(1R,3aR,7aR)-7a-methyl-1-[(2R)-6-methyl-6-trimethylsilyloxyheptan-2-yl]-2,3,3a,7-tetrahydro-1H-inden-4-one | 180040-63-5

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: (1R,3aR,7aR)-7a-methyl-1-[(2R)-6-methyl-6-trimethylsilyloxyheptan-2-yl]-2,3,3a,7-tetrahydro-1H-inden-4-one
• CAS: 180040-63-5
• 化学式: C₂₁H₃₈O₂Si
• 分子量: 350.617
• InChiKey: DMFICAHGIOOFRF-DCXXXQMHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.98
• 重原子数：
  24
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  26.3
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (1R,3aR,7aR)-7a-methyl-1-[(2R)-6-methyl-6-trimethylsilyloxyheptan-2-yl]-2,3,3a,7-tetrahydro-1H-inden-4-one 在 四(三苯基膦)钯 、 sodium hexamethyldisilazane 、 三乙胺 、 三苯基膦 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 反应 4.0h， 生成 [(6R)-6-[(1R,3aR,4E,7aR)-7a-methyl-4-[(2E)-2-(4-methylideneoxolan-3-ylidene)ethylidene]-2,3,3a,7-tetrahydro-1H-inden-1-yl]-2-methylheptan-2-yl]oxy-trimethylsilane
  参考文献：
  名称：

  Inhibitors of 25-Hydroxyvitamin D₃-1α-Hydroxylase:  A-Ring Oxa Analogs of 25-Hydroxyvitamin D₃¹

  摘要：

  The most potent inhibitor known of 25-hydroxyvitamin D-3 1 alpha-hydroxylase (1-OHase), a cytochrome P-450 mixed function oxidase involved in the production of the steroid hormone 1 alpha,25-dihydroxyvitamin D-3 (2), is 25-hydroxy-3-deoxy-2-oxavitamin D-3(3b). The latter, prepared previously in relatively low yield, is unusual because it coexists in nearly equal proportions with its [1,7]-sigmatropic shifted, previtamin D-3 tautomer 4b. A more efficient synthesis of this potent inhibitor was developed by applying Trost's enyne Pd(0) cyclization strategy. Besides succeeding in improving the synthesis of 3b/4b, extension of this approach to the synthesis of other related A-ring oxacycles for structure-function studies of the 1-OHase system has been successful. This venture has resulted not only in oxacycles 4a, 3b/4b, and 3c but also their 9,11-didehydro counterparts 5a, 5b, and 5c. The analog 5b was anticipated to be of particular interest because it represents an analog of the potent inhibitor 3b, but the presence of the 9,11-double bond renders it incapable of undergoing a [1,7]-sigmatropic shift to a form resembling 4b. Biological evaluation of 5b revealed it to be a more potent inhibitor of 1-OHase than 3b/4b, suggesting that 3b is the likely form of the inhibitor 3b/4b. Initial kinetic experiments indicate that the analogs (3b, 3c, and 5b) tested do not inhibit by direct mechanism-based enzyme inactivation, revealing rather that inhibition of 1-OHase is competitive. Finally, it should be noted that the synthetic studies described herein provide new information regarding the scope and limitations of the palladium(0)-mediated enyne cyclization strategy leading to vitamin D molecules.

  DOI：

  10.1021/jo960498g
• 作为产物：
  描述：

  (1R,3aR,7aR)-1-{(1R)-1,5-dimethyl-5-[(trimethylsilyl)oxy]hexyl}-7a-methyloctahydro-4H-inden-4-one 在 苯基氯化硒 、 间氯过氧苯甲酸 、 lithium diisopropyl amide 作用下， 生成 (1R,3aR,7aR)-7a-methyl-1-[(2R)-6-methyl-6-trimethylsilyloxyheptan-2-yl]-2,3,3a,7-tetrahydro-1H-inden-4-one
  参考文献：
  名称：

  Inhibitors of 25-Hydroxyvitamin D₃-1α-Hydroxylase:  A-Ring Oxa Analogs of 25-Hydroxyvitamin D₃¹

  摘要：

  The most potent inhibitor known of 25-hydroxyvitamin D-3 1 alpha-hydroxylase (1-OHase), a cytochrome P-450 mixed function oxidase involved in the production of the steroid hormone 1 alpha,25-dihydroxyvitamin D-3 (2), is 25-hydroxy-3-deoxy-2-oxavitamin D-3(3b). The latter, prepared previously in relatively low yield, is unusual because it coexists in nearly equal proportions with its [1,7]-sigmatropic shifted, previtamin D-3 tautomer 4b. A more efficient synthesis of this potent inhibitor was developed by applying Trost's enyne Pd(0) cyclization strategy. Besides succeeding in improving the synthesis of 3b/4b, extension of this approach to the synthesis of other related A-ring oxacycles for structure-function studies of the 1-OHase system has been successful. This venture has resulted not only in oxacycles 4a, 3b/4b, and 3c but also their 9,11-didehydro counterparts 5a, 5b, and 5c. The analog 5b was anticipated to be of particular interest because it represents an analog of the potent inhibitor 3b, but the presence of the 9,11-double bond renders it incapable of undergoing a [1,7]-sigmatropic shift to a form resembling 4b. Biological evaluation of 5b revealed it to be a more potent inhibitor of 1-OHase than 3b/4b, suggesting that 3b is the likely form of the inhibitor 3b/4b. Initial kinetic experiments indicate that the analogs (3b, 3c, and 5b) tested do not inhibit by direct mechanism-based enzyme inactivation, revealing rather that inhibition of 1-OHase is competitive. Finally, it should be noted that the synthetic studies described herein provide new information regarding the scope and limitations of the palladium(0)-mediated enyne cyclization strategy leading to vitamin D molecules.

  DOI：

  10.1021/jo960498g

文献信息

• Inhibitors of 25-Hydroxyvitamin D₃-1α-Hydroxylase:  A-Ring Oxa Analogs of 25-Hydroxyvitamin D₃¹
  作者：Dilon Daniel、Rondo Middleton、Helen L. Henry、William H. Okamura

  DOI：10.1021/jo960498g

  日期：1996.1.1

  The most potent inhibitor known of 25-hydroxyvitamin D-3 1 alpha-hydroxylase (1-OHase), a cytochrome P-450 mixed function oxidase involved in the production of the steroid hormone 1 alpha,25-dihydroxyvitamin D-3 (2), is 25-hydroxy-3-deoxy-2-oxavitamin D-3(3b). The latter, prepared previously in relatively low yield, is unusual because it coexists in nearly equal proportions with its [1,7]-sigmatropic shifted, previtamin D-3 tautomer 4b. A more efficient synthesis of this potent inhibitor was developed by applying Trost's enyne Pd(0) cyclization strategy. Besides succeeding in improving the synthesis of 3b/4b, extension of this approach to the synthesis of other related A-ring oxacycles for structure-function studies of the 1-OHase system has been successful. This venture has resulted not only in oxacycles 4a, 3b/4b, and 3c but also their 9,11-didehydro counterparts 5a, 5b, and 5c. The analog 5b was anticipated to be of particular interest because it represents an analog of the potent inhibitor 3b, but the presence of the 9,11-double bond renders it incapable of undergoing a [1,7]-sigmatropic shift to a form resembling 4b. Biological evaluation of 5b revealed it to be a more potent inhibitor of 1-OHase than 3b/4b, suggesting that 3b is the likely form of the inhibitor 3b/4b. Initial kinetic experiments indicate that the analogs (3b, 3c, and 5b) tested do not inhibit by direct mechanism-based enzyme inactivation, revealing rather that inhibition of 1-OHase is competitive. Finally, it should be noted that the synthetic studies described herein provide new information regarding the scope and limitations of the palladium(0)-mediated enyne cyclization strategy leading to vitamin D molecules.