1-(m-isothiocyanatophenyl)-4-tert-butyl-2,6,7-trioxabicyclo<2.2.2>octane | 119963-44-9

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-(m-isothiocyanatophenyl)-4-tert-butyl-2,6,7-trioxabicyclo<2.2.2>octane
• 英文别名: 4-Tert-butyl-1-(3-isothiocyanatophenyl)-2,6,7-trioxabicyclo[2.2.2]octane
• CAS: 119963-44-9
• 化学式: C₁₆H₁₉NO₃S
• 分子量: 305.398
• InChiKey: YFTFDOFUNFYMMT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  72.1
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  间硝基苯甲酰氯 在 Pd-BaSO₄ 三氟化硼乙醚 、 氢气 、 potassium carbonate 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 氯仿 、 水 、 正戊烷 为溶剂， 25.0 ℃ 、101.33 kPa 条件下， 反应 13.66h， 生成 1-(m-isothiocyanatophenyl)-4-tert-butyl-2,6,7-trioxabicyclo<2.2.2>octane
  参考文献：
  名称：

  Novel site-directed affinity ligands for GABA-gated chloride channels: synthesis, characterization, and molecular modeling of 1-(isothiocyanatophenyl)-4-tert-butyl-2,6,7-trioxabicyclo[2.2.2]octanes

  摘要：

  p-,m-, and o-isothiocyanate derivatives (1-3, respectively) of tert-butylbicycloorthobenzoate (TBOB) were synthesized from 3-tert-butyloxetane-3-methanol (4) as the starting material. While 2 was readily obtained in four steps via catalytic hydrogenation of the m-nitro-tert-butylbicycloorthobenzoate (9) intermediate, 1 and 3 could not be obtained this way. 1 and 3 were instead synthesized by an alternative four-step approach which made use of the stability of the isothiocyanate moiety to strong Lewis acids such as boron trifluoride etherate, conditions that would isomerize isothiocyanato oxetane ester intermediates to their corresponding orthoesters. The p-isothiocyanate derivative of TBOB, compound 1, inhibited [S-35]-tert-butylbicyclophosphorothionate (TBPS) binding to rat cortical membranes with a potency (IC50 62 nM) comparable to the parent compound while 2 and 3 were approximately 10-fold less potent (IC50 values 570 and 609 nM, respectively). Preincubating tissue with radioligand further reduced the potencies of 2 and 3 by approximately 1 order of magnitude (IC50 values 5400 and 7500 nM, respectively) while the potency of 1 (IC50 90 nM) was only marginally affected by this procedure. Pretreatment of membranes with 1 and 2 followed by extensive washing resulted in a concentration-dependent inhibition of [S-35]TBPS binding. In contrast, preincubating tissues with up to 2.4-mu-M of 3 did not elicit an apparent acylation of [S-35]TBPS binding sites. Molecular modeling of the effective diameters of 1-3 in their thermodynamically most stable conformations indicates a relationship between these diameters and their relative efficacies as site-directed acylators; the smaller the diameter, the more potent the acylator. This hypothesis explains both the relative potencies of these compounds and their differential abilities to acylate the TBPS binding site.

  DOI：

  10.1021/jm00109a002

文献信息

• DE, COSTA BRIAN R.;LEWIN, ANITA H.;RICE, KENNER C.;SKOLNICK, PHIL;SCHOENH+, J. MED. CHEM., 34,(1991) N, C. 1531-1538
  作者：DE, COSTA BRIAN R.、LEWIN, ANITA H.、RICE, KENNER C.、SKOLNICK, PHIL、SCHOENH+

  DOI：——

  日期：——
• Novel site-directed affinity ligands for GABA-gated chloride channels: synthesis, characterization, and molecular modeling of 1-(isothiocyanatophenyl)-4-tert-butyl-2,6,7-trioxabicyclo[2.2.2]octanes
  作者：Brian R. De Costa、Anita H. Lewin、Kenner C. Rice、Phil Skolnick、Joyce A. Schoenheimer

  DOI：10.1021/jm00109a002

  日期：1991.5

  p-,m-, and o-isothiocyanate derivatives (1-3, respectively) of tert-butylbicycloorthobenzoate (TBOB) were synthesized from 3-tert-butyloxetane-3-methanol (4) as the starting material. While 2 was readily obtained in four steps via catalytic hydrogenation of the m-nitro-tert-butylbicycloorthobenzoate (9) intermediate, 1 and 3 could not be obtained this way. 1 and 3 were instead synthesized by an alternative four-step approach which made use of the stability of the isothiocyanate moiety to strong Lewis acids such as boron trifluoride etherate, conditions that would isomerize isothiocyanato oxetane ester intermediates to their corresponding orthoesters. The p-isothiocyanate derivative of TBOB, compound 1, inhibited [S-35]-tert-butylbicyclophosphorothionate (TBPS) binding to rat cortical membranes with a potency (IC50 62 nM) comparable to the parent compound while 2 and 3 were approximately 10-fold less potent (IC50 values 570 and 609 nM, respectively). Preincubating tissue with radioligand further reduced the potencies of 2 and 3 by approximately 1 order of magnitude (IC50 values 5400 and 7500 nM, respectively) while the potency of 1 (IC50 90 nM) was only marginally affected by this procedure. Pretreatment of membranes with 1 and 2 followed by extensive washing resulted in a concentration-dependent inhibition of [S-35]TBPS binding. In contrast, preincubating tissues with up to 2.4-mu-M of 3 did not elicit an apparent acylation of [S-35]TBPS binding sites. Molecular modeling of the effective diameters of 1-3 in their thermodynamically most stable conformations indicates a relationship between these diameters and their relative efficacies as site-directed acylators; the smaller the diameter, the more potent the acylator. This hypothesis explains both the relative potencies of these compounds and their differential abilities to acylate the TBPS binding site.