(3RS,4S,5R)-4-methyl-5-[(2-tetrahydropyranyl)oxy]oct-1-en-7-yn-3-ol | 215394-36-8

• 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: (3RS,4S,5R)-4-methyl-5-[(2-tetrahydropyranyl)oxy]oct-1-en-7-yn-3-ol
• 英文别名: (4S,5R)-4-methyl-5-(oxan-2-yloxy)oct-1-en-7-yn-3-ol
• CAS: 215394-36-8
• 化学式: C₁₄H₂₂O₃
• 分子量: 238.327
• InChiKey: NZQSSDFMYCVZEN-RJZJGCCBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  17
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  38.7
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (3RS,4S,5R)-4-methyl-5-[(2-tetrahydropyranyl)oxy]oct-1-en-7-yn-3-ol 在 2,6-二甲基吡啶 、 对甲苯磺酸 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 2.0h， 生成 (3S,4R,5R)-3,5-bis(tert-butyldimethylsilanyloxy)-4-methyl-oct-1-en-7-yne
  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：

  (2S,3RS)-1-[(tert-butyldiphenylsilyl)oxy]-2-methyl-3,4-epoxybutane 在 正丁基锂 、 cerium(III) chloride 、 草酰氯 、 四丁基氟化铵 、 4-甲基苯磺酸吡啶 、 二甲基亚砜 、 三乙胺 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 为溶剂， 反应 9.16h， 生成 (3RS,4S,5R)-4-methyl-5-[(2-tetrahydropyranyl)oxy]oct-1-en-7-yn-3-ol
  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