(S)-α-3-Butynyl-2,2,5-trimethyl-1,3-dioxane-5-methanol | 129540-01-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (S)-α-3-Butynyl-2,2,5-trimethyl-1,3-dioxane-5-methanol
• 英文别名: (1S)-1-(2,2,5-trimethyl-1,3-dioxan-5-yl)pent-4-yn-1-ol
• CAS: 129540-01-8
• 化学式: C₁₂H₂₀O₃
• 分子量: 212.289
• InChiKey: RGYLAWOQFJELPQ-JTQLQIEISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  15
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.83
• 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：

  (S)-α-3-Butynyl-2,2,5-trimethyl-1,3-dioxane-5-methanol 在 硫酸 、 mercury(II) sulfate 作用下， 以 四氢呋喃 为溶剂， 反应 12.0h， 以95%的产率得到(1R-exo)-1,4-Dimethyl-2,8-dioxabicyclo<3.2.1>octane-4-methanol
  参考文献：
  名称：

  Daphniphyllum alkaloids. 13. Asymmetric total synthesis of (-)-secodaphniphylline

  摘要：

  (-)-Secodaphniphylline（1）已通过全合成制得。合成的早期阶段是之前报道的甲基同-sec-daphniphyllate（2）合成方法的不对称版本。所需的手性通过C2对称酰胺9的锂烯醇与α,β-不饱和酯10的不对称迈克尔加成反应获得，生成酯酰胺12。12向(-)-2的转化参考了之前报道的相同非对映异构系列中的合成方法，尽管在后续变换中，特别是对于相对受阻的2,5-二甲基吡咯烷酰胺，所需反应条件存在定量差异。在这种合成中获得的(-)-2的对映体过量（ee）为84%，这代表了初始迈克尔加成的对映选择性。对该材料的重结晶提供了90% ee的(-)-2。所需的2,8-二氧双环[3.2.1]辛烷羧酸氯化物5是通过从酸18开始的八步合成组装而成。所需的手性通过不对称还原乙炔酮19来获得，使用LiAlH4-Darvon醇复合物。获得的醇20具有92%的ee，并被异构化为等构体21而不损失对映体纯度。同时水合三键、裂解酮以及酮醇的环化产生5:1的醇23和24的混合物。在转化为甲基酯25和26的类似混合物后，将异构体分离，并将主要羧酸27转化为酸氯化物5。酯(-)-2和酸氯化物5通过混合Claisen凝缩连接，所得的对映异构β-酮酯在NaCN和高温DMSO处理下脱甲基化和脱羧化，获得(-)-secodaphniphylline（1）。尽管Claisen反应的两个组分仅具有适度的对映体过量（90% ee和92% ee），但所得生物碱的对映体纯度仍超过99%。

  DOI：

  10.1021/jo00035a010
• 作为产物：
  描述：

  (S)-α-1-Butynyl-2,2,5-trimethyl-1,3-dioxane-5-methanol 在 potassium aminopropylamide 作用下， 以 various solvent(s) 为溶剂， 反应 0.75h， 以87%的产率得到(S)-α-3-Butynyl-2,2,5-trimethyl-1,3-dioxane-5-methanol
  参考文献：
  名称：

  Daphniphyllum alkaloids. 13. Asymmetric total synthesis of (-)-secodaphniphylline

  摘要：

  (-)-Secodaphniphylline（1）已通过全合成制得。合成的早期阶段是之前报道的甲基同-sec-daphniphyllate（2）合成方法的不对称版本。所需的手性通过C2对称酰胺9的锂烯醇与α,β-不饱和酯10的不对称迈克尔加成反应获得，生成酯酰胺12。12向(-)-2的转化参考了之前报道的相同非对映异构系列中的合成方法，尽管在后续变换中，特别是对于相对受阻的2,5-二甲基吡咯烷酰胺，所需反应条件存在定量差异。在这种合成中获得的(-)-2的对映体过量（ee）为84%，这代表了初始迈克尔加成的对映选择性。对该材料的重结晶提供了90% ee的(-)-2。所需的2,8-二氧双环[3.2.1]辛烷羧酸氯化物5是通过从酸18开始的八步合成组装而成。所需的手性通过不对称还原乙炔酮19来获得，使用LiAlH4-Darvon醇复合物。获得的醇20具有92%的ee，并被异构化为等构体21而不损失对映体纯度。同时水合三键、裂解酮以及酮醇的环化产生5:1的醇23和24的混合物。在转化为甲基酯25和26的类似混合物后，将异构体分离，并将主要羧酸27转化为酸氯化物5。酯(-)-2和酸氯化物5通过混合Claisen凝缩连接，所得的对映异构β-酮酯在NaCN和高温DMSO处理下脱甲基化和脱羧化，获得(-)-secodaphniphylline（1）。尽管Claisen反应的两个组分仅具有适度的对映体过量（90% ee和92% ee），但所得生物碱的对映体纯度仍超过99%。

  DOI：

  10.1021/jo00035a010

文献信息

• Daphniphyllum alkaloids. 13. Asymmetric total synthesis of (-)-secodaphniphylline
  作者：Clayton H. Heathcock、Jeffrey A. Stafford

  DOI：10.1021/jo00035a010

  日期：1992.4

  (-)-Secodaphniphylline (1) has been prepared by total synthesis. The early stages of the synthesis were an asymmetric version of the previously published synthesis of methyl homosecodaphniphyllate (2). The necessary chirality was secured by an asymmetric Michael addition reaction of the lithium enolate of the C2-symmetric amide 9 to alpha,beta-unsaturated ester 10 to give ester amide 12. The conversion of 12 into (-)-2 was modelled after the previously reported synthesis in the analogous racemic series, although there were quantitative differences in the reaction conditions required for some of the succeeding transformations of the relatively hindered 2,5-dimethylpyrrolidine amides. The (-)-2 produced in this synthesis was of 84% ee, which represents the enantioselectivity of the initial Michael addition. Recrystallization of this material provided (-)-2 of 90% ee. The required 2,8-dioxabicyclo[3.2.1]octanecarboxylic acid chloride 5 was assembled in an eight-step synthesis starting with acid 18. The necessary chirality was acquired by an asymmetric reduction of acetylenic ketone 19 with the LiAlH4-Darvon alcohol complex. Alcohol 20, of 92% ee, was obtained and was isomerized to isomer 21 without loss of enantiomeric purity. Concomitant hydration of the triple bond, hydrolysis of the ketal, and cyclization of the resulting keto triol provided a 5:1 mixture of alcohols 23 and 24. After conversion to a similar mixture of methyl esters 25 and 26, the isomers were separated and the major carboxylic acid 27 was converted into acid chloride 5. Ester (-)-2 and acid chloride 5 were joined by a mixed Claisen condensation and the resulting diastereomeric beta-keto esters demethylated and decarboxylated by treatment with NaCN in hot DMSO to obtain (-)-secodaphniphylline (1). Although the two components in the Claisen reaction were enantiomerically enriched only to a modest extent (90% ee and 92% ee), the product alkaloid was > 99% ee.

  (-)-Secodaphniphylline（1）已通过全合成制得。合成的早期阶段是之前报道的甲基同-sec-daphniphyllate（2）合成方法的不对称版本。所需的手性通过C2对称酰胺9的锂烯醇与α,β-不饱和酯10的不对称迈克尔加成反应获得，生成酯酰胺12。12向(-)-2的转化参考了之前报道的相同非对映异构系列中的合成方法，尽管在后续变换中，特别是对于相对受阻的2,5-二甲基吡咯烷酰胺，所需反应条件存在定量差异。在这种合成中获得的(-)-2的对映体过量（ee）为84%，这代表了初始迈克尔加成的对映选择性。对该材料的重结晶提供了90% ee的(-)-2。所需的2,8-二氧双环[3.2.1]辛烷羧酸氯化物5是通过从酸18开始的八步合成组装而成。所需的手性通过不对称还原乙炔酮19来获得，使用LiAlH4-Darvon醇复合物。获得的醇20具有92%的ee，并被异构化为等构体21而不损失对映体纯度。同时水合三键、裂解酮以及酮醇的环化产生5:1的醇23和24的混合物。在转化为甲基酯25和26的类似混合物后，将异构体分离，并将主要羧酸27转化为酸氯化物5。酯(-)-2和酸氯化物5通过混合Claisen凝缩连接，所得的对映异构β-酮酯在NaCN和高温DMSO处理下脱甲基化和脱羧化，获得(-)-secodaphniphylline（1）。尽管Claisen反应的两个组分仅具有适度的对映体过量（90% ee和92% ee），但所得生物碱的对映体纯度仍超过99%。
• Daphniphyllum alkaloids. Part 8. Asymmetric total synthesis of (-)-secodaphniphylline
  作者：Jeffrey A. Stafford、Clayton H. Heathcock

  DOI：10.1021/jo00307a006

  日期：1990.9
• STAFFORD, JEFFREY A.;HEATHCOCK, CLAYTON H., J. ORG. CHEM., 55,(1990) N0, C. 5433-5434
  作者：STAFFORD, JEFFREY A.、HEATHCOCK, CLAYTON H.

  DOI：——

  日期：——
• Daphniphyllum Alkaloids. 16. Total Synthesis of (+)-Codaphniphylline
  作者：Clayton H. Heathcock、John C. Kath、Roger B. Ruggeri

  DOI：10.1021/jo00110a013

  日期：1995.3

  A total synthesis of (+)-codaphniphylline (3) has been developed. The synthesis begins with Noyori asymmetric reduction of methyl 2-oxocyclopentanecarboxylate (15), which gives the trans-P-hydroxy ester 16 (93% ee). Frater-Seebach alkylation of this material with homogeranyl iodide gives hydroxy esters 18 and 19 in a ratio of 15:1. This mixture is oxidized to keto ester 29, which is converted into acetal 34. Reduction of the ester function gives primary alcohol 35, which is esterified by treatment with 2-bromo-4-chlorobutanoyl chloride. The resulting keto ester, 33, is treated with unactivated zinc dust in the presence of 2 equiv of ZnCl2 to obtain lactone ether 36, which is reduced by lithium aluminum hydride to diol 9. Serial treatment of this material with Swern oxidant, methylamine, and warm acetic acid provides the hexacyclic amino ether 10 in 63% overall yield. Reductive fragmentation to 11 results when 10 is treated with excess diisobutylaluminum hydride in hot toluene. Ring closure to the daphnane skeleton (12) occurs when the N,O-bis(phenylcarbamoyl) derivative 41 is treated with hot acetic acid, followed by KOH in methanol. Displacement of the tosyl group gives sulfide 50, which is oxidized to sulfone 13. This material is metalated and coupled with enantiomerically-pure aldehyde 46 to secure the codaphniphylline skeleton, as a mixture of four diastereomeric beta-hydroxy sulfones (51). Oxidation gives a mixture of diastereomeric beta-keto sulfones (52), which is desulfonated to obtain (+)-codaphniphylline (3). The synthesis requires 12 steps from homogeranyl iodide, the more precious starting material, and provides the enantiomerically pure alkaloid in 9% overall yield.