2-[(2R)-2-methyl-1,4-dioxaspiro[4.5]decan-2-yl]ethan-1-ol | 1075686-05-3

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-[(2R)-2-methyl-1,4-dioxaspiro[4.5]decan-2-yl]ethan-1-ol
• CAS: 1075686-05-3
• 化学式: C₁₁H₂₀O₃
• 分子量: 200.278
• InChiKey: RQIAQVGPOGCZLF-SNVBAGLBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.83
• 重原子数：
  14.0
• 可旋转键数：
  2.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  38.69
• 氢给体数：
  1.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  2-[(2R)-2-methyl-1,4-dioxaspiro[4.5]decan-2-yl]ethan-1-ol 在 咪唑 、 盐酸 、 碘 、 sodium hydride 、 potassium carbonate 、 对甲苯磺酸 、 三苯基膦 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 439.0h， 生成 [(7R)-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-yl]methanol
  参考文献：
  名称：

  Heteroaryl ether analogues of an antileishmanial 7-substituted 2-nitroimidazooxazine lead afford attenuated hERG risk: In vitro and in vivo appraisal

  摘要：

  Previous investigation of the potent antileishmanial properties of antitubercular 7-substituted 2-nitroimidazo[2,1-b][1,3]oxazines with biaryl side chains led to our development of a new clinical candidate for visceral leishmaniasis (DNDI-0690). Within a collaborative backup program, a racemic monoaryl lead (3) possessing comparable activity in mice but a greater hERG liability formed the starting point for our pursuit of efficacious second generation analogues having good solubility and safety. Asymmetric synthesis and appraisal of its enantiomers first established that chiral preferences for in vivo efficacy were species dependent and that neither form afforded a reduced hERG risk. However, in line with our findings in a structurally related series, less lipophilic heteroaryl ethers provided significant solubility enhancements (up to 16-fold) and concomitantly attenuated hERG inhibition. One promising pyridine derivative (49) displayed 100% oral bioavailability in mice and delivered a 96% parasite burden reduction when dosed at 50 mg/kg in a Leishmania donovani mouse model of visceral leishmaniasis.

  DOI：

  10.1016/j.ejmech.2020.112914
• 作为产物：
  描述：

  3-甲基-3-丁烯-1-醇 在 ammonium cerium (IV) nitrate 、 AD-mix-β 、 对甲苯磺酸 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 二氯甲烷 、 水 、 乙腈 、 叔丁醇 为溶剂， 反应 54.33h， 生成 2-[(2R)-2-methyl-1,4-dioxaspiro[4.5]decan-2-yl]ethan-1-ol
  参考文献：
  名称：

  7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis

  摘要：

  Within a backup program for the clinical investigational agent pretomanid (PA-824), scaffold hopping from delamanid inspired the discovery of a novel class of potent antitubercular agents that unexpectedly possessed notable utility against the kinetoplastid disease visceral leishmaniasis (VL). Following the identification of delamanid analogue DNDI-VL-2098 as a VL preclinical candidate, this structurally related 7 substituted 2-nitro-5,6-dihydroimidazo [2,1-b][1,3]oxazine class was further explored, seeking efficacious backup compounds with improved solubility and safety. Commencing with a biphenyl lead, bioisosteres formed by replacing one phenyl by pyridine or pyrimidine showed improved solubility and potency, whereas more hydrophilic side chains reduced VL activity. In a Leishmania donovani mouse model, two racemic phenylpyridines (71 and 93) were superior, with the former providing >99% inhibition at 12.5 mg/kg (b.i.d., orally) in the Leishmania infantum hamster model. Overall, the 7R enantiomer of 71 (79) displayed more optimal efficacy, pharmacokinetics, and safety, leading to its selection as the preferred development candidate.

  DOI：

  10.1021/acs.jmedchem.7b00034

文献信息

• First total synthesis of (R,R,R)- and (3R,5S,9R)-bejarol by gold-catalyzed allene cycloisomerization and determination of absolute configuration of the natural product
  作者：Yoshinari Sawama、Yuka Sawama、Norbert Krause

  DOI：10.1039/b807733a

  日期：——

  The first total synthesis of (R,R,R)-bejarol and its (3R,5S,9R)-isomer has been accomplished which confirms the absolute configuration of the natural products. The key step is the gold-catalyzed cycloisomerization of the enantiomerically pure beta-hydroxyallenes 12/13 to the corresponding dihydropyrans 14/15.

  （R，R，R）-bejarol及其（3R，5S，9R）-异构体的第一个全合成反应已经完成，这证实了天然产物的绝对构型。关键步骤是对映体纯的β-羟基丙二烯12/13到相应的二氢吡喃14/15的金催化环异构化。