(1R,2R,4S,5S,6S)-8,8-dimethyl-2-(phenylmethoxymethyl)-7,9-dioxatricyclo[4.3.0.02,4]nonan-5-ol | 156126-13-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (1R,2R,4S,5S,6S)-8,8-dimethyl-2-(phenylmethoxymethyl)-7,9-dioxatricyclo[4.3.0.02,4]nonan-5-ol
• CAS: 156126-13-5
• 化学式: C₁₇H₂₂O₄
• 分子量: 290.359
• InChiKey: JBKUESGTXDZTBE-MDLJMBGESA-N

物化性质

• 沸点：
  408.2±30.0 °C(Predicted)
• 密度：
  1.216±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  47.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (1R,2R,4S,5S,6S)-8,8-dimethyl-2-(phenylmethoxymethyl)-7,9-dioxatricyclo[4.3.0.02,4]nonan-5-ol 在 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 为溶剂， 反应 15.0h， 生成 (1'S,2'R,3'S,4'R,5'S)-4-(6-methylamino-2-chloro-9H-purin-9-yl)-1-[(phenylmethoxy)methyl]bicyclo[3.1.0]hexane-2,3-(O-isopropylidene)
  参考文献：
  名称：

  Adenine Nucleotide Analogues Locked in a Northern Methanocarba Conformation:  Enhanced Stability and Potency as P2Y₁ Receptor Agonists

  摘要：

  Preference for the Northern (N) ring conformation of the ribose moiety of nucleotide 5'-triphosphate agonists at P2Y(1), P2Y(2), P2Y(4), and P2Y(11) receptors, but not P2Y(6) receptors, was established using a ring-constrained methanocarba (a 3.1.0-bicyclohexane) ring as a ribose substitute (Kim et al. J. Med. Chem. 2002, 45, 208-218.). We have now combined the ring-constrained (N)-methanocarba modification of adenine nucleotides with other functionalities known to enhance potency at P2 receptors. The potency of the newly synthesized analogues was determined in the stimulation of phospholipase C through activation of turkey erythrocyte P2Y, or human P2Y, and P2Y2 receptors stably expressed in astrocytoma cells. An (N)methanocarba-2-methylthio-ADP analogue displayed an EC50 at the hP2Y(1) receptor of 0.40 nM and was 55-fold more potent than the corresponding triphosphate and 16-fold more potent than the riboside 5'-diphosphate. 2-Cl-(N)-methanocarba-ATP and its N-6-Me analogue were also highly selective, full agonists at P2Y, receptors. The (N)-methanocarba-2-methylthio and 2-chloromonophosphate analogues were full agonists exhibiting micromolar potency at P2Y(1) receptors, while the corresponding ribosides were inactive. Although beta,y-methylene-ATP was inactive at P2Y receptors beta,y-methylene-(N)-methanocarba-ATP was a potent hP2Y1 receptor agonist with an EC50 of 160 nM and was selective versus hP2Y(2) and hP2Y(4) receptors. The rates of hydrolysis of Northern (N) and Southern (S) methanocarba analogues of AMP by rat 5'-ectonucleotidase were negligible. The rates of hydrolysis of the corresponding triphosphates by recombinant rat NTPDase 1 and 2 were studied. Both isomers were hydrolyzed by NTPDase 1 at about half the rate of ATP hydrolysis. The (N) isomer was hardly hydrolyzed by NTPDase 2, while the (S) isomer was hydrolyzed at one-third of the rate of ATP hydrolysis. This suggests that new, more stable and selective nucleotide agonists may be designed on the basis of the (N)-conformation, which greatly enhanced potency at P2Y, receptors.

  DOI：

  10.1021/jm010538v
• 作为产物：
  描述：

  (4R,5R)-3-benzyloxymethyl-4,5-isopropylidenedioxycyclopent-2-enone 在 cerium(III) chloride 、 diethylzinc 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 7.0h， 生成 (1R,2R,4S,5S,6S)-8,8-dimethyl-2-(phenylmethoxymethyl)-7,9-dioxatricyclo[4.3.0.02,4]nonan-5-ol
  参考文献：
  名称：

  Synthesis and Anti-HIV Activity of Carbocyclic Ring-Enlarged 4′,1′a-Methano Oxetanocin Analogues

  摘要：

  Synthesis of carbocyclic ring-enlarged 4',1'a-methano oxetanocin analogues via completely regioselective opening of cyclic sulfites by sodium azide or purine bases is described.

  DOI：

  10.1080/07328319708006132

文献信息

• Synthesis Using Ring Closure Metathesis and Effect on Nucleoside Transport of a (N)-Methanocarba <i>S</i>-(4-Nitrobenzyl)thioinosine Derivative
  作者：Kyeong Lee、Carol Cass、Kenneth A. Jacobson

  DOI：10.1021/ol006999c

  日期：2001.2.1

  [reaction: see text] A new synthetic route to ring-constrained (N)-methanocarba nucleosides and nucleotides is presented. Ring closure of a diene intermediate using Grubbs catalyst provides a new avenue for the preparation of the cyclopentenone derivative 6, which is a versatile intermediate for various carbocycles. The product was almost as potent an inhibitor of es-mediated nucleoside transport as

  [反应：见正文] 提出了环约束（N）-甲烷卡巴核苷和核苷酸的新合成路线。使用格鲁布斯催化剂使二烯中间体闭环，为环戊烯酮衍生物6的制备提供了新途径，环戊烯酮衍生物6是各种碳环的通用中间体。该产品几乎与母体化合物一样有效，是 es 介导的核苷转运抑制剂，在大约 30-50 nM 的浓度下，可将培养的 CCRF-CEM 细胞中尿苷的初始摄取率抑制 50%。
• Synthesis of Cyclopropyl-Fused Carbocyclic Nucleosides via the Regioselective Opening of Cyclic Sulfites
  作者：Hyung Ryong Moon、Hea Ok Kim、Moon Woo Chun、Lak Shin Jeong、Victor E. Marquez

  DOI：10.1021/jo990010m

  日期：1999.6.1

  The syntheses of some carbocyclic nucleosides that are conformationally locked as "northern" mimics of antiviral active, ring-expanded oxetanocin analogues are reported. The target compounds derived their rigid conformation from a common bicyclo[3.1.0]hexane template. The uracil (3a), cytosine (3b), and adenine (3c) analogues were synthesized from an intermediate cyclic sulfite (12a) that underwent

  据报道，某些碳环核苷的合成被构象锁定为抗病毒活性，扩环的氧杂环丁烷类似物的“北方”模拟物。目标化合物从常见的双环[3.1.0]己烷模板获得其刚性构象。尿嘧啶（3a），胞嘧啶（3b）和腺嘌呤（3c）类似物是由中间体环状亚硫酸盐（12a）合成的，该中间体经过亲核试剂选择性开环。12a与叠氮化钠的反应可在嘧啶环建成后提供尿嘧啶和胞嘧啶类似物（3a和3b），而与腺嘌呤钠盐的反应则提供了一种有效的3c收敛方法。由12a与2-氨基-6-氯嘌呤偶联获得的不期望的N-7区域异构体占优势。因此，将二醇衍生物11选择性地保护并在Mitsunobu条件下偶联，以在脱保护后得到所需的鸟嘌呤类似物3d。除鸟嘌呤类似物外，本文所述的环亚硫酸盐化学代表了一种有用的替代方法，可作为碳环核苷的一般方法。目标核苷3a-d均未显示出对HIV-1，HSV-1，HSV-2和HCMV的显着抗病毒活性。相对于已显示出良好的抗HSV和抗
• Use of a cyclic sulfite as an epoxide surrogate in the regioselective synthesis of a carbocyclic ring-enlarged 4′,1′a-methano oxetanocin analogue
  作者：Lak S. Jeong、Victor E. Marquez

  DOI：10.1016/0040-4039(96)00289-4

  日期：1996.4

  Although cyclic sulfites are less reactive than their cyclic sulfate counterparts, the present work shows that cyclic sulfite 15a is a useful synthon for the convergent synthesis of carbocyclic nucleosides. Target compound 6, which represents a rigid carbocyclic nucleoside mimic of anti-HIV active 9-[2′,3′-dideoxy-3′-C-(hydroxymethyl)-β-erythro-pentofuranosyl]adenine (3), was obtained after regioselective

  尽管环状亚硫酸盐的反应性比环状硫酸盐的反应性低，但目前的工作表明，环状亚硫酸盐15a是碳环核苷聚合合成的有用合成子。获得了目标化合物6，该化合物代表抗HIV活性9- [2'，3'-二脱氧-3'- C-（羟甲基）-β-赤型-戊呋喃糖基]腺嘌呤的刚性碳环核苷类似物（3），15a具有腺嘌呤的区域选择性开环和自由基诱导的额外羟基脱氧。
• Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists
  作者：Kenneth A. Jacobson、Xiao-duo Ji、An-Hu Li、Neli Melman、Maqbool A. Siddiqui、Kye-Jung Shin、Victor E. Marquez、R. Gnana Ravi

  DOI：10.1021/jm9905965

  日期：2000.6.1

  (N)-Methanocarba analogues of various N(6)-substituted adenosine derivatives, including cyclopentyl and 3-iodobenzyl, in which the parent compounds are potent agonists at either A(1) or A(3) receptors, respectively, were synthesized. The N(6)-cyclopentyl derivatives were A(1) receptor-selective and maintained high efficacy at recombinant human but not rat brain A(1) receptors, as indicated by stimulation of binding

  腺苷受体激动剂具有心脏保护、脑保护和抗炎特性。我们报告核糖部分纳入环约束的碳环修饰是设计具有良好药效学特性的 A(1) 和 A(3) 受体激动剂的一般方法。虽然腺苷激动剂的简单碳环取代大大降低了效力，但甲卡巴-腺苷类似物现在已经确定了糖褶皱在稳定活性腺苷受体结合构象中的作用，从而可以识别出一种有利的异构体。在此类类似物中，稠合环丙烷部分将核苷的假糖环限制为北（N）或南（S）构象，如假旋转循环中所定义。在 A(1)、A(2A) 和 A(3) 受体的结合试验中，(N)-methanocarba-腺苷比 (S)-类似物具有更高的亲和力，特别是在人类 A(3) 受体上（N/S 亲和力比为 150）。(N)-Methanocarba 类似物的各种 N(6)-取代的腺苷衍生物，包括环戊基和 3-碘苄基，其中母体化合物分别是 A(1) 或 A(3) 受体的有效激动剂，被合成。N(6)-环戊基衍生物对 A(1)
• Synthesis and purine receptor affinity of 6-oxopurine nucleosides and nucleotides containing (N)-methanocarba-pseudoribose rings
  作者：Gnana Ravi、Kyeong Lee、Xiao-duo Ji、Hak Sung Kim、Kelly A. Soltysiak、Victor E. Marquez、Kenneth A. Jacobson

  DOI：10.1016/s0960-894x(01)00450-4

  日期：2001.9

  6-Oxopurine derivatives containing a northern (N) methanocarba modification (i.e., fused cyclopropane and cyclopentane rings in place of the ribose) were synthesized and the adenosine receptor affinity measured. Guanine or hypoxanthine was coupled at the 7-position, or 1,3-diblitylxanthine was coupled at the 9-position. The pseudoribose ring was also substituted at the 5 ' -position with an N-methyluronamide or with phosphate groups. Published by Elsevier Science Ltd.