(3S,4R)-(3-hydroxy-4-(thymin-1-yl)-pyrrolidin-1-yl)methylphosphonic acid | 883872-98-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: (3S,4R)-(3-hydroxy-4-(thymin-1-yl)-pyrrolidin-1-yl)methylphosphonic acid
• 英文别名: (3S,4R)-4-(thymin-1-yl)-3-hydroxypyrrolidin-N-ylmethylphosphonic acid；[(3S,4R)-3-hydroxy-4-(5-methyl-2,4-dioxopyrimidin-1-yl)pyrrolidin-1-yl]methylphosphonic acid
• CAS: 883872-98-8
• 化学式: C₁₀H₁₆N₃O₆P
• 分子量: 305.227
• InChiKey: IEWVSQMDFYBJGG-SFYZADRCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -5.2
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  130
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  diisopropyl (3S,4R)-(3-hydroxy-4-(thymin-1-yl)-pyrrolidin-1-yl)methylphosphonate 在 三甲基溴硅烷 、 水 、 tetraethylammonium borohydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以38%的产率得到(3S,4R)-(3-hydroxy-4-(thymin-1-yl)-pyrrolidin-1-yl)methylphosphonic acid
  参考文献：
  名称：

  吡咯烷N-烷基膦酸酯及相关核苷酸类似物：合成与立体化学

  摘要：

  合成了N-膦酰基烷基-反式-3,4-二羟基吡咯烷衍生物，并将其用作合成子来制备羟基吡咯烷核苷膦酸，即3'-脱氧核苷5'-磷酸类似物。同时，研究了另一种途径，即利用曼尼希和迈克尔型反应对预先形成的吡咯烷核苷进行N-磷酸烷基化，以获得所需的核苷酸类似物。与后一种方法相反，前一种方法很可能由于亲核置换过程中存在两个可能的S N 2过渡态而形成了两个非对映异构体。通过NMR光谱研究了所制备的核苷酸类似物的立体化学。

  DOI：

  10.1016/j.tet.2009.02.071

文献信息

• Pyrrolidine N-alkylphosphonates and related nucleotide analogues: synthesis and stereochemistry
  作者：Dominik Rejman、Radek Pohl、Petr Kočalka、Milena Masojídková、Ivan Rosenberg

  DOI：10.1016/j.tet.2009.02.071

  日期：2009.5

  4-dihydroxypyrrolidine derivatives were synthesized and exploited as synthons for the preparation of hydroxypyrrolidine nucleoside phosphonic acids, the 3′-deoxynucleoside 5′-phosphate analogues. Simultaneously, an alternative route, the N-phosphoalkylation of the preformed pyrrolidine nucleosides employing Mannich- and Michael-type reactions, was investigated to obtain desired nucleotide analogues. In contrast to

  合成了N-膦酰基烷基-反式-3,4-二羟基吡咯烷衍生物，并将其用作合成子来制备羟基吡咯烷核苷膦酸，即3'-脱氧核苷5'-磷酸类似物。同时，研究了另一种途径，即利用曼尼希和迈克尔型反应对预先形成的吡咯烷核苷进行N-磷酸烷基化，以获得所需的核苷酸类似物。与后一种方法相反，前一种方法很可能由于亲核置换过程中存在两个可能的S N 2过渡态而形成了两个非对映异构体。通过NMR光谱研究了所制备的核苷酸类似物的立体化学。
• Structural diversity of nucleoside phosphonic acids as a key factor in the discovery of potent inhibitors of rat T-cell lymphoma thymidine phosphorylase
  作者：Petr Kočalka、Dominik Rejman、Václav Vaněk、Markéta Rinnová、Ivana Tomečková、Šárka Králíková、Magdalena Petrová、Ondřej Páv、Radek Pohl、Miloš Buděšínský、Radek Liboska、Zdeněk Točík、Natalya Panova、Ivan Votruba、Ivan Rosenberg

  DOI：10.1016/j.bmcl.2009.12.081

  日期：2010.2

  Structurally diverse, sugar-modified, thymine-containing nucleoside phosphonic acids were evaluated for their ability to inhibit thymidine phosphorylase (TP, EC 2.4.2.4) purified from spontaneous T-cell lymphomas of an inbred Sprague-Dawley rat strain. From a large set of tested compounds, among them a number of pyrrolidine-based derivatives, 10 nucleotide analogues with IC50 values below 1 mu M were selected. Out of them, four compounds strongly inhibited the enzyme with IC50 values lying in a range of 11-45 nM. These most potent compounds might be bi-substrate analogues. (C) 2009 Elsevier Ltd. All rights reserved.
• Pyrrolidine nucleotide analogs with a tunable conformation
  作者：Lenka Poštová Slavětínská、Dominik Rejman、Radek Pohl

  DOI：10.3762/bjoc.10.205

  日期：——

  Conformational preferences of the pyrrolidine ring in nucleotide analogs 7–14 were investigated by means of NMR and molecular modeling. The effect of the relative configuration of hydroxy and nucleobase substituents as well as the effect of the alkylation or acylation of the pyrrolidine nitrogen atom on the conformation of the pyrrolidine ring were studied. The results of a conformational analysis show that the alkylation/acylation can be effectively used for tuning the pyrrolidine conformation over the whole pseudorotation cycle.

  核苷酸类似物中吡咯烷环的构象偏好通过核磁共振和分子建模进行了研究。研究了羟基和核碱基取代基的相对构型以及吡咯烷氮原子的烷基化或酰化对吡咯烷环构象的影响。构象分析结果表明，烷基化/酰化可以有效地用于调节整个伪旋转周期中吡咯烷环的构象。