methyl N-[N-(tert-butyloxycarbonyl)-L-(3-isopropyloxy-4-methoxyphenylalanyl)]-L-4-fluoro-3-nitrophenylalaninate | 244769-36-6

• 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: methyl N-[N-(tert-butyloxycarbonyl)-L-(3-isopropyloxy-4-methoxyphenylalanyl)]-L-4-fluoro-3-nitrophenylalaninate
• 英文别名: methyl (2S)-2-[[(2S)-3-(4-fluoro-3-nitrophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]-3-(4-methoxy-3-propan-2-yloxyphenyl)propanoate
• CAS: 244769-36-6
• 化学式: C₂₈H₃₆FN₃O₉
• 分子量: 577.607
• InChiKey: GCQYNLPBVXODCC-SFTDATJTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  41
• 可旋转键数：
  14
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  158
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  methyl N-[N-(tert-butyloxycarbonyl)-L-(3-isopropyloxy-4-methoxyphenylalanyl)]-L-4-fluoro-3-nitrophenylalaninate 在 palladium on activated charcoal copper(I) oxide 、 3 A molecular sieve 、 氢气 、 亚膦酸 、 三氯化硼 、 potassium carbonate 、 sodium nitrite 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 二甲基亚砜 为溶剂， 反应 4.83h， 生成 (9S,12S)-12-[N-(tert-butyloxycarbonyl)amino]-2,11-dioxo-4-methoxy-9-methoxycarbonyl-10-azatricyclo[12.2.2.1^3,7]nonadeca-3,5,7(19),14,16,17-hexaene
  参考文献：
  名称：

  Total Synthesis of an Antitumor Agent RA-VII via an Efficient Preparation of Cycloisodityrosine

  摘要：

  Details of efficient syntheses of (9S, 12S)-cycloisodityrosine (6) and a concise total synthesis of RA-VII(1) were described. An intramolecular SNAr-based cycloetherification reaction was employed as the key ring-closure step for construction of the illusive 14-membered m,p-cyclophane. Treatment of methyl N-[N-(tert-butyloxycarbonyl)-L(3-hydroxy-4-methoxyphenylalanyl)]-L-4-fluoro-3-nitrophenylalaninate ((9S,12S)-10) with potassium carbonate in DMSO at room temperature provided a mixture of two atropdiastereomers 20a and 20b in 75% yield that were transformed into cycloisodityrosine 6 in good overall yield. Furthermore, a size-selective ring-forming process was established for methyl N-[N-(tert-butyloxycarbonyl)-L-(3,4-dihydroxyphenlalanyl)]-L-4-fluoro-3- nitrophenylalaninate ((9S,12S)-11). Thus, cyclization of 11 (K2CO3, DMSO, rt), followed by in situ methylation, gave exclusively the 14-membered m,p-cyclphane 20a and 20b without competitive formation of the alternative 15-membered p,p-cyclophane. The selective ring-forming process allowed us to develop one of the shortest and the most efficient synthesis of cycloisodityrosine to date. Computational studies have shown that it was the elimination, but not the addition, step that determined the ring-size selectivity observed in the cyclization of substrate 11. Coupling of 6 with L-N-Boc-Ala (51) proceeded efficiently to provide the corresponding tripeptide 52 that, after removal of the N-Boc function, was allowed to react with another tripeptide 53 to afford the hexapeptide 50 in good overall yield. Saponification followed by liberation of amino function from 50 gave the seco-acid, whose cyclization (DPPA, DMF, NaHCO3) afforded the natural product RA-VII (1).

  DOI：

  10.1021/jo990432w
• 作为产物：
  描述：

  (2S)-methyl 2-azido-3-(3-isopropyloxy-4-methoxyphenyl)propionate 在 palladium on activated charcoal 氢气 、 1-羟基苯并三唑一水物 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 2.33h， 生成 methyl N-[N-(tert-butyloxycarbonyl)-L-(3-isopropyloxy-4-methoxyphenylalanyl)]-L-4-fluoro-3-nitrophenylalaninate
  参考文献：
  名称：

  Total Synthesis of an Antitumor Agent RA-VII via an Efficient Preparation of Cycloisodityrosine

  摘要：

  Details of efficient syntheses of (9S, 12S)-cycloisodityrosine (6) and a concise total synthesis of RA-VII(1) were described. An intramolecular SNAr-based cycloetherification reaction was employed as the key ring-closure step for construction of the illusive 14-membered m,p-cyclophane. Treatment of methyl N-[N-(tert-butyloxycarbonyl)-L(3-hydroxy-4-methoxyphenylalanyl)]-L-4-fluoro-3-nitrophenylalaninate ((9S,12S)-10) with potassium carbonate in DMSO at room temperature provided a mixture of two atropdiastereomers 20a and 20b in 75% yield that were transformed into cycloisodityrosine 6 in good overall yield. Furthermore, a size-selective ring-forming process was established for methyl N-[N-(tert-butyloxycarbonyl)-L-(3,4-dihydroxyphenlalanyl)]-L-4-fluoro-3- nitrophenylalaninate ((9S,12S)-11). Thus, cyclization of 11 (K2CO3, DMSO, rt), followed by in situ methylation, gave exclusively the 14-membered m,p-cyclphane 20a and 20b without competitive formation of the alternative 15-membered p,p-cyclophane. The selective ring-forming process allowed us to develop one of the shortest and the most efficient synthesis of cycloisodityrosine to date. Computational studies have shown that it was the elimination, but not the addition, step that determined the ring-size selectivity observed in the cyclization of substrate 11. Coupling of 6 with L-N-Boc-Ala (51) proceeded efficiently to provide the corresponding tripeptide 52 that, after removal of the N-Boc function, was allowed to react with another tripeptide 53 to afford the hexapeptide 50 in good overall yield. Saponification followed by liberation of amino function from 50 gave the seco-acid, whose cyclization (DPPA, DMF, NaHCO3) afforded the natural product RA-VII (1).

  DOI：

  10.1021/jo990432w

文献信息

• Total Synthesis of an Antitumor Agent RA-VII via an Efficient Preparation of Cycloisodityrosine
  作者：Antony Bigot、Marie Elise Tran Huu Dau、Jieping Zhu

  DOI：10.1021/jo990432w

  日期：1999.8.1

  Details of efficient syntheses of (9S, 12S)-cycloisodityrosine (6) and a concise total synthesis of RA-VII(1) were described. An intramolecular SNAr-based cycloetherification reaction was employed as the key ring-closure step for construction of the illusive 14-membered m,p-cyclophane. Treatment of methyl N-[N-(tert-butyloxycarbonyl)-L(3-hydroxy-4-methoxyphenylalanyl)]-L-4-fluoro-3-nitrophenylalaninate ((9S,12S)-10) with potassium carbonate in DMSO at room temperature provided a mixture of two atropdiastereomers 20a and 20b in 75% yield that were transformed into cycloisodityrosine 6 in good overall yield. Furthermore, a size-selective ring-forming process was established for methyl N-[N-(tert-butyloxycarbonyl)-L-(3,4-dihydroxyphenlalanyl)]-L-4-fluoro-3- nitrophenylalaninate ((9S,12S)-11). Thus, cyclization of 11 (K2CO3, DMSO, rt), followed by in situ methylation, gave exclusively the 14-membered m,p-cyclphane 20a and 20b without competitive formation of the alternative 15-membered p,p-cyclophane. The selective ring-forming process allowed us to develop one of the shortest and the most efficient synthesis of cycloisodityrosine to date. Computational studies have shown that it was the elimination, but not the addition, step that determined the ring-size selectivity observed in the cyclization of substrate 11. Coupling of 6 with L-N-Boc-Ala (51) proceeded efficiently to provide the corresponding tripeptide 52 that, after removal of the N-Boc function, was allowed to react with another tripeptide 53 to afford the hexapeptide 50 in good overall yield. Saponification followed by liberation of amino function from 50 gave the seco-acid, whose cyclization (DPPA, DMF, NaHCO3) afforded the natural product RA-VII (1).