(3R,4S,5S)-4-methyloct-1-en-7-yne-3,5-diol | 309716-28-7

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: (3R,4S,5S)-4-methyloct-1-en-7-yne-3,5-diol
• 英文别名: 1-Octen-7-yne-3,5-diol, 4-methyl-, (3R,4S,5S)-
• CAS: 309716-28-7
• 化学式: C₉H₁₄O₂
• 分子量: 154.209
• InChiKey: QJLPSSSPXITMCC-HLTSFMKQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  11
• 可旋转键数：
  4
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  40.5
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (3R,4S,5S)-4-methyloct-1-en-7-yne-3,5-diol 在 2,6-二甲基吡啶 、 tris(dibenzylideneacetone)dipalladium(0) chloroform complex 、 三乙胺 、 三苯基膦 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 反应 7.0h， 生成
  参考文献：
  名称：

  Synthesis, Biological Evaluation, and Conformational Analysis of A-Ring Diastereomers of 2-Methyl-1,25-dihydroxyvitamin D₃ and Their 20-Epimers:  Unique Activity Profiles Depending on the Stereochemistry of the A-Ring and at C-20

  摘要：

  All eight; possible A-ring diastereomers of 2-methyl-1,25-dihydroxyvitamin D-3 (2) and 2-methyl-20-epi-1,25-dihydroxyvitamin D-3 (3) were convergently synthesized. The A-ring enyne synthons 19 were synthesized starting with methyl(S)-(+)- or (R)-(-)-3-hydroxy-2-methylpropionate (8). This was converted to the alcohol 14 as a 1:1 epimeric mixture in several steps. After having been separated by column chromatography, each isomer led to the requisite A-ring enyne synthons 19 again as 1:1 mixtures at C-1. Coupling of the resulting A-ring enynes 20a-h with the CD-ring portions 5a,b in the presence of a Pd catalyst afforded the 2-methyl analogues 2a-h and 3a-h in good yield. In this way, all possible A-ring diastereomers were synthesized. The synthesized analogues were biologically evaluated both in vitro and in vivo. The potency was highly dependent on the stereochemistry of each isomer. In particular, the alpha alpha beta -isomer 2g exhibited 4-fold higher potency than 1 alpha ,25-dihydroxyvitamin D-3 (1) both in bovine thymus VDR binding and in elevation of rat serum calcium concentration and was twice as potent, as the parent compound in HL-60 cell differentiation. Furthermore, its 20-epimer, that is, 20epi-alpha alpha beta 3g, exhibited exceptionally high activities: 12-fold higher in VDR binding affinity, 7-fold higher in calcium mobilization, and 590-fold higher in HL-60 cell differentiation, as compared to 1 alpha ,25-dihydroxyvitamin D3 (1). Accordingly, the double modification of 2-methyl substitution and 20-epimerization resulted in unique activity profiles. Conformational analysis of the A-ring by H-1 NMR and an X-ray crystallographic analysis of the alpha alpha beta -isomer 2g are also described.

  DOI：

  10.1021/jm000261j
• 作为产物：
  描述：

  (-)-(S)-4-[(tert-butyldiphenylsilyl)oxy]-3-methylbut-1-ene 在 正丁基锂 、 cerium(III) chloride 、 三氟化硼乙醚 、 四丁基氟化铵 、 对甲苯磺酸 、 间氯过氧苯甲酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 39.0h， 生成 (3R,4S,5S)-4-methyloct-1-en-7-yne-3,5-diol
  参考文献：
  名称：

  系统研究合成，结构阐明和生物学评估的A环非对映体的2-甲基-1α，25-二羟基维生素D（3）和20-表-2-甲基-1α，25-二羟基维生素D（3）。

  摘要：

  通过钯催化合成了2-甲基-1α，25-二羟基维生素D（3）（2）和20-表-2-甲基-1α，25-二羟基维生素D（3）（3）的所有可能的A环非对映异构体。 A环“烯炔”合成子与CD环部分的偶联反应。A环合成子是通过新颖而实用的途径合理合成的，从（R）-（+）-和（S）-（-）-3-羟基-2-甲基丙酸甲酯开始，收率很高。X射线晶体学分析的2alpha-甲基-1alpha，25-二羟基维生素D（3）（2b）和构象分析的2alpha-甲基-（2b）和2beta-甲基-1alpha，25-二羟基维生素D（A环） 3）进行（2f），并对结果进行说明。如此合成的所有A环非对映异构体（2和3）均在体外和体内进行了生物学评估。生物学效力高度依赖于A环取代基的立体化学。特别是2b的维生素D受体[VDR]结合活性比天然激素高4倍，而其20受体（3b）则表现出异常高的活性，VDR结合的效力高12倍，钙动员7倍与

  DOI：

  10.1016/s0039-128x(00)00141-0

文献信息

• A novel and practical route to A-ring enyne synthon for 1α,25-dihydroxyvitamin D3 analogs: Synthesis of A-ring diastereomers of 1α,25-dihydroxyvitamin D3 and 2-methyl-1,25-dihydroxyvitamin D3
  作者：Katsuhiro Konno、Shojiro Maki、Toshie Fujishima、Zhaopeng Liu、Daishiro Miura、Manabu Chokki、Hiroaki Takayama

  DOI：10.1016/s0960-894x(97)10204-9

  日期：1998.1

  A novel and practical route to the A-ring enyne synthon (2), which can be versatile for a variety of A-ring analogs of 1 alpha,25-dihydroxyvitamin D3 (1), was developed. This novel method led to an improved synthesis of the A-ring diastereomers of 1, the compounds 13-15, and synthesis of the new analogs, 2-methyl-1,25-dihydroxyvitamin D3 (4) with its all possible diastereomers. The biological evaluation

  开发了一种新颖而实用的通往A环烯炔合子（2）的途径，该途径可用于多种1α，25-二羟基维生素D3（1）的A环类似物。这种新方法改进了1的A环非对映异构体，化合物13-15的合成，以及新的类似物2-甲基-1,25-二羟基维生素D3（4）及其所有可能的非对映异构体的合成。对2-甲基类似物的生物学评估表明，α-α-β-异构体的效力比1。
• VITAMIN D3 DERIVATIVES AND PROCESS FOR PRODUCING THE SAME
  申请人：TEIJIN LIMITED

  公开号：EP0957088B1

  公开（公告）日：2002-12-18
• US6982257B1
  申请人：——

  公开号：US6982257B1

  公开（公告）日：2006-01-03
• Synthesis, Biological Evaluation, and Conformational Analysis of A-Ring Diastereomers of 2-Methyl-1,25-dihydroxyvitamin D₃ and Their 20-Epimers:  Unique Activity Profiles Depending on the Stereochemistry of the A-Ring and at C-20
  作者：Katsuhiro Konno、Toshie Fujishima、Shojiro Maki、Zhaopeng Liu、Daishiro Miura、Manabu Chokki、Seiichi Ishizuka、Kentaro Yamaguchi、Yukiko Kan、Masaaki Kurihara、Naoki Miyata、Connie Smith、Hector F. DeLuca、Hiroaki Takayama

  DOI：10.1021/jm000261j

  日期：2000.11.1

  All eight; possible A-ring diastereomers of 2-methyl-1,25-dihydroxyvitamin D-3 (2) and 2-methyl-20-epi-1,25-dihydroxyvitamin D-3 (3) were convergently synthesized. The A-ring enyne synthons 19 were synthesized starting with methyl(S)-(+)- or (R)-(-)-3-hydroxy-2-methylpropionate (8). This was converted to the alcohol 14 as a 1:1 epimeric mixture in several steps. After having been separated by column chromatography, each isomer led to the requisite A-ring enyne synthons 19 again as 1:1 mixtures at C-1. Coupling of the resulting A-ring enynes 20a-h with the CD-ring portions 5a,b in the presence of a Pd catalyst afforded the 2-methyl analogues 2a-h and 3a-h in good yield. In this way, all possible A-ring diastereomers were synthesized. The synthesized analogues were biologically evaluated both in vitro and in vivo. The potency was highly dependent on the stereochemistry of each isomer. In particular, the alpha alpha beta -isomer 2g exhibited 4-fold higher potency than 1 alpha ,25-dihydroxyvitamin D-3 (1) both in bovine thymus VDR binding and in elevation of rat serum calcium concentration and was twice as potent, as the parent compound in HL-60 cell differentiation. Furthermore, its 20-epimer, that is, 20epi-alpha alpha beta 3g, exhibited exceptionally high activities: 12-fold higher in VDR binding affinity, 7-fold higher in calcium mobilization, and 590-fold higher in HL-60 cell differentiation, as compared to 1 alpha ,25-dihydroxyvitamin D3 (1). Accordingly, the double modification of 2-methyl substitution and 20-epimerization resulted in unique activity profiles. Conformational analysis of the A-ring by H-1 NMR and an X-ray crystallographic analysis of the alpha alpha beta -isomer 2g are also described.
• Systematic studies on synthesis, structural elucidation, and biological evaluation of A-ring diastereomers of 2-methyl-1α,25-dihydroxyvitamin D3 and 20-epi-2-methyl-1α,25-dihydroxyvitamin D3
  作者：Hiroaki Takayama、Katsuhiro Konno、Toshie Fujishima、Shojiro Maki、Zhaopeng Liu、Daishiro Miura、Manabu Chokki、Seiichi Ishizuka、Connie Smith、Hector F. DeLuca、Kimie Nakagawa、Mayuko Kurobe、Toshio Okano

  DOI：10.1016/s0039-128x(00)00141-0

  日期：2001.3

  diastereomers of 2-methyl-1alpha,25-dihydroxyvitamin D(3) (2) and 20-epi-2-methyl-1alpha,25-dihydroxyvitamin D(3) (3) were synthesized by palladium-catalyzed coupling reaction of A-ring 'enyne' synthons with CD-ring portions. The A-ring synthons were rationally synthesized via a novel and practical route, starting with methyl (R)-(+)- and (S)-(-)-3-hydroxy-2-methyl-propionate, in good yields. X-ray

  通过钯催化合成了2-甲基-1α，25-二羟基维生素D（3）（2）和20-表-2-甲基-1α，25-二羟基维生素D（3）（3）的所有可能的A环非对映异构体。 A环“烯炔”合成子与CD环部分的偶联反应。A环合成子是通过新颖而实用的途径合理合成的，从（R）-（+）-和（S）-（-）-3-羟基-2-甲基丙酸甲酯开始，收率很高。X射线晶体学分析的2alpha-甲基-1alpha，25-二羟基维生素D（3）（2b）和构象分析的2alpha-甲基-（2b）和2beta-甲基-1alpha，25-二羟基维生素D（A环） 3）进行（2f），并对结果进行说明。如此合成的所有A环非对映异构体（2和3）均在体外和体内进行了生物学评估。生物学效力高度依赖于A环取代基的立体化学。特别是2b的维生素D受体[VDR]结合活性比天然激素高4倍，而其20受体（3b）则表现出异常高的活性，VDR结合的效力高12倍，钙动员7倍与