(1R,4S,7R,8R)-8-(tert-Butyl-dimethyl-silanyloxy)-7-(3-fluoro-propyl)-3-oxo-2-oxa-bicyclo[2.2.2]oct-5-ene-4-carboxylic acid (S)-3-(tert-butyl-dimethyl-silanyloxy)-1-methyl-propyl ester | 166819-25-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡喃
• 英文名称: (1R,4S,7R,8R)-8-(tert-Butyl-dimethyl-silanyloxy)-7-(3-fluoro-propyl)-3-oxo-2-oxa-bicyclo[2.2.2]oct-5-ene-4-carboxylic acid (S)-3-(tert-butyl-dimethyl-silanyloxy)-1-methyl-propyl ester
• 英文别名: [(2S)-4-[tert-butyl(dimethyl)silyl]oxybutan-2-yl] (1R,4S,7R,8R)-8-[tert-butyl(dimethyl)silyl]oxy-7-(3-fluoropropyl)-3-oxo-2-oxabicyclo[2.2.2]oct-5-ene-4-carboxylate
• CAS: 166819-25-6
• 化学式: C₂₇H₄₉FO₆Si₂
• 分子量: 544.852
• InChiKey: LFDGIWSYIXWNGB-RUGVOOQCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.57
• 重原子数：
  36
• 可旋转键数：
  14
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  71.1
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (1R,4S,7R,8R)-8-(tert-Butyl-dimethyl-silanyloxy)-7-(3-fluoro-propyl)-3-oxo-2-oxa-bicyclo[2.2.2]oct-5-ene-4-carboxylic acid (S)-3-(tert-butyl-dimethyl-silanyloxy)-1-methyl-propyl ester 在 2,6-二甲基吡啶 、 Sodium orthovanadate 、 9-芴酮 、 2,4,6-三甲基苯甲酸 、 lithium allyl oxide 、 二异丁基氢化铝 、 N-chlorosuccinimide-dimethylsulfide complex 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 78.42h， 生成 [(2Z)-2-[(3R,4R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-(3-fluoropropyl)-2-methylidenecyclohexylidene]ethyl]-diphenylphosphane
  参考文献：
  名称：

  2-Fluoroalkyl A-Ring Analogs of 1,25-Dihydroxyvitamin D3. Stereocontrolled Total Synthesis via Intramolecular and Intermolecular Diels-Alder Cycloadditions. Preliminary Biological Testing

  摘要：

  Intramolecular Diels-Alder (IMDA) cycloadditions of electron-rich trans-vinylic silaketal groups tethered via a chiral, nonracemic 1,3-butanediol auxiliary to electron-poor 2-pyrone-3-carboxylates (e.g. (R)-9, (S)-14) were promoted by zinc dibromide and proceeded unexpectedly in a stepwise, ionic fashion to form exclusively cis-4,5-disubstituted bicyclic lactones 10 and 15 with nearly complete asymmetric induction. Confirmation of the stereochemical outcome of these nonconcerted IMDA cycloadditions was achieved by H-1 NMR spectroscopy and by X-ray crystallography. Fluorinated bicycloadduct (-)-15a was converted smoothly in 13 steps into the lipophilic calcitriol analog 2 beta-(3'-flubropropyl)-1 beta,25-dihydroxyvitam D-3 ((-)-5). Intermolecular, concerted, 11 kbar, inverse-electron-demand 4 + 2-cycloaddition of bis-silylated Z-enol ether 22c, carrying two different silyl groups, with commercial methyl 2-pyrone-3-carboxylate gave in gram amounts only vicinally cis-disubstituted bicycloadduct (+/-)-23c. Chemospecific monodesilylation using sodium azide and then fluorination using Et(2)NSF(3) (DAST) gave fluoroalkyl bicyclic lactone (+/-)-25. This bicyclic lactone (+/-)-25 was transformed into fluorinated, racemic, A-ring phosphine oxide (+/-)-30 that was coupled with enantiomerically pure C,D-ring ketone (+)-21 to form enantiomerically pure diastereomers (-)-4 and (+)-4' as fluorinated, lipophilic, A-ring analogs of 1,25-dihydroxyvitamin D-3(calcitriol). Preliminary biological testing (Table I) showed that only those diastereomers having the unnatural 1 beta-hydroxyl group stereochemistry (i.e. (+)-3', (+)-4', and (-)-5) had relatively high affinities for the calf thymus vitamin D receptor and significant antiproliferative and differentiation-inducing potencies in HL-60 cells.

  DOI：

  10.1021/jo00119a045
• 作为产物：
  描述：

  Chloro-((E)-5-fluoro-pent-1-enyloxy)-diisopropyl-silane 在 2,6-二甲基吡啶 、 氢氟酸 、 三乙胺 、 zinc dibromide 作用下， 以 乙醚 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 反应 253.08h， 生成 (1R,4S,7R,8R)-8-(tert-Butyl-dimethyl-silanyloxy)-7-(3-fluoro-propyl)-3-oxo-2-oxa-bicyclo[2.2.2]oct-5-ene-4-carboxylic acid (S)-3-(tert-butyl-dimethyl-silanyloxy)-1-methyl-propyl ester
  参考文献：
  名称：

  2-Fluoroalkyl A-Ring Analogs of 1,25-Dihydroxyvitamin D3. Stereocontrolled Total Synthesis via Intramolecular and Intermolecular Diels-Alder Cycloadditions. Preliminary Biological Testing

  摘要：

  Intramolecular Diels-Alder (IMDA) cycloadditions of electron-rich trans-vinylic silaketal groups tethered via a chiral, nonracemic 1,3-butanediol auxiliary to electron-poor 2-pyrone-3-carboxylates (e.g. (R)-9, (S)-14) were promoted by zinc dibromide and proceeded unexpectedly in a stepwise, ionic fashion to form exclusively cis-4,5-disubstituted bicyclic lactones 10 and 15 with nearly complete asymmetric induction. Confirmation of the stereochemical outcome of these nonconcerted IMDA cycloadditions was achieved by H-1 NMR spectroscopy and by X-ray crystallography. Fluorinated bicycloadduct (-)-15a was converted smoothly in 13 steps into the lipophilic calcitriol analog 2 beta-(3'-flubropropyl)-1 beta,25-dihydroxyvitam D-3 ((-)-5). Intermolecular, concerted, 11 kbar, inverse-electron-demand 4 + 2-cycloaddition of bis-silylated Z-enol ether 22c, carrying two different silyl groups, with commercial methyl 2-pyrone-3-carboxylate gave in gram amounts only vicinally cis-disubstituted bicycloadduct (+/-)-23c. Chemospecific monodesilylation using sodium azide and then fluorination using Et(2)NSF(3) (DAST) gave fluoroalkyl bicyclic lactone (+/-)-25. This bicyclic lactone (+/-)-25 was transformed into fluorinated, racemic, A-ring phosphine oxide (+/-)-30 that was coupled with enantiomerically pure C,D-ring ketone (+)-21 to form enantiomerically pure diastereomers (-)-4 and (+)-4' as fluorinated, lipophilic, A-ring analogs of 1,25-dihydroxyvitamin D-3(calcitriol). Preliminary biological testing (Table I) showed that only those diastereomers having the unnatural 1 beta-hydroxyl group stereochemistry (i.e. (+)-3', (+)-4', and (-)-5) had relatively high affinities for the calf thymus vitamin D receptor and significant antiproliferative and differentiation-inducing potencies in HL-60 cells.

  DOI：

  10.1021/jo00119a045

文献信息

• 2-Fluoroalkyl A-Ring Analogs of 1,25-Dihydroxyvitamin D3. Stereocontrolled Total Synthesis via Intramolecular and Intermolecular Diels-Alder Cycloadditions. Preliminary Biological Testing
  作者：Gary H. Posner、Cheon-Gyu Cho、Tizah E. N. Anjeh、Neil Johnson、Ronald L. Horst、Tadashi Kobayashi、Toshio Okano、Naoko Tsugawa

  DOI：10.1021/jo00119a045

  日期：1995.7

  Intramolecular Diels-Alder (IMDA) cycloadditions of electron-rich trans-vinylic silaketal groups tethered via a chiral, nonracemic 1,3-butanediol auxiliary to electron-poor 2-pyrone-3-carboxylates (e.g. (R)-9, (S)-14) were promoted by zinc dibromide and proceeded unexpectedly in a stepwise, ionic fashion to form exclusively cis-4,5-disubstituted bicyclic lactones 10 and 15 with nearly complete asymmetric induction. Confirmation of the stereochemical outcome of these nonconcerted IMDA cycloadditions was achieved by H-1 NMR spectroscopy and by X-ray crystallography. Fluorinated bicycloadduct (-)-15a was converted smoothly in 13 steps into the lipophilic calcitriol analog 2 beta-(3'-flubropropyl)-1 beta,25-dihydroxyvitam D-3 ((-)-5). Intermolecular, concerted, 11 kbar, inverse-electron-demand 4 + 2-cycloaddition of bis-silylated Z-enol ether 22c, carrying two different silyl groups, with commercial methyl 2-pyrone-3-carboxylate gave in gram amounts only vicinally cis-disubstituted bicycloadduct (+/-)-23c. Chemospecific monodesilylation using sodium azide and then fluorination using Et(2)NSF(3) (DAST) gave fluoroalkyl bicyclic lactone (+/-)-25. This bicyclic lactone (+/-)-25 was transformed into fluorinated, racemic, A-ring phosphine oxide (+/-)-30 that was coupled with enantiomerically pure C,D-ring ketone (+)-21 to form enantiomerically pure diastereomers (-)-4 and (+)-4' as fluorinated, lipophilic, A-ring analogs of 1,25-dihydroxyvitamin D-3(calcitriol). Preliminary biological testing (Table I) showed that only those diastereomers having the unnatural 1 beta-hydroxyl group stereochemistry (i.e. (+)-3', (+)-4', and (-)-5) had relatively high affinities for the calf thymus vitamin D receptor and significant antiproliferative and differentiation-inducing potencies in HL-60 cells.