(1R,3R,4R,5S,6S,7S)-7-benzyloxy-1-benzyloxymethyl-6-hydroxy-5-methyl-3-(thymin-1-yl)-2-oxa-bicyclo[2.2.1]heptane | 1095153-49-3

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (1R,3R,4R,5S,6S,7S)-7-benzyloxy-1-benzyloxymethyl-6-hydroxy-5-methyl-3-(thymin-1-yl)-2-oxa-bicyclo[2.2.1]heptane
• 英文别名: 1-[(1S,3R,4R,5S,6S,7S)-6-hydroxy-5-methyl-7-phenylmethoxy-1-(phenylmethoxymethyl)-2-oxabicyclo[2.2.1]heptan-3-yl]-5-methylpyrimidine-2,4-dione
• CAS: 1095153-49-3
• 化学式: C₂₇H₃₀N₂O₆
• 分子量: 478.545
• InChiKey: JBSDBIVAKVKNEI-QUUAIHPVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  35
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  97.3
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (1R,3R,4R,5S,6S,7S)-7-benzyloxy-1-benzyloxymethyl-6-hydroxy-5-methyl-3-(thymin-1-yl)-2-oxa-bicyclo[2.2.1]heptane 在 戴斯-马丁氧化剂 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 以100%的产率得到(1R,3R,4R,5S,7S)-7-benzyloxy-1-benzyloxymethyl-5-methyl-6-oxo-3-(thymin-1-yl)-2-oxa-bicyclo[2.2.1]heptane
  参考文献：
  名称：

  通过结合修饰的2'，4'-碳环LNA和-ENAs对核苷酸间磷酸周围的静电进行微调导致反义特性的显着调节

  摘要：

  在反义（AS）和RNA干扰（RNAi）技术中，对天然单链2'-脱氧寡核苷酸（用于AS）或双链RNA（用于RNAi）进行化学修饰，使其与目标RNA结合，从而获得更好的通过抑制RNA翻译来下调基因表达。此处显示了通过改变取代基的静电相互作用以及围绕反义寡核苷酸（AON）-RNA异源双链体的小树林边缘附近的核苷酸间磷酸二酯部分周围的立体化学环境的精细调节，如何导致调节反义性质。通过合成各种修饰的碳环锁核酸（LNA）和在碳环部分连接有羟基和/或甲基取代基的-亚乙基桥核酸（ENA）并通过固相DNA合成将其整合到AON中来证明这一点。 。这些修饰的AON对互补RNA和DNA的靶标亲和力，核酸酶抗性和RNase H诱导表明，修饰的性质（-OH与-CH3）及其相对于邻位磷酸盐的立体化学取向在调节AON特性方面起着非常重要的作用。尽管对靶RNA的亲和力和AONs的酶稳定性受小沟中心的疏水和空间大体积修饰的不

  DOI：

  10.1021/jo8016742
• 作为产物：
  描述：

  1-[3,5-di-O-benzyl-4-C-(1-hydroxy-allyl)-2-O-phenoxythiocarbonyl-β-D-ribofuranosyl]thymine 在 偶氮二异丁腈 、 三正丁基氢锡 作用下， 以 甲苯 为溶剂， 反应 4.5h， 以49%的产率得到(1R,3R,4R,5S,6S,7S)-7-benzyloxy-1-benzyloxymethyl-6-hydroxy-5-methyl-3-(thymin-1-yl)-2-oxa-bicyclo[2.2.1]heptane
  参考文献：
  名称：

  通过结合修饰的2'，4'-碳环LNA和-ENAs对核苷酸间磷酸周围的静电进行微调导致反义特性的显着调节

  摘要：

  在反义（AS）和RNA干扰（RNAi）技术中，对天然单链2'-脱氧寡核苷酸（用于AS）或双链RNA（用于RNAi）进行化学修饰，使其与目标RNA结合，从而获得更好的通过抑制RNA翻译来下调基因表达。此处显示了通过改变取代基的静电相互作用以及围绕反义寡核苷酸（AON）-RNA异源双链体的小树林边缘附近的核苷酸间磷酸二酯部分周围的立体化学环境的精细调节，如何导致调节反义性质。通过合成各种修饰的碳环锁核酸（LNA）和在碳环部分连接有羟基和/或甲基取代基的-亚乙基桥核酸（ENA）并通过固相DNA合成将其整合到AON中来证明这一点。 。这些修饰的AON对互补RNA和DNA的靶标亲和力，核酸酶抗性和RNase H诱导表明，修饰的性质（-OH与-CH3）及其相对于邻位磷酸盐的立体化学取向在调节AON特性方面起着非常重要的作用。尽管对靶RNA的亲和力和AONs的酶稳定性受小沟中心的疏水和空间大体积修饰的不

  DOI：

  10.1021/jo8016742

文献信息

• Unusual radical 6-endo cyclization to carbocyclic-ENA and elucidation of its solution conformation by 600 MHz NMR and ab initio calculations
  作者：Chuanzheng Zhou、Oleksandr Plashkevych、Jyoti Chattopadhyaya

  DOI：10.1039/b813870b

  日期：——

  through 5-hexenyl or 6-heptenyl radical cyclization. Both 5-hexenyl and 6-heptenyl radical cyclized exclusively in the exo form, giving unwanted exocyclic C7-methyl group. In the present study, we showed that the regioselectivity of the 5-hexenyl radical cyclization could be favorably tuned by introduction of a hydroxyl group to the olefinic double bond, yielding about 9% of the 6-endo cyclization product

  在我们以前的论文（J. Am。Chem。Soc。，2007，129，8362）中，我们报道了通过5-己烯基或6-庚烯基合成7-Me-Carba-LNA和8-Me-Carba-ENA胸腺嘧啶核苷自由基环化。5-己烯基和6-庚烯基均以环外形式环化，从而得到不需要的环外C7-甲基。在本研究中，我们表明，可以通过将羟基引入烯属双键来调节5-己烯基自由基环化的区域选择性，产生约9％的6-内环化环化产物。与负责产生5-exo环化产物5的中间体相比，已经讨论了产生6-endo环化产物9的可能途径。基于这种独特的6内环化策略，已成功合成了碳环ENA修饰的胸苷（carba-ENA），
• Double Sugar and Phosphate Backbone-Constrained Nucleotides: Synthesis, Structure, Stability, and Their Incorporation into Oligodeoxynucleotides
  作者：Chuanzheng Zhou、Oleksandr Plashkevych、Jyoti Chattopadhyaya

  DOI：10.1021/jo900391n

  日期：2009.5.1

  Two diastereomerically pure carba-LNA dioxaphosphorinane nucleotides [(S-p)- or (R-p)-D-2-CNA], simultaneously conformationally locked at the sugar and the phosphate backbone, have been designed and synthesized. Structural studies by NMR as well as by ab initio calculations showed that in (S-p)- and (R-p)-D-2-CNA the Mowing occur: (i) the sugar is locked in extreme North-type conformation with P = 11 degrees and Phi(m) (ii) the six-membered 1,3,2-dioxaphosphorinane ring adopts a half-chair conformation; (iii) the fixed phosphate backbone delta, epsilon, and zeta torsions were found to be delta [gauch(+)], epsilon (cis), zeta[anticlinal(+)] for (S-p)-D-2-CNA, and delta [gaitche(+)], epsilon(cis), zeta[anticlittal(-)] for (R-p)-D-2-CNA. It has been found that F- ion can catalyze the isomerization of pure (S-p)-D-2-CNA or (R-p)-D-2-CNA to give an equilibrium mixture (K = 1.94). It turned out that at equilibrium concentration the (S-p)-D-2-CNA isomer is preferred over the (R-p)-D-2-CNA isomer by 0.39 kcal/mol. The chemical reactivity of the six-membered dioxaphosphorinane ring in D-2-CNA was found to be dependent on the internucleotidic phosphate stereochemistry. Thus, both (Sp)- and (Rp)-D2-CNA dimers (17a and 17b) were very labile toward nucleophile attack in concentrated aqueous ammonia [t(1/2) = 12 and 6 min, respectively] to give carba-LNA-6',5'-phosphodiester (21) approximate to 70-90%, carba-LNA-3',5'-phosphodiester (22) approximate to 10%, and carba-LNA-6',3'-phosphodiester (23) < 10%. In contrasts the (S-p)-D-2-CNA was about 2 times more stable than (Rp)-D2-CNA under hydrazine hydrate/pyficfine/AcOH (pH = 5.6) [t(1/2) = 178 and 99 h, respectively], which was exploited in the deprotection of pure (S-p)-D-2-CNA incorporated antisense oligodeoxynucleotides (AON). Thus, after removal of the solid supports from the (S-p)-D-2-CNA-modified AON by BDU/MeCN, they were treated with hydrazine hydrate in pyridine/AcOH to give pure AONs in 35-40% yield, which was unequivocally characterized by MALDI-TOF to show that they have an intact six-membered dioxaphosphorinane ring. The effect of pure (S-p)-D-2-CNA niodification in the AONs was estimated by complexing to the complementary RNA and DNA strands by the thermal denaturation studies. This showed that this cyclic phosphotriester modification destabilizes the AON/DNA and AON/RNA duplex by about -6 to -9 degrees C/modification. Treatment of (Sp)-D-2-CNA-modified AON with concentrated aqueous ammonia gave cwba-LNA-6',5'-phosphodiester modified AON (similar to 80%) plus a small amount of carba-LNA-3',5'-Phosphodiester-modified AON (similar to 20%). It is noteworthy that Carba-LNA-3',5'-phosphodiester modification stabilized the AON/RNA duplex by +4 degrees C/modificafion (J. Org. Chem. 2009, 74, 118), whereas carba-LNA-6', 5'-phosphodiester modification destabilizes both AON/RNA and AON/DNA significantly (by -10 to -19 degrees C/modification), which, as shown in our comparative CD studies, that the cyclic phosphotriester modified AONs as well as carba-LNA-6'.5'-phosphodiester modified AONs are much more weakly stacked than carba-LNA-3',5'-phosphodiester-modified AONs.
• Synthesis and Structure of New Methylene-Bridged Hexopyranosyl Nucleoside (BHNA)
  作者：Jyoti Chattopadhyaya、Chuanzheng Zhou、Oleksandr Plashkevych、Yi Liu、Naresh Badgujar

  DOI：10.3987/com-09-11660

  日期：——

  A new member of hexopyranosyl nucleoside family, methylene-bridged hexopyranosyl nucleoside (BHNA), has been synthesized through generation of carbon radical at C6' in [6'S-Me, 7'S-Me]-carba-LNA T nucleoside, followed by rearrangement to C4' radical which was quenched by hydrogen atom to give BHNA. The stereoelectronic requirement for this unusual radical rearrangement has been elucidated by chemical model building and ab intio calculations to show that the coplanarity of the single electron occupied p-orbital at C6' with sigma*(O4'-C4') plays an important role for the rearrangement reaction to take place. The solution structure of BHNA has also been studied using NMR as well as by ab initio calculations. The new six-membered pyranosyl ring in BHNA, unlike other known hexopyranosyl nucleosides, adopts a twist conformation, with base moiety occupying the axial position while 3'-hydroxymethyl and 4'-hydroxyl occupying the equatorial position.