ent-N-methoxycarbonyl-8β-aminomethyl-13-methyl-12-podocarpene | 957466-15-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 菲及其衍生物
• 英文名称: ent-N-methoxycarbonyl-8β-aminomethyl-13-methyl-12-podocarpene
• 英文别名: methyl N-[[(4aR,4bS,8aS,10aR)-1,1,4a,7-tetramethyl-3,4,4b,5,8,9,10,10a-octahydro-2H-phenanthren-8a-yl]methyl]carbamate
• CAS: 957466-15-8
• 化学式: C₂₁H₃₅NO₂
• 分子量: 333.514
• InChiKey: XJQQTWKFIKVATI-HRQSHJORSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  38.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  ent-N-methoxycarbonyl-8β-aminomethyl-13-methyl-12-podocarpene 在 氢氧化钾 作用下， 以 甲醇 、 水 为溶剂， 反应 8.0h， 以95%的产率得到ent-8β-aminomethyl-13-methyl-12-podocarpene
  参考文献：
  名称：

  16-Aza-ent-beyerane and 16-Aza-ent-trachylobane:  Potent Mechanism-Based Inhibitors of Recombinant ent-Kaurene Synthase from Arabidopsis thaliana

  摘要：

  The secondary ent-beyeran-16-yl carbocation (7) is a key branch point intermediate in mechanistic schemes to rationalize the cyclic structures of many tetra- and pentacyclic diterpenes, including ent-beyerene, ent-kaurene, ent-trachylobane, and ent-atiserene, presumed precursors to >1000 known diterpenes. To evaluate these mechanistic hypotheses, we synthesized the heterocyclic analogues 16-aza-ent-beyerane (12) and 16-aza-ent-trachylobane (13) by means of Hg(Il)- and Pb(IV)-induced cyclizations onto the A12 double bonds of tricyclic intermediates bearing carbamoylmethyl and aminomethyl groups at C-8. The 13,16-seco-16-norcarbamate (20a) was obtained from ent-beyeran-16-one oxime (17) by Beckmann fragmentation, hydrolysis, and Curtius rearrangement. The aza analogues inhibited recombinant ent-kaurene synthase from Arabidopsis thaliana (GST-rAtKS) with inhibition constants (IC50 = 1 X 10(-7) and 1 X 10(-6) M) similar in magnitude to the pseudo-binding constant of the bicyclic ent-copalyl cliphosphate substrate (K-m = 3 x 10-7 M). Large enhancements of binding affinities (ICK = 4 x 10(-9) and 2 x 10(-8) M) were observed in the presence of 1 mM pyrophosphate, which is consistent with a tightly bound ent-beyeranyl(+)/ pyrophosphate- ion pair intermediate in the cyclization -rearrangement catalyzed by this diterpene synthase. The weak inhibition (IC50 = 1 x 10(-5) M) exhibited by ent-beyeran-16-exo-yl diphosphate (111) and its failure to undergo bridge rearrangement to kaurene appear to rule out the covalent cliphosphate as a free intermediate. 16-Aza-ent-beyerane is proposed as an effective mimic for the ent-beyeran-1 6-yl carbocation with potential applications as an active site probe for the various ent-diterpene cyclases and as a novel, selective inhibitor of gibberellin biosynthesis in plants.

  DOI：

  10.1021/ja072447e
• 作为产物：
  描述：

  甲醇 、 在 三乙胺 作用下， 以 苯 为溶剂， 反应 15.0h， 以267 mg的产率得到ent-N-methoxycarbonyl-8β-aminomethyl-13-methyl-12-podocarpene
  参考文献：
  名称：

  16-Aza-ent-beyerane and 16-Aza-ent-trachylobane:  Potent Mechanism-Based Inhibitors of Recombinant ent-Kaurene Synthase from Arabidopsis thaliana

  摘要：

  The secondary ent-beyeran-16-yl carbocation (7) is a key branch point intermediate in mechanistic schemes to rationalize the cyclic structures of many tetra- and pentacyclic diterpenes, including ent-beyerene, ent-kaurene, ent-trachylobane, and ent-atiserene, presumed precursors to >1000 known diterpenes. To evaluate these mechanistic hypotheses, we synthesized the heterocyclic analogues 16-aza-ent-beyerane (12) and 16-aza-ent-trachylobane (13) by means of Hg(Il)- and Pb(IV)-induced cyclizations onto the A12 double bonds of tricyclic intermediates bearing carbamoylmethyl and aminomethyl groups at C-8. The 13,16-seco-16-norcarbamate (20a) was obtained from ent-beyeran-16-one oxime (17) by Beckmann fragmentation, hydrolysis, and Curtius rearrangement. The aza analogues inhibited recombinant ent-kaurene synthase from Arabidopsis thaliana (GST-rAtKS) with inhibition constants (IC50 = 1 X 10(-7) and 1 X 10(-6) M) similar in magnitude to the pseudo-binding constant of the bicyclic ent-copalyl cliphosphate substrate (K-m = 3 x 10-7 M). Large enhancements of binding affinities (ICK = 4 x 10(-9) and 2 x 10(-8) M) were observed in the presence of 1 mM pyrophosphate, which is consistent with a tightly bound ent-beyeranyl(+)/ pyrophosphate- ion pair intermediate in the cyclization -rearrangement catalyzed by this diterpene synthase. The weak inhibition (IC50 = 1 x 10(-5) M) exhibited by ent-beyeran-16-exo-yl diphosphate (111) and its failure to undergo bridge rearrangement to kaurene appear to rule out the covalent cliphosphate as a free intermediate. 16-Aza-ent-beyerane is proposed as an effective mimic for the ent-beyeran-1 6-yl carbocation with potential applications as an active site probe for the various ent-diterpene cyclases and as a novel, selective inhibitor of gibberellin biosynthesis in plants.

  DOI：

  10.1021/ja072447e

文献信息

• 16-Aza-<i>ent</i>-beyerane and 16-Aza-<i>ent</i>-trachylobane:  Potent Mechanism-Based Inhibitors of Recombinant <i>ent</i>-Kaurene Synthase from <i>Arabidopsis thaliana</i>
  作者：Arnab Roy、Frank G. Roberts、P. Ross Wilderman、Ke Zhou、Reuben J. Peters、Robert M. Coates

  DOI：10.1021/ja072447e

  日期：2007.10.1

  The secondary ent-beyeran-16-yl carbocation (7) is a key branch point intermediate in mechanistic schemes to rationalize the cyclic structures of many tetra- and pentacyclic diterpenes, including ent-beyerene, ent-kaurene, ent-trachylobane, and ent-atiserene, presumed precursors to >1000 known diterpenes. To evaluate these mechanistic hypotheses, we synthesized the heterocyclic analogues 16-aza-ent-beyerane (12) and 16-aza-ent-trachylobane (13) by means of Hg(Il)- and Pb(IV)-induced cyclizations onto the A12 double bonds of tricyclic intermediates bearing carbamoylmethyl and aminomethyl groups at C-8. The 13,16-seco-16-norcarbamate (20a) was obtained from ent-beyeran-16-one oxime (17) by Beckmann fragmentation, hydrolysis, and Curtius rearrangement. The aza analogues inhibited recombinant ent-kaurene synthase from Arabidopsis thaliana (GST-rAtKS) with inhibition constants (IC50 = 1 X 10(-7) and 1 X 10(-6) M) similar in magnitude to the pseudo-binding constant of the bicyclic ent-copalyl cliphosphate substrate (K-m = 3 x 10-7 M). Large enhancements of binding affinities (ICK = 4 x 10(-9) and 2 x 10(-8) M) were observed in the presence of 1 mM pyrophosphate, which is consistent with a tightly bound ent-beyeranyl(+)/ pyrophosphate- ion pair intermediate in the cyclization -rearrangement catalyzed by this diterpene synthase. The weak inhibition (IC50 = 1 x 10(-5) M) exhibited by ent-beyeran-16-exo-yl diphosphate (111) and its failure to undergo bridge rearrangement to kaurene appear to rule out the covalent cliphosphate as a free intermediate. 16-Aza-ent-beyerane is proposed as an effective mimic for the ent-beyeran-1 6-yl carbocation with potential applications as an active site probe for the various ent-diterpene cyclases and as a novel, selective inhibitor of gibberellin biosynthesis in plants.