Synthesis and Biological Activities of Sugar Modified 4'-Thionucleosides

糖修饰4-硫代核苷的合成及生物活性

• 批准号: 17590093
• 负责人: HARAGUCHI Kazuhiro
• 金额: $ 1.86万
• 依托单位: Showa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590093/
• 关键词: nucleoside; glycal; glycosidation; sulfoxide; Pummerer reaction; thymine; antitumor; antiviral; グリコシル化; 分岐糖; チオ糖; グリコシル化反応; 置換反応; 有機シリコン試剤

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

3，5-O-（1，1，3，3-四异丙基-1，3-二基）-4-硫代呋喃糖醛（1）在N-碘代琥珀酰亚胺存在下与硅烷基化胸腺嘧啶反应，立体选择性地得到4 '-硫代胸腺嘧啶核苷（2）的β-端基异构体。将糖基化产物2进行锡自由基还原和随后的保护基操作以得到4 '-硫代胸苷（3）。3的5 ′-羟基用碘/三苯基膦/吡啶碘化，仲羟基乙酰化，得到3 ′-乙酰基-5 ′-脱氧-5 ′-碘-4 ′-硫代胸苷（4）。通过用DBN处理4将化合物4转化为4 '，5'-不饱和核苷5。将所得5的3 '位的乙酰基改变为TBDMS基团以提供6。4 ′-乙酰氧基-4 ′-硫代胸苷衍生物7可通过醋酸铅介导的二乙酰氧基化反应合成。在SnCl_4存在下，7与苯基三甲基硫代硅烷（TMSSPh）反应，4 ′-位的亲核取代反应顺利进行，得到4 ′-α-苯基三甲基硫代硅烷（TMSSPh）。 ...更多信息 4 '-硫代胸苷衍生物（8）。用叠氮基三甲基硅烷（TMSN_3）和甲氧基三甲基硅烷（TMSOMe）也可得到4 ′-α-叠氮基-（9）和4 ′-α-甲氧基-4 ′-硫代胸苷衍生物（10）。7与烯丙基三甲基硅烷（TMSCH_2CH=CH_2）反应合成了4 ′-α-C-烯丙基-4 ′-硫代胸苷（11），但与氰基三甲基硅烷（TMSCN）反应时发生了分子内环化反应。以3 '，5'-bis-O-TBDMS-4 '-乙酰氧基-4'-硫代胸苷（13）为原料，经DIBAL-H还原、酸水解制得4 '-α-甲酰基核苷（15），经Wittig反应合成4'-α-C-乙炔基-4 '-硫代胸苷衍生物（14）。5-O-（二叔丁基亚硅基）-4-硫代呋喃类化合物（16）与m-CPBA反应得到相应的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，进行“加成Pummerer反应”，立体选择性地得到1，2-二-O-乙酰基-3，5-O-（二叔丁基亚硅基）-4-硫代呋喃核糖（18）。TMSOTf介导的18和甲硅烷基化嘧啶核碱基之间的糖苷化产生4 '-硫代嘧啶核糖核苷的β-单体（19）。同样，相应的嘌呤核苷（20）也可以立体选择性地获得。硫代糖基供体18也可用于C-糖苷化。因此，3，5-O-（二叔丁基亚甲硅烷基）-4-硫代呋喃核糖基噻吩（21）和呋喃（22）。3，5-O-（D1-叔丁基亚硅基）-4-硫代呋喃糖基氰化物（23）经转化为4 '-硫代三氮唑呋喃（24），在本研究中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 '-胸腺嘧啶核苷（27）具有较强的抗HIV活性。