methyl 4-methoxy-12(S)-<amino>-10-methyl-11-oxo-10-aza-2-oxatricyclo<12.2.2.1^3,7>nonadeca-3,5,7-(19),14,16,17-hexaen-9(S)-carboxylate | 160480-08-0

• 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(S)-<amino>-10-methyl-11-oxo-10-aza-2-oxatricyclo<12.2.2.1^3,7>nonadeca-3,5,7-(19),14,16,17-hexaen-9(S)-carboxylate
• 英文别名: methyl (9S,12S)-4-methoxy-10-methyl-12-[(2-methylpropan-2-yl)oxycarbonylamino]-11-oxo-2-oxa-10-azatricyclo[12.2.2.13,7]nonadeca-1(16),3,5,7(19),14,17-hexaene-9-carboxylate
• CAS: 160480-08-0
• 化学式: C₂₆H₃₂N₂O₇
• 分子量: 484.549
• InChiKey: BGMJTZJQHMHPRY-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(S)-<amino>-10-methyl-11-oxo-10-aza-2-oxatricyclo<12.2.2.1^3,7>nonadeca-3,5,7-(19),14,16,17-hexaen-9(S)-carboxylate 在 盐酸 作用下， 以 四氢呋喃 、 乙酸乙酯 为溶剂， 反应 2.5h， 生成 BOC-D-alanyl-L-alanyl-O4-methyl-L-tyrosyl-L-alanyl-L-tyrosyl-N,O4-dimethyl-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：

  (S)-3-(3-Acetoxy-4-methoxy-phenyl)-2-(benzyloxycarbonyl-methyl-amino)-propionic acid methyl ester 在 palladium on activated charcoal 2,3,5-三甲基吡啶 、 氢气 、 双(2-氧代-3-恶唑烷基)次磷酰氯 、 sodium hydride 、 potassium carbonate 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 25.0 ℃ 、101.33 kPa 条件下， 反应 38.25h， 生成 methyl 4-methoxy-12(S)-<amino>-10-methyl-11-oxo-10-aza-2-oxatricyclo<12.2.2.1^3,7>nonadeca-3,5,7-(19),14,16,17-hexaen-9(S)-carboxylate
  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

文献信息

• RA-XXV and RA-XXVI, Bicyclic Hexapeptides from <i>Rubia cordifolia</i> L.: Structure, Synthesis, and Conformation
  作者：Yukio Hitotsuyanagi、Masahito Hirai、Masumi Odagiri、Miho Komine、Tomoyo Hasuda、Haruhiko Fukaya、Koichi Takeya

  DOI：10.1002/asia.201801466

  日期：2019.1.4

  Two RA‐series bicyclic hexapeptides, RA‐XXV (4) and RA‐XXVI (5), which have no N‐methyl group at Tyr‐5, were isolated from the roots of Rubia cordifolia L. Their amino acid compositions and sequences were determined by interpretation of MS, and 1D and 2D NMR data and their relative structures were elucidated by XRD analysis of 4 and RA‐XXVI acetate (6). The absolute stereochemistry of 4 was established

  从茜草的根中分离出两个在Tyr-5处没有N-甲基的RA系列双环六肽RA-XXV（4）和RA-XXVI（5）。其氨基酸组成和序列分别为通过对MS的分析确定，并通过XRD分析4和RA-XXVI乙酸酯（1）阐明1D和2D NMR数据及其相对结构。的绝对立体化学4用的全合成建立4，和的5，通过与化学相关性4。肽 4和5展出的细胞毒性对人类前骨髓性白血病HL-60（IC 50 = 0.062和0.066μ米，分别地）和人结肠癌HCT-116（IC 50 = 0.028和0.051μ米，分别地）的细胞系。对4和6处于结晶状态的构象结构以及溶液中4和5的构象结构的分析表明，Tyr-5的N-甲基起到使该系列肽优先采用活性构象的作用。