙酰氧基化合成。当7在SnCl_4存在下与苯基硫三甲基硅烷（TMSSPh）反应时，7的4′位置的亲核取代顺利进行，得到4′-α-苯基硫代嘧啶衍生物(8)。用叠氮三甲基硅烷（TMSN_3）和甲氧基三甲基硅烷（TMSOMe）也可以得到4′-α-叠氮-(9)和4′-α-甲氧基-4′-硫代胸腺嘧啶衍生物（10）。4′-α- c -烯丙基-4′-硫代胸腺嘧啶（11）与烯丙基三甲基硅烷（TMSCH_2CH=CH_2）反应7合成，与氰三甲基硅烷（TMSCN）反应发生分子内环化。靶标4′-α- c -氰基核苷（12）可由3′，5′-双- o - tbdms -4′-乙酰氧基-4′-硫代胸苷（13）得到。以4′-α-甲酰基核苷（15）为原料，经DIBAL-H还原，酸水解12后，采用wittig型反应合成4′-α- c -乙基-4′-甲酰基核苷衍生物（14）。用m-CPBA氧化3,5- o -（二叔丁基硅烯）-4-硫代铀醛酸（16）得到相应的s -氧化物（17）为非对映体混合物。当s -氧化物17与Ac_2O/TMSOAc/BF_3OEt_2反应时，“添加剂Pummerer反应”进行了立体选择性地生成1,2-二-o -乙基-3,5- o -（二-t-丁基硅烯）-4-硫代氨基呋喃糖（18）。tmsotf介导的18和硅基化嘧啶核碱基之间的糖苷化得到了4'-硫代嘧啶核糖核苷的β-分子（19）。同样，相应的嘌呤核苷（20）也可以通过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 -（二叔丁基硅烯）-4-硫基溴呋喃基噻吩（21）和呋喃（22）。3,5- o -（dl -t-丁基硅烯）-4-硫代呋喃基氰化物（23）转化为4'-硫代噻唑呋喃（24）。在本研究合成的新型核苷类似物中，发现4'-叠氮-(25)、4'-α- c -氰基-(26)和4'-α- c -乙基-4'-thlothymidine（27）具有较强的抗hiv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