methyl 4-methoxy-12-amino>-11-oxo-2-azatricyclo<12.2.2.1^3,7>nonadeca-3,5,7(19),14,16,17-hexaene-9-carboxylate | 138571-37-6

• 分子结构分类: 有机化合物 - 木脂素、新木脂素和相关化合物
• 英文名称: methyl 4-methoxy-12-amino>-11-oxo-2-azatricyclo<12.2.2.1^3,7>nonadeca-3,5,7(19),14,16,17-hexaene-9-carboxylate
• 英文别名: methyl 12(S)--4-methoxy-11-oxo-10-aza-2-oxatricyclo<12.2.2.1^3,7>-nonadeca-3,5,7(19),14,16,17-hexaene-9(R)-carboxylate；methyl (9S,12S)-4-methoxy-12-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]-11-oxo-2-oxa-10-azatricyclo[12.2.2.13,7]nonadeca-1(16),3,5,7(19),14,17-hexaene-9-carboxylate
• CAS: 138571-37-6
• 化学式: C₂₆H₃₂N₂O₇
• 分子量: 484.549
• InChiKey: AFIVBHWCNCTPQG-PMACEKPBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  35
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  103
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  methyl 4-methoxy-12-amino>-11-oxo-2-azatricyclo<12.2.2.1^3,7>nonadeca-3,5,7(19),14,16,17-hexaene-9-carboxylate 在 盐酸 作用下， 以 四氢呋喃 、 乙酸乙酯 为溶剂， 反应 12.5h， 生成 BOC-D-alanyl-L-alanyl-O4-methyl-L-tyrosyl-L-alanyl-N-methyl-L-tyrosyl-O4-methyl-L-tyrosine cyclic 54<*>63 ether, methyl ester
  参考文献：
  名称：

  N-Desmethyl Derivatives of Deoxybouvardin and RA-VII: Synthesis and Evaluation

  摘要：

  The synthesis of the complete set of seven N-desmethyl derivatives of RA-VII (8) are described. Thus, the synthesis of the four 14-membered cycloisodityrosine derivatives 21-24 and their coupling with the two tetrapeptides 32 and 33 followed by formation of the 18-membered ring with macrocyclization provided the full set of seven desmethyl derivatives 14-20 of RA-VII (8). The solution phase conformational properties of 8 and 14-20 were examined by 1D and 2D H-1 NMR to reveal the role of N-methylation on the key conformational aspects of the natural agents. In contrast to each of the simple cycloisodityrosine derivatives 21-24 which adopt a single, rigid solution conformation possessing a secondary or tertiary trans amide central to the 14-membered ring, the natural agents including 8 adopt a single predominant solution conformation (83-88%) that corresponds closely to the X-ray structure conformation which possesses an inherently disfavored cis C-30-N-29 tertiary amide central to the 14-membered cycloisodityrosine subunit. Moreover, this cis amide is the predominant conformation (85-95%) observed with N-29-desmethyl RA-VII (14) indicating that even a secondary C-30-N-29 amide adopts this inherently disfavored cis amide stereochemistry. The minor conformation of 8 observed in solution (12-17%) is shown to be derived from a minor cis C-8-N-9 tertiary amide which was not observed with its conversion to a secondary amide. Both N-9-desmethyl RA-VII (15) and N-9,N-29-desmethyl RA-VII (18) adopt exclusively a single solution conformation that corresponds to the major solution conformations of 8 and 14. This conformation contains a characteristic cis C-30-N-29 amide central to a type VI beta-turn and the cycloisodityrosine subunit, a trans C-8-N-9 amide central to a typical type II beta-turn capped with a tight Ala(4)-NH-O=C-Ala(1) hydrogen bond, and a trans C-14-N-15 N-methyl amide. In sharp contrast, removal of the N-15 methyl group within 16, 17, 19, and 20 results in the adoption of solution conformations possessing the inherently favored trans C-30-N-29 amide central to the cycloisodityrosine (14)-membered subunit. Thus, the N-15-methyl group within 8 is responsible for the agents adoption of the disfavored cis C-30-N-29 amide central to the cycloisodityrosine subunit. Importantly, preceding studies have defined the cycloisodityrosine subunit of 8 as the pharmacophore and, in a reversal of the initially assigned roles, revealed that it is the tetrapeptide housed in the 18-membered ring that induces and maintains the rigid, normally inaccessible cis C-30-N-29 amide conformation within the 14-membered cycloisodityrosine subunit. The studies detailed herein reveal that it is the N-15-methyl group that induces this conformational preference for the disfavored cis C-30-N-29 amide and that its removal results in a major conformational change with adoption of the trans C-30-N-29 amide and a loss of biological activity.Thus, the N-15-methyl group is essential for maintenance of the conformational and biological properties of 8; the N-9-methyl group is not essential, and its removal leads to exclusive population of a single biologically active conformation; and the N-29-methyl group once thought essential td the adoption of the C-30-N-29 cis amide is not essential, and its removal does not alter the conformational or biological properties of 8.

  DOI：

  10.1021/ja00133a010
• 作为产物：
  描述：

  Boc-4-碘-L-苯丙氨酸 在 sodium hydride 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 28.0h， 生成 methyl 4-methoxy-12-amino>-11-oxo-2-azatricyclo<12.2.2.1^3,7>nonadeca-3,5,7(19),14,16,17-hexaene-9-carboxylate
  参考文献：
  名称：

  环异二酪氨酸、RA-VII、脱氧布瓦丁和 N29-去甲基-RA-VII 的全合成：药效团的鉴定和亚基功能作用的逆转

  摘要：

  基于有效的分子内 Ullmann 反应作为制备难以捉摸的 14 元环异二酪氨酸亚基 (33) 的关键大环化反应的实施，描述了 RA-VII (1) 和脱氧布瓦丁 (2) 的简明全合成的全部细节的双环六肽。随后 34 与四肽 17 偶联以及大环化与 C 2 -N 3 酰胺键形成提供了 1 和 2。在解决有助于其抗肿瘤活性的药物的关键结构和构象特征的努力中，N 29 -去甲基-RA-制备了 VII 并详细说明了其化学、构象和初步生物学特性

  DOI：

  10.1021/ja00062a004

文献信息

• Synthesis of (9<i>R</i>,12<i>S</i>)- and (9<i>S</i>,12<i>S</i>)-Cycloisodityrosine and Their <i>N</i>-Methyl Derivatives
  作者：Dale L. Boger、Jiacheng Zhou、Robert M. Borzilleri、Seiji Nukui、Steven L. Castle

  DOI：10.1021/jo961346o

  日期：1997.4.1

  Full details of the synthesis of (9R,12S)- and (9S,12S)-cycloisodityrosine and their N-methyl derivatives are detailed based on an intramolecular nucleophilic aromatic substitution reaction for formation of the key biaryl ether with 14-membered ring macrocyclization. Their comparison with prior samples and the documentation of a facile C9 epimerization within the natural 9S series are described.

  基于分子内亲核芳族取代反应以形成具有14元环大环化的关键联芳基醚，详细描述了（9R，12S）-和（9S，12S）-环异酪氨酸及其N-甲基衍生物的合成的详细信息。描述了它们与先前样品的比较以及天然9S系列中C9差向异构酶的简便记录。
• Synthesis of N29-desmethyl RA-VII. Identification of the pharmacophore of RA-I-VII and deoxybouvardin and reassignment of the subunit functional roles
  作者：Dale L. Boger、Daniel Yohannes、James B. Myers

  DOI：10.1021/jo00031a001

  日期：1992.2

  N29-Desmethyl RA-VII was prepared in efforts that address the key structural and conformational features of the agent that contribute to its antitumor activity.
• N-Desmethyl Derivatives of Deoxybouvardin and RA-VII: Synthesis and Evaluation
  作者：Dale L. Boger、Jiacheng Zhou

  DOI：10.1021/ja00133a010

  日期：1995.7

  The synthesis of the complete set of seven N-desmethyl derivatives of RA-VII (8) are described. Thus, the synthesis of the four 14-membered cycloisodityrosine derivatives 21-24 and their coupling with the two tetrapeptides 32 and 33 followed by formation of the 18-membered ring with macrocyclization provided the full set of seven desmethyl derivatives 14-20 of RA-VII (8). The solution phase conformational properties of 8 and 14-20 were examined by 1D and 2D H-1 NMR to reveal the role of N-methylation on the key conformational aspects of the natural agents. In contrast to each of the simple cycloisodityrosine derivatives 21-24 which adopt a single, rigid solution conformation possessing a secondary or tertiary trans amide central to the 14-membered ring, the natural agents including 8 adopt a single predominant solution conformation (83-88%) that corresponds closely to the X-ray structure conformation which possesses an inherently disfavored cis C-30-N-29 tertiary amide central to the 14-membered cycloisodityrosine subunit. Moreover, this cis amide is the predominant conformation (85-95%) observed with N-29-desmethyl RA-VII (14) indicating that even a secondary C-30-N-29 amide adopts this inherently disfavored cis amide stereochemistry. The minor conformation of 8 observed in solution (12-17%) is shown to be derived from a minor cis C-8-N-9 tertiary amide which was not observed with its conversion to a secondary amide. Both N-9-desmethyl RA-VII (15) and N-9,N-29-desmethyl RA-VII (18) adopt exclusively a single solution conformation that corresponds to the major solution conformations of 8 and 14. This conformation contains a characteristic cis C-30-N-29 amide central to a type VI beta-turn and the cycloisodityrosine subunit, a trans C-8-N-9 amide central to a typical type II beta-turn capped with a tight Ala(4)-NH-O=C-Ala(1) hydrogen bond, and a trans C-14-N-15 N-methyl amide. In sharp contrast, removal of the N-15 methyl group within 16, 17, 19, and 20 results in the adoption of solution conformations possessing the inherently favored trans C-30-N-29 amide central to the cycloisodityrosine (14)-membered subunit. Thus, the N-15-methyl group within 8 is responsible for the agents adoption of the disfavored cis C-30-N-29 amide central to the cycloisodityrosine subunit. Importantly, preceding studies have defined the cycloisodityrosine subunit of 8 as the pharmacophore and, in a reversal of the initially assigned roles, revealed that it is the tetrapeptide housed in the 18-membered ring that induces and maintains the rigid, normally inaccessible cis C-30-N-29 amide conformation within the 14-membered cycloisodityrosine subunit. The studies detailed herein reveal that it is the N-15-methyl group that induces this conformational preference for the disfavored cis C-30-N-29 amide and that its removal results in a major conformational change with adoption of the trans C-30-N-29 amide and a loss of biological activity.Thus, the N-15-methyl group is essential for maintenance of the conformational and biological properties of 8; the N-9-methyl group is not essential, and its removal leads to exclusive population of a single biologically active conformation; and the N-29-methyl group once thought essential td the adoption of the C-30-N-29 cis amide is not essential, and its removal does not alter the conformational or biological properties of 8.
• Total synthesis of cycloisodityrosine, RA-VII, deoxybouvardin, and N29-desmethyl-RA-VII: Identification of the pharmacophore and reversal of the subunit functional roles
  作者：Dale L. Boger、Daniel Yohannes、Jiacheng Zhou、Michael A. Patane

  DOI：10.1021/ja00062a004

  日期：1993.5

  Full details of a concise total synthesis of RA-VII (1) and deoxybouvardin (2) are described based on the implementation of an effective intramolecular Ullmann reaction as the key macrocyclization reaction in the preparation of the elusive 14-membered cycloisodityrosine subunit (33) of the bicyclic hexapeptides. Subsequent coupling of 34 to tetrapeptide 17 and macrocyclization with C 2 -N 3 amide bond

  基于有效的分子内 Ullmann 反应作为制备难以捉摸的 14 元环异二酪氨酸亚基 (33) 的关键大环化反应的实施，描述了 RA-VII (1) 和脱氧布瓦丁 (2) 的简明全合成的全部细节的双环六肽。随后 34 与四肽 17 偶联以及大环化与 C 2 -N 3 酰胺键形成提供了 1 和 2。在解决有助于其抗肿瘤活性的药物的关键结构和构象特征的努力中，N 29 -去甲基-RA-制备了 VII 并详细说明了其化学、构象和初步生物学特性