tert-butyl-[[(1R,2R,4S,5S,6R)-2-[(E)-2-di(propan-2-yloxy)phosphorylethenyl]-8,8-dimethyl-7,9-dioxatricyclo[4.3.0.02,4]nonan-5-yl]oxy]-diphenylsilane | 1215320-32-3

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: tert-butyl-[[(1R,2R,4S,5S,6R)-2-[(E)-2-di(propan-2-yloxy)phosphorylethenyl]-8,8-dimethyl-7,9-dioxatricyclo[4.3.0.02,4]nonan-5-yl]oxy]-diphenylsilane
• CAS: 1215320-32-3
• 化学式: C₃₃H₄₇O₆PSi
• 分子量: 598.792
• InChiKey: YWQMFQBZKHKBSK-BSKKTCLVSA-N

物化性质

• 沸点：
  615.2±55.0 °C(predicted)
• 密度：
  1.14±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  7.03
• 重原子数：
  41
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  63.2
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  tert-butyl-[[(1R,2R,4S,5S,6R)-2-[(E)-2-di(propan-2-yloxy)phosphorylethenyl]-8,8-dimethyl-7,9-dioxatricyclo[4.3.0.02,4]nonan-5-yl]oxy]-diphenylsilane 在 四丁基氟化铵 作用下， 以 四氢呋喃 为溶剂， 反应 13.0h， 以98%的产率得到(1S,2R,3S,4S,5S)-1-[diisopropyl-(E)-phosphonoethenyl]-4-(hydroxy)-2,3-O-(isopropylidene)-bicyclo[3.1.0]hexane
  参考文献：
  名称：

  Structure−Activity Relationship of (N)-Methanocarba Phosphonate Analogues of 5′-AMP as Cardioprotective Agents Acting Through a Cardiac P2X Receptor

  摘要：

  P2X receptor activation protects in heart failure models. MRS2339 3, a 2-chloro-AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) system, activates this cardioprotective channel. Michaelis-Arbuzov and Wittig reactions provided phosphonate analogues of 3, expected to be stable in vivo due to the C P bond. After chronic administration via a mini-osmotic pump (Alzet), some analogues significantly increased intact heart contractile function in calsequestrin-overexpressing mice (genetic model of heart failure) compared to vehicle-infused mice (all inactive at the vasodilatory P2Y(1) receptor). Two phosphonates, (1'S,2'R,3',5,4'R,5'S)-4'-(6-amino-2-chloropurin-9-y1)-2',3'-(dihydroxy)-1'-(phosphonomethylene)-bicyclo[3.1.0]hexane, 4 (MRS2775), and its homologue 9 (MRS2935), both 5'-saturated, containing a 2-Cl substitution, improved echocardiography-derived fractional shortening (20.25% and 19.26%, respectively, versus 13.78% in controls), while unsaturated 5'-extended phosphonates, all 2-H analogues, and a CH3-phosphonate were inactive. Thus, chronic administration of nucleotidase-resistant phosphonates conferred a beneficial effect, likely via cardiac P2X receptor activation. Thus, we have greatly expanded the range of carbocyclic nucleotide analogues that represent potential candidates for the treatment of heart failure.

  DOI：

  10.1021/jm9018542
• 作为产物：
  描述：

  亚甲基二磷酸四异丙酯 、 (1R,2S,4S,5S,6R)-5-[tert-butyl(diphenyl)silyl]oxy-8,8-dimethyl-7,9-dioxatricyclo[4.3.0.02,4]nonane-2-carbaldehyde 在 sodium hydride 作用下， 以 四氢呋喃 、 mineral oil 为溶剂， 反应 2.0h， 以46%的产率得到tert-butyl-[[(1R,2R,4S,5S,6R)-2-[(E)-2-di(propan-2-yloxy)phosphorylethenyl]-8,8-dimethyl-7,9-dioxatricyclo[4.3.0.02,4]nonan-5-yl]oxy]-diphenylsilane
  参考文献：
  名称：

  Structure−Activity Relationship of (N)-Methanocarba Phosphonate Analogues of 5′-AMP as Cardioprotective Agents Acting Through a Cardiac P2X Receptor

  摘要：

  P2X receptor activation protects in heart failure models. MRS2339 3, a 2-chloro-AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) system, activates this cardioprotective channel. Michaelis-Arbuzov and Wittig reactions provided phosphonate analogues of 3, expected to be stable in vivo due to the C P bond. After chronic administration via a mini-osmotic pump (Alzet), some analogues significantly increased intact heart contractile function in calsequestrin-overexpressing mice (genetic model of heart failure) compared to vehicle-infused mice (all inactive at the vasodilatory P2Y(1) receptor). Two phosphonates, (1'S,2'R,3',5,4'R,5'S)-4'-(6-amino-2-chloropurin-9-y1)-2',3'-(dihydroxy)-1'-(phosphonomethylene)-bicyclo[3.1.0]hexane, 4 (MRS2775), and its homologue 9 (MRS2935), both 5'-saturated, containing a 2-Cl substitution, improved echocardiography-derived fractional shortening (20.25% and 19.26%, respectively, versus 13.78% in controls), while unsaturated 5'-extended phosphonates, all 2-H analogues, and a CH3-phosphonate were inactive. Thus, chronic administration of nucleotidase-resistant phosphonates conferred a beneficial effect, likely via cardiac P2X receptor activation. Thus, we have greatly expanded the range of carbocyclic nucleotide analogues that represent potential candidates for the treatment of heart failure.

  DOI：

  10.1021/jm9018542

文献信息

• Structure−Activity Relationship of (<i>N</i>)-Methanocarba Phosphonate Analogues of 5′-AMP as Cardioprotective Agents Acting Through a Cardiac P2X Receptor
  作者：T. Santhosh Kumar、Si-Yuan Zhou、Bhalchandra V. Joshi、Ramachandran Balasubramanian、Tiehong Yang、Bruce T. Liang、Kenneth A. Jacobson

  DOI：10.1021/jm9018542

  日期：2010.3.25

  P2X receptor activation protects in heart failure models. MRS2339 3, a 2-chloro-AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) system, activates this cardioprotective channel. Michaelis-Arbuzov and Wittig reactions provided phosphonate analogues of 3, expected to be stable in vivo due to the C P bond. After chronic administration via a mini-osmotic pump (Alzet), some analogues significantly increased intact heart contractile function in calsequestrin-overexpressing mice (genetic model of heart failure) compared to vehicle-infused mice (all inactive at the vasodilatory P2Y(1) receptor). Two phosphonates, (1'S,2'R,3',5,4'R,5'S)-4'-(6-amino-2-chloropurin-9-y1)-2',3'-(dihydroxy)-1'-(phosphonomethylene)-bicyclo[3.1.0]hexane, 4 (MRS2775), and its homologue 9 (MRS2935), both 5'-saturated, containing a 2-Cl substitution, improved echocardiography-derived fractional shortening (20.25% and 19.26%, respectively, versus 13.78% in controls), while unsaturated 5'-extended phosphonates, all 2-H analogues, and a CH3-phosphonate were inactive. Thus, chronic administration of nucleotidase-resistant phosphonates conferred a beneficial effect, likely via cardiac P2X receptor activation. Thus, we have greatly expanded the range of carbocyclic nucleotide analogues that represent potential candidates for the treatment of heart failure.