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【结 构 式】 
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【分子编号】52375 【品名】{5-(2,3-dihydroxypropyl)-4-(methyloxy)-3-[(phenylmethyl)oxy]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate 【CA登记号】 |
【 分 子 式 】C21H32O7 【 分 子 量 】396.48088 【元素组成】C 63.62% H 8.14% O 28.25% |
合成路线1
该中间体在本合成路线中的序号：(XII)Treatment of L-arabinose (I) with tert-butyldiphenylsilyl chloride and imidazole provided the mono-silylated furanose (II). The free hydroxyl groups of (II) were subsequently acylated with Ac2O, yielding the triacetate (III). Introduction of an allyl group in (III) by using the silyl reagent (IV) and boron trifluoride produced the allyl derivative (V) as a diastereomeric mixture. After basic hydrolysis of the acetate esters of (V), the required diastereoisomer (VI) was isolated by means of flash chromatography. Regioselective silylation of diol (VI) with tert-butyldiphenylsilyl chloride furnished (VII). Following methylation of the remaining free hydroxyl, the resultant methyl ether (VIII) was desilylated with methanolic HCl, giving diol (IX). Protection of the primary alcohol of (IX) was accomplished by acylation with pivaloyl chloride in pyridine, yielding (X). The secondary alcohol group of (X) was then converted to the benzyl ether (XI). Subsequent Sharpless asymmetric dihydroxylation of the allyl moiety of (XI) produced glycol (XII).
| 【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 |
|---|---|---|---|---|---|---|
| (Va) | 52367 | 4-(acetyloxy)-2-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-5-(2-propenyl)tetrahydro-3-furanyl acetate | C28H36O6Si | 详情 | 详情 | |
| (Vb) | 52368 | 4-(acetyloxy)-2-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-5-(2-propenyl)tetrahydro-3-furanyl acetate | C28H36O6Si | 详情 | 详情 | |
| (I) | 52364 | 2,3,4,5-tetrahydroxypentanal | C5H10O5 | 详情 | 详情 | |
| (II) | 52365 | 5-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)tetrahydro-2,3,4-furantriol | C21H28O5Si | 详情 | 详情 | |
| (III) | 52366 | 2,4-bis(acetyloxy)-5-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)tetrahydro-3-furanyl acetate | C27H34O8Si | 详情 | 详情 | |
| (IV) | 15775 | Allyltrimethylsilane; allyl(trimethyl)silane | 762-72-1 | C6H14Si | 详情 | 详情 |
| (VI) | 52369 | 2-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-5-(2-propenyl)tetrahydro-3,4-furandiol | C24H32O4Si | 详情 | 详情 | |
| (VII) | 52370 | 4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-2-(2-propenyl)tetrahydro-3-furanol | C30H46O4Si2 | 详情 | 详情 | |
| (VIII) | 52371 | (1,1-dimethylethyl)({[3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4-(methyloxy)-5-(2-propenyl)tetrahydro-2-furanyl]methyl}oxy)diphenylsilane; (1,1-dimethylethyl)(dimethyl)silyl 2-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-4-(methyloxy)-5-(2-propenyl)tetrahydro-3-furanyl ether | C31H48O4Si2 | 详情 | 详情 | |
| (IX) | 52372 | 2-(hydroxymethyl)-4-(methyloxy)-5-(2-propenyl)tetrahydro-3-furanol | C9H16O4 | 详情 | 详情 | |
| (X) | 52373 | [3-hydroxy-4-(methyloxy)-5-(2-propenyl)tetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate | C14H24O5 | 详情 | 详情 | |
| (XI) | 52374 | [4-(methyloxy)-3-[(phenylmethyl)oxy]-5-(2-propenyl)tetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate | C21H30O5 | 详情 | 详情 | |
| (XII) | 52375 | {5-(2,3-dihydroxypropyl)-4-(methyloxy)-3-[(phenylmethyl)oxy]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate | C21H32O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)After silylation of diol (XII) to give (XIII), the O-benzyl group of (XIII) was removed by hydrogenolysis in the presence of Pearlman’s catalyst, yielding alcohol (XIV). Oxidation of alcohol (XIV) to the corresponding ketone (XV) was carried out by means of N-methylmorpholine-N-oxide in the presence of a catalytic amount of tetrapropylammonium perruthenate (TPAP). Ketone (XV) was then converted to the methylene derivative (XVI) by treatment with Tebbe's reagent, generated from bis(cyclopentadienyl)titanium and trimethylaluminum. Olefin (XVI) hydroboration by means of 9-borabicyclononane, followed by oxidative work-up with sodium perborate, provided the primary alcohol (XVII) as the undesired diastereoisomer. Configuration of alcohol (XVII) was inverted via Swern oxidation to the corresponding aldehyde, which was epimerized to (XVIII) under basic conditions. Further, aldehyde (XVIII) reduction with NaBH4 at 0 C generated alcohol (XIX). This was protected as the methoxybenzyl ether (XXI) by condensation with p-methoxybenzyl trichloroacetimidate (XX). The pivaloyl ester of (XXI) was then removed by reductive cleavage with LiAlH4, affording alcohol (XXII).
| 【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 |
|---|---|---|---|---|---|---|
| (XII) | 52375 | {5-(2,3-dihydroxypropyl)-4-(methyloxy)-3-[(phenylmethyl)oxy]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate | C21H32O7 | 详情 | 详情 | |
| (XIII) | 52376 | {5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[(phenylmethyl)oxy]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate | C33H60O7Si2 | 详情 | 详情 | |
| (XIV) | 52377 | [5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-hydroxy-4-(methyloxy)tetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate | C26H54O7Si2 | 详情 | 详情 | |
| (XV) | 52378 | [5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-oxotetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate | C26H52O7Si2 | 详情 | 详情 | |
| (XVI) | 52379 | [(2R,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-4-methoxy-3-methylenetetrahydro-2-furanyl]methyl pivalate | C27H54O6Si2 | 详情 | 详情 | |
| (XVII) | 52380 | [(2R,3S,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-3-(hydroxymethyl)-4-methoxytetrahydro-2-furanyl]methyl pivalate | C27H56O7Si2 | 详情 | 详情 | |
| (XVIII) | 52381 | [(2R,3R,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-3-formyl-4-methoxytetrahydro-2-furanyl]methyl pivalate | C27H54O7Si2 | 详情 | 详情 | |
| (XIX) | 52382 | [5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-(hydroxymethyl)-4-(methyloxy)tetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate | C27H56O7Si2 | 详情 | 详情 | |
| (XX) | 52385 | [4-(methyloxy)phenyl]methyl 2,2,2-trichloroethanimidoate | C10H10Cl3NO2 | 详情 | 详情 | |
| (XXI) | 52383 | {5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate | C35H64O8Si2 | 详情 | 详情 | |
| (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 |
合成路线3
该中间体在本合成路线中的序号：(XII)Treatment of L-arabinose (I) with tert-butyldiphenylsilyl chloride and imidazole provided the mono-silylated furanose (II). The free hydroxyl groups of (II) were subsequently acylated with Ac2O, yielding the triacetate (III). Introduction of an allyl group in (III) by using the silyl reagent (IV) and boron trifluoride produced the allyl derivative (V) as a diastereomeric mixture. After basic hydrolysis of the acetate esters of (V), the required diastereoisomer (VI) was isolated by means of flash chromatography. Regioselective silylation of diol (VI) with tert-butyldiphenylsilyl chloride furnished (VII). Following methylation of the remaining free hydroxyl group of (VII), the resultant methyl ether (VIII) was desilylated with methanolic HCl, giving diol (IX). Protection of the primary alcohol of (IX) was accomplished by acylation with pivaloyl chloride in pyridine, yielding (X). The secondary alcohol group of (X) was then converted to the benzyl ether (XI). Subsequent Sharpless asymmetric dihydroxylation of the allyl moiety of (XI) produced glycol (XII).
| 【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 |
|---|---|---|---|---|---|---|
| (Va) | 52367 | 4-(acetyloxy)-2-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-5-(2-propenyl)tetrahydro-3-furanyl acetate | C28H36O6Si | 详情 | 详情 | |
| (Vb) | 52368 | 4-(acetyloxy)-2-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-5-(2-propenyl)tetrahydro-3-furanyl acetate | C28H36O6Si | 详情 | 详情 | |
| (I) | 52364 | 2,3,4,5-tetrahydroxypentanal | C5H10O5 | 详情 | 详情 | |
| (II) | 52365 | 5-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)tetrahydro-2,3,4-furantriol | C21H28O5Si | 详情 | 详情 | |
| (III) | 52366 | 2,4-bis(acetyloxy)-5-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)tetrahydro-3-furanyl acetate | C27H34O8Si | 详情 | 详情 | |
| (IV) | 15775 | Allyltrimethylsilane; allyl(trimethyl)silane | 762-72-1 | C6H14Si | 详情 | 详情 |
| (VI) | 52369 | 2-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-5-(2-propenyl)tetrahydro-3,4-furandiol | C24H32O4Si | 详情 | 详情 | |
| (VII) | 52370 | 4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-2-(2-propenyl)tetrahydro-3-furanol | C30H46O4Si2 | 详情 | 详情 | |
| (VIII) | 52371 | (1,1-dimethylethyl)({[3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4-(methyloxy)-5-(2-propenyl)tetrahydro-2-furanyl]methyl}oxy)diphenylsilane; (1,1-dimethylethyl)(dimethyl)silyl 2-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-4-(methyloxy)-5-(2-propenyl)tetrahydro-3-furanyl ether | C31H48O4Si2 | 详情 | 详情 | |
| (IX) | 52372 | 2-(hydroxymethyl)-4-(methyloxy)-5-(2-propenyl)tetrahydro-3-furanol | C9H16O4 | 详情 | 详情 | |
| (X) | 52373 | [3-hydroxy-4-(methyloxy)-5-(2-propenyl)tetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate | C14H24O5 | 详情 | 详情 | |
| (XI) | 52374 | [4-(methyloxy)-3-[(phenylmethyl)oxy]-5-(2-propenyl)tetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate | C21H30O5 | 详情 | 详情 | |
| (XII) | 52375 | {5-(2,3-dihydroxypropyl)-4-(methyloxy)-3-[(phenylmethyl)oxy]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate | C21H32O7 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XII)After silylation of diol (XII) to yield (XIII), the O-benzyl group of (XIII) was removed by hydrogenolysis in the presence of Pearlman’s catalyst, yielding alcohol (XIV). Oxidation of alcohol (XIV) to the corresponding ketone (XV) was carried out by means of N-methylmorpholine-N-oxide in the presence of a catalytic amount of tetrapropylammonium perruthenate (TPAP). Ketone (XV) was then converted to the methylene derivative (XVI) by treatment with Tebbe’s reagent, generated from bis(cyclopentadienyl)titanium and trimethylaluminum. Olefin (XVI) hydroboration by means of 9-borabicyclononane, followed by oxidative work-up with sodium perborate, provided the primary alcohol (XVII) as the undesired diastereoisomer. Configuration of alcohol (XVII) was inverted via Swern oxidation to the corresponding aldehyde, which was epimerized to (XVIII) under basic conditions. Further, aldehyde (XVIII) reduction with NaBH4 at 0 C generated alcohol (XIX). This was protected as the methoxybenzyl ether (XXI) by condensation with p-methoxybenzyl trichloroacetimidate (XX). The pivaloyl ester (XXI) was then removed by reductive cleavage with LiAlH4, affording alcohol (XXII).
| 【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 |
|---|---|---|---|---|---|---|
| (XII) | 52375 | {5-(2,3-dihydroxypropyl)-4-(methyloxy)-3-[(phenylmethyl)oxy]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate | C21H32O7 | 详情 | 详情 | |
| (XIII) | 52376 | {5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[(phenylmethyl)oxy]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate | C33H60O7Si2 | 详情 | 详情 | |
| (XIV) | 52377 | [5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-hydroxy-4-(methyloxy)tetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate | C26H54O7Si2 | 详情 | 详情 | |
| (XV) | 52378 | [5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-oxotetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate | C26H52O7Si2 | 详情 | 详情 | |
| (XVI) | 52379 | [(2R,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-4-methoxy-3-methylenetetrahydro-2-furanyl]methyl pivalate | C27H54O6Si2 | 详情 | 详情 | |
| (XVII) | 52380 | [(2R,3S,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-3-(hydroxymethyl)-4-methoxytetrahydro-2-furanyl]methyl pivalate | C27H56O7Si2 | 详情 | 详情 | |
| (XVIII) | 52381 | [(2R,3R,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-3-formyl-4-methoxytetrahydro-2-furanyl]methyl pivalate | C27H54O7Si2 | 详情 | 详情 | |
| (XIX) | 52382 | [5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-(hydroxymethyl)-4-(methyloxy)tetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate | C27H56O7Si2 | 详情 | 详情 | |
| (XX) | 52385 | [4-(methyloxy)phenyl]methyl 2,2,2-trichloroethanimidoate | C10H10Cl3NO2 | 详情 | 详情 | |
| (XXI) | 52383 | {5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate | C35H64O8Si2 | 详情 | 详情 | |
| (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 |