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【结 构 式】 
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【分子编号】52392 【品名】3-{5-[2-(6-{[5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-(hydroxymethyl)-4-(methyloxy)tetrahydro-2-furanyl]methyl}-4-methyl-5-methylidenetetrahydro-2H-pyran-2-yl)ethyl]-4-methylidenetetrahydro-2-furanyl}propyl 2,2-dimethylpropanoate 【CA登记号】 |
【 分 子 式 】C44H82O9Si2 【 分 子 量 】811.30068 【元素组成】C 65.14% H 10.19% O 17.75% Si 6.92% |
合成路线1
该中间体在本合成路线中的序号：(XXIX)Homologation of alcohol (XXII) was effected by Swern oxidation to aldehyde (XXIII), which was then converted to the vinyl derivative (XXIV) by Wittig reaction with methylene triphenylphosphorane. Hydroboration of olefin (XXIV), followed by oxidative work-up, furnished alcohol (XXV). This was subjected to a further Swern oxidation to aldehyde (XXVI). Coupling of aldehyde (XXVI) with the known vinyl iodide (XXVII) produced a mixture of pyran derivative (XXVIII) and some uncyclized intermediate. Cyclization to (XXVIII) was completed by subsequent treatment of the reaction mixture with potassium hexamethyldisilazide. The p-methoxybenzyl protecting group of (XXVIII) was removed by oxidative treatment with DDQ. The desired diastereomer (XXIX) was then isolated by column chromatography.
| 【1】 Littlefield, B.A.; Zheng, W.; Seletsky, B.M.; Yu, M.J.; Palme, M.H.; Towle, M.J. (Eisai Co., Ltd.); Macrocyclic analogs and methods of their use and preparation. US 6214865; WO 9965894 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXII) | 52384 | {5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}methanol | C30H56O7Si2 | 详情 | 详情 | |
| (XXIII) | 52386 | 5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furancarbaldehyde | C30H54O7Si2 | 详情 | 详情 | |
| (XXIV) | 52387 | 5-({5-ethenyl-3-(methyloxy)-4-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane; 2-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-5-ethenyl-4-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-3-furanyl methyl ether | C31H56O6Si2 | 详情 | 详情 | |
| (XXV) | 52388 | 2-{5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}-1-ethanol | C31H58O7Si2 | 详情 | 详情 | |
| (XXVI) | 52389 | 2-{5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}acetaldehyde | C31H56O7Si2 | 详情 | 详情 | |
| (XXVII) | 52390 | 3-(5-{6-iodo-5-methyl-3-[(methylsulfonyl)oxy]-6-heptenyl}-4-methylidenetetrahydro-2-furanyl)propyl 2,2-dimethylpropanoate | C22H37IO6S | 详情 | 详情 | |
| (XXVIII) | 52391 | 3-[(2S,5S)-5-(2-{(2S,4R)-6-[((2S,3R,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-4-methoxy-3-{[(4-methoxybenzyl)oxy]methyl}tetrahydro-2-furanyl)methyl]-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl}ethyl)-4-methylenetetrahydro-2-furanyl]propyl 2,2-dimethylpropanoate | C52H90O10Si2 | 详情 | 详情 | |
| (XXIX) | 52392 | 3-{5-[2-(6-{[5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-(hydroxymethyl)-4-(methyloxy)tetrahydro-2-furanyl]methyl}-4-methyl-5-methylidenetetrahydro-2H-pyran-2-yl)ethyl]-4-methylidenetetrahydro-2-furanyl}propyl 2,2-dimethylpropanoate | C44H82O9Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXIX)Alcohol (XXIX) was converted to the corresponding tosylate (XXX) employing p-toluenesulfonyl chloride and pyridine. Replacement of the pivaloyl protecting group of (XXX) for a mono-methoxytrityl group, yielding (XXXII), was effected by reductive cleavage of the pivaloyl ester of (XXX) and then treatment of alcohol (XXXI) with methoxytrityl chloride. Displacement of the tosylate group of (XXXII) by NaI in refluxing acetone provided the alkyl iodide (XXXIII).
| 【1】 Littlefield, B.A.; Zheng, W.; Seletsky, B.M.; Yu, M.J.; Palme, M.H.; Towle, M.J. (Eisai Co., Ltd.); Macrocyclic analogs and methods of their use and preparation. US 6214865; WO 9965894 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIX) | 52392 | 3-{5-[2-(6-{[5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-(hydroxymethyl)-4-(methyloxy)tetrahydro-2-furanyl]methyl}-4-methyl-5-methylidenetetrahydro-2H-pyran-2-yl)ethyl]-4-methylidenetetrahydro-2-furanyl}propyl 2,2-dimethylpropanoate | C44H82O9Si2 | 详情 | 详情 | |
| (XXX) | 52393 | 3-{(2S,5S)-5-[2-((2S,4R,6R)-6-{[(2S,3R,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-4-methoxy-3-({[(4-methylphenyl)sulfonyl]oxy}methyl)tetrahydro-2-furanyl]methyl}-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl]-4-methylenetetrahydro-2-furanyl}propyl 2,2-dimethylpropanoate | C51H88O11SSi2 | 详情 | 详情 | |
| (XXXI) | 52394 | [5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-2-[(6-{2-[5-(3-hydroxypropyl)-3-methylidenetetrahydro-2-furanyl]ethyl}-4-methyl-3-methylidenetetrahydro-2H-pyran-2-yl)methyl]-4-(methyloxy)tetrahydro-3-furanyl]methyl 4-methylbenzenesulfonate | C46H80O10SSi2 | 详情 | 详情 | |
| (XXXII) | 52395 | C66H96O11SSi2 | 详情 | 详情 | ||
| (XXXIII) | 52396 | C59H89IO8Si2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXIX)An alternative, more convenient preparation of intermediate (XXXVIII) from (XXIX) was also reported. Activation of alcohol (XXIX) as the triflate (XXXIX) by means of trifluoromethanesulfonic anhydride, followed by condensation with thiophenol, gave the phenyl thioether (XL). This was oxidized to sulfone (XLI) using N-methylmorpholine-N-oxide in the presence of TPAP. The pivaloyl protecting group of (XLI) was reductively cleaved with DIBAL, giving (XLII). The lithium anion generated from sulfone (XLII) in the presence of n-BuLi was then condensed with aldehyde (XXXV) to furnish the carbinol adduct (XLIII).
| 【1】 Littlefield, B.A.; Zheng, W.; Seletsky, B.M.; Yu, M.J.; Palme, M.H.; Towle, M.J. (Eisai Co., Ltd.); Macrocyclic analogs and methods of their use and preparation. US 6214865; WO 9965894 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIX) | 52392 | 3-{5-[2-(6-{[5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-(hydroxymethyl)-4-(methyloxy)tetrahydro-2-furanyl]methyl}-4-methyl-5-methylidenetetrahydro-2H-pyran-2-yl)ethyl]-4-methylidenetetrahydro-2-furanyl}propyl 2,2-dimethylpropanoate | C44H82O9Si2 | 详情 | 详情 | |
| (XXXV) | 52397 | C31H61IO6Si3 | 详情 | 详情 | ||
| (XXXIX) | 52401 | C45H81F3O11SSi2 | 详情 | 详情 | ||
| (XL) | 52402 | C50H86O8SSi2 | 详情 | 详情 | ||
| (XLI) | 52403 | C50H86O10SSi2 | 详情 | 详情 | ||
| (XLII) | 52404 | C45H78O9SSi2 | 详情 | 详情 | ||
| (XLIII) | 52405 | C76H139IO15SSi5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXIX)Homologation of alcohol (XXII) was effected by Swern oxidation to aldehyde (XXIII), which was then converted to the vinyl derivative (XXIV) by Wittig reaction with methylene triphenylphosphorane. Hydroboration of olefin (XXIV), followed by oxidative work-up, furnished alcohol (XXV). This was subjected to a further Swern oxidation to aldehyde (XXVI). Coupling of aldehyde (XXVI) with the known vinyl iodide (XXVII) produced a mixture of pyran derivative (XXVIII) and some uncyclized intermediate. Cyclization to (XXVIII) was completed by subsequent treatment of the reaction mixture with potassium hexamethyldisilazide. The p-methoxybenzyl protecting group of (XXVIII) was removed by oxidative treatment with DDQ. The desired diastereomer (XXIX) was then isolated by column chromatography.
| 【1】 Littlefield, B.A.; Zheng, W.; Seletsky, B.M.; Yu, M.J.; Palme, M.H.; Towle, M.J. (Eisai Co., Ltd.); Macrocyclic analogs and methods of their use and preparation. US 6214865; WO 9965894 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXII) | 52384 | {5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}methanol | C30H56O7Si2 | 详情 | 详情 | |
| (XXIII) | 52386 | 5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furancarbaldehyde | C30H54O7Si2 | 详情 | 详情 | |
| (XXIV) | 52387 | 5-({5-ethenyl-3-(methyloxy)-4-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane; 2-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-5-ethenyl-4-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-3-furanyl methyl ether | C31H56O6Si2 | 详情 | 详情 | |
| (XXV) | 52388 | 2-{5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}-1-ethanol | C31H58O7Si2 | 详情 | 详情 | |
| (XXVI) | 52389 | 2-{5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}acetaldehyde | C31H56O7Si2 | 详情 | 详情 | |
| (XXVII) | 52390 | 3-(5-{6-iodo-5-methyl-3-[(methylsulfonyl)oxy]-6-heptenyl}-4-methylidenetetrahydro-2-furanyl)propyl 2,2-dimethylpropanoate | C22H37IO6S | 详情 | 详情 | |
| (XXVIII) | 52391 | 3-[(2S,5S)-5-(2-{(2S,4R)-6-[((2S,3R,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-4-methoxy-3-{[(4-methoxybenzyl)oxy]methyl}tetrahydro-2-furanyl)methyl]-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl}ethyl)-4-methylenetetrahydro-2-furanyl]propyl 2,2-dimethylpropanoate | C52H90O10Si2 | 详情 | 详情 | |
| (XXIX) | 52392 | 3-{5-[2-(6-{[5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-(hydroxymethyl)-4-(methyloxy)tetrahydro-2-furanyl]methyl}-4-methyl-5-methylidenetetrahydro-2H-pyran-2-yl)ethyl]-4-methylidenetetrahydro-2-furanyl}propyl 2,2-dimethylpropanoate | C44H82O9Si2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XXIX)Alcohol (XXIX) was converted to the corresponding tosylate (XXX) employing p-toluenesulfonyl chloride and pyridine. Replacement of the pivaloyl protecting group of (XXX) for a mono-methoxytrityl group, yielding (XXXII), was effected by reductive cleavage of the pivaloyl ester of (XXX) and then treatment of alcohol (XXXI) with methoxytrityl chloride. Displacement of the tosylate group of (XXXII) by NaI in refluxing acetone provided the alkyl iodide (XXXIII).
| 【1】 Littlefield, B.A.; Zheng, W.; Seletsky, B.M.; Yu, M.J.; Palme, M.H.; Towle, M.J. (Eisai Co., Ltd.); Macrocyclic analogs and methods of their use and preparation. US 6214865; WO 9965894 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIX) | 52392 | 3-{5-[2-(6-{[5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-(hydroxymethyl)-4-(methyloxy)tetrahydro-2-furanyl]methyl}-4-methyl-5-methylidenetetrahydro-2H-pyran-2-yl)ethyl]-4-methylidenetetrahydro-2-furanyl}propyl 2,2-dimethylpropanoate | C44H82O9Si2 | 详情 | 详情 | |
| (XXX) | 52393 | 3-{(2S,5S)-5-[2-((2S,4R,6R)-6-{[(2S,3R,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-4-methoxy-3-({[(4-methylphenyl)sulfonyl]oxy}methyl)tetrahydro-2-furanyl]methyl}-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl]-4-methylenetetrahydro-2-furanyl}propyl 2,2-dimethylpropanoate | C51H88O11SSi2 | 详情 | 详情 | |
| (XXXI) | 52394 | [5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-2-[(6-{2-[5-(3-hydroxypropyl)-3-methylidenetetrahydro-2-furanyl]ethyl}-4-methyl-3-methylidenetetrahydro-2H-pyran-2-yl)methyl]-4-(methyloxy)tetrahydro-3-furanyl]methyl 4-methylbenzenesulfonate | C46H80O10SSi2 | 详情 | 详情 | |
| (XXXII) | 52395 | C66H96O11SSi2 | 详情 | 详情 | ||
| (XXXIII) | 52396 | C59H89IO8Si2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XXIX)An alternative, more convenient preparation of intermediate (XXXVIII) from (XXIX) was also reported. Activation of alcohol (XXIX) as the triflate (XXXIX) by means of trifluoromethanesulfonic anhydride, followed by condensation with thiophenol, gave the phenyl thioether (XL). This was oxidized to sulfone (XLI) using N-methylmorpholine-N-oxide in the presence of TPAP. The pivaloyl protecting group of (XLI) was reductively cleaved with DIBAL giving (XLII). The lithium anion generated from sulfone (XLII) in the presence of n-BuLi was then condensed with aldehyde (XXXV) to furnish the carbinol adduct (XLIII).
| 【1】 Littlefield, B.A.; Zheng, W.; Seletsky, B.M.; Yu, M.J.; Palme, M.H.; Towle, M.J. (Eisai Co., Ltd.); Macrocyclic analogs and methods of their use and preparation. US 6214865; WO 9965894 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIX) | 52392 | 3-{5-[2-(6-{[5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-(hydroxymethyl)-4-(methyloxy)tetrahydro-2-furanyl]methyl}-4-methyl-5-methylidenetetrahydro-2H-pyran-2-yl)ethyl]-4-methylidenetetrahydro-2-furanyl}propyl 2,2-dimethylpropanoate | C44H82O9Si2 | 详情 | 详情 | |
| (XXXV) | 52397 | C31H61IO6Si3 | 详情 | 详情 | ||
| (XXXIX) | 52401 | C45H81F3O11SSi2 | 详情 | 详情 | ||
| (XL) | 52402 | C50H86O8SSi2 | 详情 | 详情 | ||
| (XLI) | 52403 | C50H86O10SSi2 | 详情 | 详情 | ||
| (XLII) | 52404 | C45H78O9SSi2 | 详情 | 详情 | ||
| (XLIII) | 52405 | C76H139IO15SSi5 | 详情 | 详情 |