(E)-3-[(3S,6S,9R,10R,11S,12S,13E,15E,18S,21S)-10,12-dihydroxy-3-[(3-hydroxyphenyl)methyl]-11-methyl-2,5,8,20-tetraoxo-9-(3-oxobutyl)-6-propan-2-yl-19-oxa-1,4,7,25-tetrazabicyclo[19.3.1]pentacosa-13,15-dien-18-yl]but-2-enal | 256424-81-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (E)-3-[(3S,6S,9R,10R,11S,12S,13E,15E,18S,21S)-10,12-dihydroxy-3-[(3-hydroxyphenyl)methyl]-11-methyl-2,5,8,20-tetraoxo-9-(3-oxobutyl)-6-propan-2-yl-19-oxa-1,4,7,25-tetrazabicyclo[19.3.1]pentacosa-13,15-dien-18-yl]but-2-enal
• CAS: 256424-81-4
• 化学式: C₃₉H₅₄N₄O₁₀
• 分子量: 738.879
• InChiKey: ZXJUOIVAKCVMQK-APBCKSDASA-N

物化性质

• 密度：
  1.27±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  53
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  212
• 氢给体数：
  6
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  (E)-3-[(3S,6S,9R,10R,11S,12S,13E,15E,18S,21S)-10,12-dihydroxy-3-[(3-hydroxyphenyl)methyl]-11-methyl-2,5,8,20-tetraoxo-9-(3-oxobutyl)-6-propan-2-yl-19-oxa-1,4,7,25-tetrazabicyclo[19.3.1]pentacosa-13,15-dien-18-yl]but-2-enal 在 氟化氢吡啶 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 反应 1.0h， 生成 C₄₆H₆₈N₄O₈Si
  参考文献：
  名称：

  Sanglifehrin−Cyclophilin Interaction:  Degradation Work, Synthetic Macrocyclic Analogues, X-ray Crystal Structure, and Binding Data

  摘要：

  Sanglifehrin A (SFA) is a novel immunosuppressive natural product isolated from Streptomyces sp. A92-308110. SFA has a very strong affinity for cyclophilin A (IC50 = 6.9 +/- 0.9 nM) but is structurally different from cyclosporin A (CsA) and exerts its immunosuppressive activity via a novel mechanism. SFA has a complex molecular structure consisting of a 22-membered macrocycle, bearing in position 23 a nine-carbon tether terminated by a highly substituted spirobicyclic moiety. Selective oxidative cleavage of the C-26=C-27 exocyclic double bond affords the spirolactam containing fragment 1 and macrolide 2. The affinity of 2 for cyclophilin (IC50 = 29 +/- 2.1 nM) is essentially identical to SFA, which indicates that the interaction between SFA and cyclophilin A is mediated exclusively by the macrocyclic portion of the molecule. This observation was confirmed by the X-ray crystal structure resolved at 2.1 Angstrom of cyclophilin A complexed to macrolide 16, a close analogue of 2. The X-ray crystal structure showed that macrolide 16 binds to the same deep hydrophobic pocket of cyclophilin A as CsA. Additional valuable details of the structure-activity relationship were obtained by two different chemical approaches: (1) degradation work on macrolide 2 or (2) synthesis of a library of macrolide analogues using the ring-closing metathesis reaction as the key step. Altogether, it appears that the complex macrocyclic fragment of SFA is a highly optimized combination of multiple functionalities including an (E,E)-diene, a short polypropionate fragment, and an unusual tripeptide unit, which together provide an extremely strong affinity for cyclophilin A.

  DOI：

  10.1021/ja021327y
• 作为产物：
  描述：

  sanglifehrin A 在 sodium periodate 、 四氧化锇 、 Hydroquinone 1,4-phthalazinediyl diether 、 甲基磺酰胺 、 potassium carbonate 、 potassium hexacyanoferrate(III) 作用下， 以 四氢呋喃 、 水 、 叔丁醇 为溶剂， 反应 3.0h， 生成 (E)-3-[(3S,6S,9R,10R,11S,12S,13E,15E,18S,21S)-10,12-dihydroxy-3-[(3-hydroxyphenyl)methyl]-11-methyl-2,5,8,20-tetraoxo-9-(3-oxobutyl)-6-propan-2-yl-19-oxa-1,4,7,25-tetrazabicyclo[19.3.1]pentacosa-13,15-dien-18-yl]but-2-enal
  参考文献：
  名称：

  Toward a Total Synthesis of the Immunosuppressant Sanglifehrin A. Preparation of Two Relay Compounds by Degradation and Their Use in the Reassembly of the Natural Product

  摘要：

  A potential relay route for the synthesis of the novel immunosuppressive agent sanglifehrin A (1) has been developed. Degradation of 1 by a sequence involving regioselective dihydroxylation of the C26,C27 double bond, followed by periodate cleavage of the resulting diol 4, afforded lactol 2 and macrocyclic aldehyde 3. Intramolecular ketal formation between the 1,3-diol and ketone functions present in 3 gave ketal-aldehyde 5. Lactol 2 was converted into sulfone 14 in four steps. The fragments 5 and 14 were reassembled, using the Julia-Kocienski olefination procedure, to afford intermediate 15, which was converted back to sanglifehrin A (1) after two deprotection steps.

  DOI：

  10.1021/jo9912395

文献信息

• Sanglifehrin−Cyclophilin Interaction:  Degradation Work, Synthetic Macrocyclic Analogues, X-ray Crystal Structure, and Binding Data
  作者：Richard Sedrani、Jörg Kallen、Luisa M. Martin Cabrejas、Charles D. Papageorgiou、Francesco Senia、Stefan Rohrbach、Dieter Wagner、Binh Thai、Anne-Marie Jutzi Eme、Julien France、Lukas Oberer、Grety Rihs、Gerhard Zenke、Jürgen Wagner

  DOI：10.1021/ja021327y

  日期：2003.4.1

  Sanglifehrin A (SFA) is a novel immunosuppressive natural product isolated from Streptomyces sp. A92-308110. SFA has a very strong affinity for cyclophilin A (IC50 = 6.9 +/- 0.9 nM) but is structurally different from cyclosporin A (CsA) and exerts its immunosuppressive activity via a novel mechanism. SFA has a complex molecular structure consisting of a 22-membered macrocycle, bearing in position 23 a nine-carbon tether terminated by a highly substituted spirobicyclic moiety. Selective oxidative cleavage of the C-26=C-27 exocyclic double bond affords the spirolactam containing fragment 1 and macrolide 2. The affinity of 2 for cyclophilin (IC50 = 29 +/- 2.1 nM) is essentially identical to SFA, which indicates that the interaction between SFA and cyclophilin A is mediated exclusively by the macrocyclic portion of the molecule. This observation was confirmed by the X-ray crystal structure resolved at 2.1 Angstrom of cyclophilin A complexed to macrolide 16, a close analogue of 2. The X-ray crystal structure showed that macrolide 16 binds to the same deep hydrophobic pocket of cyclophilin A as CsA. Additional valuable details of the structure-activity relationship were obtained by two different chemical approaches: (1) degradation work on macrolide 2 or (2) synthesis of a library of macrolide analogues using the ring-closing metathesis reaction as the key step. Altogether, it appears that the complex macrocyclic fragment of SFA is a highly optimized combination of multiple functionalities including an (E,E)-diene, a short polypropionate fragment, and an unusual tripeptide unit, which together provide an extremely strong affinity for cyclophilin A.
• Toward a Total Synthesis of the Immunosuppressant Sanglifehrin A. Preparation of Two Relay Compounds by Degradation and Their Use in the Reassembly of the Natural Product
  作者：Rainer Metternich、Donatienne Denni、Binh Thai、Richard Sedrani

  DOI：10.1021/jo9912395

  日期：1999.12.1

  A potential relay route for the synthesis of the novel immunosuppressive agent sanglifehrin A (1) has been developed. Degradation of 1 by a sequence involving regioselective dihydroxylation of the C26,C27 double bond, followed by periodate cleavage of the resulting diol 4, afforded lactol 2 and macrocyclic aldehyde 3. Intramolecular ketal formation between the 1,3-diol and ketone functions present in 3 gave ketal-aldehyde 5. Lactol 2 was converted into sulfone 14 in four steps. The fragments 5 and 14 were reassembled, using the Julia-Kocienski olefination procedure, to afford intermediate 15, which was converted back to sanglifehrin A (1) after two deprotection steps.