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【结 构 式】 
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【分子编号】54359 【品名】(5R,6S,7S)-6,8-bis{[tert-butyl(dimethyl)silyl]oxy}-3,3,5,7-tetramethyl-1-octen-4-one 【CA登记号】 |
【 分 子 式 】C24H50O3Si2 【 分 子 量 】442.8302 【元素组成】C 65.1% H 11.38% O 10.84% Si 12.68% |
合成路线1
该中间体在本合成路线中的序号：(XXXIV)The reaction of the glucoside (I) with Me2CuLi in THF gives the methyl derivative (II), which is oxidized with oxalyl chloride in DMSO to yield the tetrahydropyranone (XVIII). The treatment of (XVIII) with TEA in dichloromethane/methanol causes isomerization of the methyl group of (XVIII) to (XIX), which is reduced with NaBH4 in methanol/DMF to afford the secondary alcohol (XX). The cleavage of the benzylidene protecting group of (XX) with H2 over Pd/C in ethyl acetate provides the trihydroxy compound (XXI), which is regioselectively monosilylated at the primary OH group with Tbdms-Cl and pyridine to gives the silyl ether (XXII). The epoxidation of (XXII) by the orthoester method yields the epoxide (XXIII), which is opened with dimethylmagnesium in ethyl ether to afford the methylated secondary alcohol (XXIV). The desilylation of (XXIV) by means of TBAF in THF provides the dihydroxy compound (XXV), which is regioselectively brominated with CBr4 and PPh3 to give the bromomethyl compound (XXVI). The silylation of the remaining OH group of (XXVI) with Tbdms-Cl and imidazole in DMF yields the silyl ether (XXVII), which is treated with Zn in hot isopropanol/water to open the tetrahydropyran ring to afford, with simultaneous dehydrobromination, the unsaturated aldehyde (XXVIII). The reduction of (XXVIII) with NaBH4 provides the corresponding alcohol (XXIX), which is silylated with Tbdms-Cl as before to give the fully silylated diol (XXX). The oxidation of the terminal double bond of (XXX) first with OsO4 and then with H5IO6 yields the aldehyde (XXXI), which is condensed with the Grignard reagent (XXXII) to afford the secondary alcohol (XXXIII). The oxidation of (XXXIII) with TPAP and NMO in acetonitrile provides the ketone (XXXIV), which is oxidized at its terminal double bond with OsO4 and H5IO6 to give the carbaldehyde (XXXV). The condensation of (XXXV) with the lithium derivative of tert-butyl acetate (XXXVI), followed by silylation of the intermediate alcohol, yields the nonanoic ester (XXXVII), which is regioselectively monodesilylated with PPTS in ethanol to afford the primary alcohol (XXXVIII).
| 【1】 Potier, P.; Ermolenko, M.S.; Synthesis of epothilones B and D from D-glucose. Tetrahedron Lett 2002, 43, 16, 2895. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 54335 | (1aR,2S,3aR,6R,7aS,7bS)-2-methoxy-6-phenylhexahydrooxireno[2',3':4,5]pyrano[3,2-d][1,3]dioxine; (1aR,2S,3aR,6R,7aS,7bS)-6-phenylhexahydrooxireno[2',3':4,5]pyrano[3,2-d][1,3]dioxin-2-yl methyl ether | n/a | C14H16O5 | 详情 | 详情 |
| (II) | 54336 | (2R,4aR,6S,7S,8S,8aS)-6-methoxy-7-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-ol | n/a | C15H20O5 | 详情 | 详情 |
| (XVIII) | 54346 | (2R,4aR,6S,7R,8aR)-6-methoxy-7-methyl-2-phenyltetrahydropyrano[3,2-d][1,3]dioxin-8(4H)-one | n/a | C15H18O5 | 详情 | 详情 |
| (XIX) | 54347 | (2R,4aR,6S,7S,8aR)-6-methoxy-7-methyl-2-phenyltetrahydropyrano[3,2-d][1,3]dioxin-8(4H)-one | n/a | C15H18O5 | 详情 | 详情 |
| (XX) | 54348 | (2R,4aR,6S,7R,8S,8aS)-6-methoxy-7-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-ol | n/a | C15H20O5 | 详情 | 详情 |
| (XXI) | 54349 | (2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-methoxy-5-methyltetrahydro-2H-pyran-3,4-diol | n/a | C8H16O5 | 详情 | 详情 |
| (XXII) | 54350 | (2R,3S,4S,5R,6S)-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-methoxy-5-methyltetrahydro-2H-pyran-3,4-diol | n/a | C24H34O5Si | 详情 | 详情 |
| (XXIII) | 54351 | tert-butyl{[(1S,2R,4S,5R,6S)-4-methoxy-5-methyl-3,7-dioxabicyclo[4.1.0]hept-2-yl]methoxy}diphenylsilane; tert-butyl(diphenyl)silyl [(1S,2R,4S,5R,6S)-4-methoxy-5-methyl-3,7-dioxabicyclo[4.1.0]hept-2-yl]methyl ether | n/a | C24H32O4Si | 详情 | 详情 |
| (XXIV) | 54352 | (2S,3R,4R,5R,6S)-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-ol | n/a | C25H36O4Si | 详情 | 详情 |
| (XXV) | 54353 | (2S,3R,4R,5R,6S)-2-(hydroxymethyl)-6-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-ol | n/a | C9H18O4 | 详情 | 详情 |
| (XXVI) | 54354 | (2S,3R,4R,5R,6S)-2-(bromomethyl)-6-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-ol | C9H17BrO3 | 详情 | 详情 | |
| (XXVII) | 54355 | (2S,3R,4R,5S,6S)-6-(bromomethyl)-4-{[tert-butyl(dimethyl)silyl]oxy}-3,5-dimethyltetrahydro-2H-pyran-2-yl methyl ether; {[(2S,3S,4R,5R,6S)-2-(bromomethyl)-6-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-yl]oxy}(tert-butyl)dimethylsilane | C15H31BrO3Si | 详情 | 详情 | |
| (XXVIII) | 54356 | (2R,3R,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2,4-dimethyl-5-hexenal | C14H28O2Si | 详情 | 详情 | |
| (XXIX) | 54357 | (2S,3R,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2,4-dimethyl-5-hexen-1-ol | C14H30O2Si | 详情 | 详情 | |
| (XXX) | 42381 | (5S,6R)-2,2,3,3,6,9,9,10,10-nonamethyl-5-[(1R)-1-methyl-2-propenyl]-4,8-dioxa-3,9-disilaundecane; tert-butyl(dimethyl)silyl (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-hexenyl ether | C20H44O2Si2 | 详情 | 详情 | |
| (XXXI) | 42702 | (2R,3S,4S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethylpentanal | C19H42O3Si2 | 详情 | 详情 | |
| (XXXII) | 27170 | chloro(3-methyl-2-butenyl)magnesium | C5H9ClMg | 详情 | 详情 | |
| (XXXIII) | 54358 | (5S,6S,7S)-6,8-bis{[tert-butyl(dimethyl)silyl]oxy}-3,3,5,7-tetramethyl-1-octen-4-ol | C24H52O3Si2 | 详情 | 详情 | |
| (XXXIV) | 54359 | (5R,6S,7S)-6,8-bis{[tert-butyl(dimethyl)silyl]oxy}-3,3,5,7-tetramethyl-1-octen-4-one | C24H50O3Si2 | 详情 | 详情 | |
| (XXXV) | 54360 | (4R,5S,6S)-5,7-bis{[tert-butyl(dimethyl)silyl]oxy}-2,2,4,6-tetramethyl-3-oxoheptanal | C23H48O4Si2 | 详情 | 详情 | |
| (XXXVI) | 15593 | [2-(tert-butoxy)-2-oxoethyl]lithium | C6H11LiO2 | 详情 | 详情 | |
| (XXXVII) | 54361 | tert-butyl (3S,6R,7S,8S)-3,7,9-tris{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8-tetramethyl-5-oxononanoate | C35H74O6Si3 | 详情 | 详情 | |
| (XXXVIII) | 54362 | tert-butyl (3S,6R,7S,8S)-3,7-bis{[tert-butyl(dimethyl)silyl]oxy}-9-hydroxy-4,4,6,8-tetramethyl-5-oxononanoate | C29H60O6Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXXIV)The reaction of the glucoside (I) with Me2CuLi in THF gives the methyl derivative (II), which is oxidized with oxalyl chloride in DMSO to yield the tetrahydropyranone (XVIII). The treatment of (XVIII) with TEA in dichloromethane/methanol causes isomerization of the methyl group of (XVIII) to (XIX), which is reduced with NaBH4 in methanol/DMF to afford the secondary alcohol (XX). The cleavage of the benzylidene protecting group of (XX) with H2 over Pd/C in ethyl acetate provides the trihydroxy compound (XXI), which is regioselectively monosilylated at the primary OH group with Tbdms-Cl and pyridine to give the silyl ether (XXII). The epoxidation of (XXII) by the orthoester method yields the epoxide (XXIII), which is opened with dimethylmagnesium in ethyl ether to afford the methylated secondary alcohol (XXIV). The desilylation of (XXIV) by means of TBAF in THF provides the dihydroxy compound (XXV), which is regioselectively brominated with CBr4 and PPh3 to give the bromomethyl compound (XXVI). The silylation of the remaining OH group of (XXVI) with Tbdms-Cl and imidazole in DMF yields the silyl ether (XXVII), which is treated with Zn in hot isopropanol/water to open the tetrahydropyran ring to afford, with simultaneous dehydrobromination, the unsaturated aldehyde (XXVIII). The reduction of (XXVIII) with NaBH4 provides the corresponding alcohol (XXIX), which is silylated with Tbdms-Cl as before to give the fully silylated diol (XXX). The oxidation of the terminal double bond of (XXX) first with OsO4 and then with H5IO6 yields the aldehyde (XXXI), which is condensed with the Grignard reagent (XXXII) to afford the secondary alcohol (XXXIII). The oxidation of (XXXIII) with TPAP and NMO in acetonitrile provides the ketone (XXXIV), which is oxidized at its terminal double bond with OsO4 and H5IO6 to give the carbaldehyde (XXXV). The condensation of (XXXV) with the lithium derivative of tert-butyl acetate (XXXVI), followed by silylation of the intermediate alcohol, yields the nonanoic ester (XXXVII), which is regioselectively monodesilylated with PPTS in ethanol to afford the primary alcohol (XXXVIII).
| 【1】 Potier, P.; Ermolenko, M.S.; Synthesis of epothilones B and D from D-glucose. Tetrahedron Lett 2002, 43, 16, 2895. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 54335 | (1aR,2S,3aR,6R,7aS,7bS)-2-methoxy-6-phenylhexahydrooxireno[2',3':4,5]pyrano[3,2-d][1,3]dioxine; (1aR,2S,3aR,6R,7aS,7bS)-6-phenylhexahydrooxireno[2',3':4,5]pyrano[3,2-d][1,3]dioxin-2-yl methyl ether | n/a | C14H16O5 | 详情 | 详情 |
| (II) | 54336 | (2R,4aR,6S,7S,8S,8aS)-6-methoxy-7-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-ol | n/a | C15H20O5 | 详情 | 详情 |
| (XVIII) | 54346 | (2R,4aR,6S,7R,8aR)-6-methoxy-7-methyl-2-phenyltetrahydropyrano[3,2-d][1,3]dioxin-8(4H)-one | n/a | C15H18O5 | 详情 | 详情 |
| (XIX) | 54347 | (2R,4aR,6S,7S,8aR)-6-methoxy-7-methyl-2-phenyltetrahydropyrano[3,2-d][1,3]dioxin-8(4H)-one | n/a | C15H18O5 | 详情 | 详情 |
| (XX) | 54348 | (2R,4aR,6S,7R,8S,8aS)-6-methoxy-7-methyl-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-ol | n/a | C15H20O5 | 详情 | 详情 |
| (XXI) | 54349 | (2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-methoxy-5-methyltetrahydro-2H-pyran-3,4-diol | n/a | C8H16O5 | 详情 | 详情 |
| (XXII) | 54350 | (2R,3S,4S,5R,6S)-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-methoxy-5-methyltetrahydro-2H-pyran-3,4-diol | n/a | C24H34O5Si | 详情 | 详情 |
| (XXIII) | 54351 | tert-butyl{[(1S,2R,4S,5R,6S)-4-methoxy-5-methyl-3,7-dioxabicyclo[4.1.0]hept-2-yl]methoxy}diphenylsilane; tert-butyl(diphenyl)silyl [(1S,2R,4S,5R,6S)-4-methoxy-5-methyl-3,7-dioxabicyclo[4.1.0]hept-2-yl]methyl ether | n/a | C24H32O4Si | 详情 | 详情 |
| (XXIV) | 54352 | (2S,3R,4R,5R,6S)-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)-6-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-ol | n/a | C25H36O4Si | 详情 | 详情 |
| (XXV) | 54353 | (2S,3R,4R,5R,6S)-2-(hydroxymethyl)-6-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-ol | n/a | C9H18O4 | 详情 | 详情 |
| (XXVI) | 54354 | (2S,3R,4R,5R,6S)-2-(bromomethyl)-6-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-ol | C9H17BrO3 | 详情 | 详情 | |
| (XXVII) | 54355 | (2S,3R,4R,5S,6S)-6-(bromomethyl)-4-{[tert-butyl(dimethyl)silyl]oxy}-3,5-dimethyltetrahydro-2H-pyran-2-yl methyl ether; {[(2S,3S,4R,5R,6S)-2-(bromomethyl)-6-methoxy-3,5-dimethyltetrahydro-2H-pyran-4-yl]oxy}(tert-butyl)dimethylsilane | C15H31BrO3Si | 详情 | 详情 | |
| (XXVIII) | 54356 | (2R,3R,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2,4-dimethyl-5-hexenal | C14H28O2Si | 详情 | 详情 | |
| (XXIX) | 54357 | (2S,3R,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2,4-dimethyl-5-hexen-1-ol | C14H30O2Si | 详情 | 详情 | |
| (XXX) | 42381 | (5S,6R)-2,2,3,3,6,9,9,10,10-nonamethyl-5-[(1R)-1-methyl-2-propenyl]-4,8-dioxa-3,9-disilaundecane; tert-butyl(dimethyl)silyl (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-hexenyl ether | C20H44O2Si2 | 详情 | 详情 | |
| (XXXI) | 42702 | (2R,3S,4S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethylpentanal | C19H42O3Si2 | 详情 | 详情 | |
| (XXXII) | 27170 | chloro(3-methyl-2-butenyl)magnesium | C5H9ClMg | 详情 | 详情 | |
| (XXXIII) | 54358 | (5S,6S,7S)-6,8-bis{[tert-butyl(dimethyl)silyl]oxy}-3,3,5,7-tetramethyl-1-octen-4-ol | C24H52O3Si2 | 详情 | 详情 | |
| (XXXIV) | 54359 | (5R,6S,7S)-6,8-bis{[tert-butyl(dimethyl)silyl]oxy}-3,3,5,7-tetramethyl-1-octen-4-one | C24H50O3Si2 | 详情 | 详情 | |
| (XXXV) | 54360 | (4R,5S,6S)-5,7-bis{[tert-butyl(dimethyl)silyl]oxy}-2,2,4,6-tetramethyl-3-oxoheptanal | C23H48O4Si2 | 详情 | 详情 | |
| (XXXVI) | 15593 | [2-(tert-butoxy)-2-oxoethyl]lithium | C6H11LiO2 | 详情 | 详情 | |
| (XXXVII) | 54361 | tert-butyl (3S,6R,7S,8S)-3,7,9-tris{[tert-butyl(dimethyl)silyl]oxy}-4,4,6,8-tetramethyl-5-oxononanoate | C35H74O6Si3 | 详情 | 详情 | |
| (XXXVIII) | 54362 | tert-butyl (3S,6R,7S,8S)-3,7-bis{[tert-butyl(dimethyl)silyl]oxy}-9-hydroxy-4,4,6,8-tetramethyl-5-oxononanoate | C29H60O6Si2 | 详情 | 详情 |