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【结 构 式】 
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【分子编号】40844 【品名】methyl (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethylpentanoate 【CA登记号】 |
【 分 子 式 】C20H44O4Si2 【 分 子 量 】404.73796 【元素组成】C 59.35% H 10.96% O 15.81% Si 13.88% |
合成路线1
该中间体在本合成路线中的序号：(XXXV)The intermediate chiral ketone (XIX) has been obtained as follows: The silylation of 3(S)-hydroxy-2,2-dimethyl-5-(TBDMSO)pentanoic acid methyl ester (XXXIV) with TBDMS-triflate gives the fully silylated ester (XXXV), which is reduced with DIBAL in THF to yield the alcohol (XXXVI). The oxidation of (XXXVI) with Dess Martin periodinane (DMP) affords the aldehyde (XXXVII), which by reaction with ethylmagnesium bromide in ethyl ether provides the expected secondary alcohol (XXXVIII). Finally, this compound is oxidized with Dess Martin periodinane (DMP) to furnish the target chiral ketone (XIX).
| 【1】 Mulzer, J.; Ohler, E.; Mantoulidis, A. (Schering AG); Method for producing epothilone B and derivs., and intermediate products for this method. WO 0023452 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIX) | 40830 | (5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone | C21H46O3Si2 | 详情 | 详情 | |
| (XXXIV) | 40843 | methyl (3S)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-2,2-dimethylpentanoate | C14H30O4Si | 详情 | 详情 | |
| (XXXV) | 40844 | methyl (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethylpentanoate | C20H44O4Si2 | 详情 | 详情 | |
| (XXXVI) | 40845 | (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethyl-1-pentanol | C19H44O3Si2 | 详情 | 详情 | |
| (XXXVII) | 40846 | (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethylpentanal | C19H42O3Si2 | 详情 | 详情 | |
| (XXXVIII) | 40847 | (5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanol | C21H48O3Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXIII)The enantioselective condensation of 3-(tert-butyldimethylsilyloxy)propanal (XX) with ketene acetal (XXI) catalyzed by N-tosyl-D-valine and BH3/THF gives the beta-hydroxyester (XXII), which is silylated with Tbdms-OTf, yielding the bis-silyl ether (XXIII). The reduction of (XXIII) with DIBAL in toluene affords the carbinol (XXIV), which is oxidized to the corresponding aldehyde (XXV) with DMP in dichloromethane. The Grignard condensation of (XXV) with Et-MgBr in ethyl ether gives the secondary alcohol (XXVI), which is oxidized with DMP as before to yield the ketone (XXVII). Alternatively, the silylated ester (XXIII) can be treated with Tms-CH2-Li in pentane/methanol to give the methyl ketone (XXVIII), which is methylated again with MeI and LDA in THF to afford the ketone (XXVII). The condensation of ketone (XXVII) with the intermediate carbaldehyde (XIX) by means of BuLi in THF gives the adduct (XXIX), which is silylated with Tbdms-OTf, yielding the fully silylated compound (XXX). The selective monodesilylation of (XXX) with CSA in MeOH/dichloromethane affords the primary alcohol (XXXI), which is oxidized with DMP and NaClO2 to provide the carboxylic acid (XXXII).
| 【1】 Mulzer, J.; et al.; Total synthesis of epothilones B and D. J Org Chem 2000, 65, 22, 7456. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIX) | 40829 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal | C24H41NO2SSi | 详情 | 详情 | |
| (XX) | 45546 | 3-[[tert-butyl(dimethyl)silyl]oxy]propanal | 570-24-1 | C9H20O2Si | 详情 | 详情 |
| (XXI) | 42016 | 1-Methoxy-2-methyl-1-(trimethylsiloxy)propene;1-Methoxy-2,2-dimethyl-1-(trimethylsiloxy)ethene;1-Methoxy-1-(trimethylsilyloxy)-2-methylpropene;[(1-methoxy-2-methyl-1-propenyl)oxy](trimethyl)silane; 1-methoxy-2-methyl-1-propenyl trimethylsilyl ether ;dimethylketene methyl trimethylsilyl acetal | 31469-15-5 | C8H18O2Si | 详情 | 详情 |
| (XXII) | 40843 | methyl (3S)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-2,2-dimethylpentanoate | C14H30O4Si | 详情 | 详情 | |
| (XXIII) | 40844 | methyl (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethylpentanoate | C20H44O4Si2 | 详情 | 详情 | |
| (XXIV) | 40845 | (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethyl-1-pentanol | C19H44O3Si2 | 详情 | 详情 | |
| (XXV) | 40846 | (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethylpentanal | C19H42O3Si2 | 详情 | 详情 | |
| (XXVI) | 40847 | (5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanol | C21H48O3Si2 | 详情 | 详情 | |
| (XXVII) | 40830 | (5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone | C21H46O3Si2 | 详情 | 详情 | |
| (XXVIII) | 46137 | (4S)-4,6-bis[[tert-butyl(dimethyl)silyl]oxy]-3,3-dimethyl-2-hexanone | C20H44O3Si2 | 详情 | 详情 | |
| (XXIX) | 40831 | (7S,10R,11S,12S,16Z,19S)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one | C45H87NO5SSi3 | 详情 | 详情 | |
| (XXX) | 40832 | (7S,10R,11S,12S,16Z,19S)-7,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one | C51H101NO5SSi4 | 详情 | 详情 | |
| (XXXI) | 40833 | (5S,8R,9S,10S,14Z,17S)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,10,14,19,19,20,20-tridecamethyl-17-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,18-dioxa-3,19-disila-14-henicosen-7-one | C45H87NO5SSi3 | 详情 | 详情 | |
| (XXXII) | 40834 | (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C45H85NO6SSi3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXIII)Assembly of the target compound: The enantioselective condensation of 3-(tert-butyldimethylsilyloxy)propanal (XX) with ketene acetal (XXI) catalyzed by N-tosyl-D-valine and BH3/THF gives the beta-hydroxyester (XXII), which is silylated with Tbdms-OTf, yielding the bis-silyl ether (XXIII). The reduction of (XXIII) with DIBAL in toluene affords the carbinol (XXIV), which is oxidized to the corresponding aldehyde (XXV) with DMP in dichloromethane. The Grignard condensation of (XXV) with Et-MgBr in ethyl ether gives the secondary alcohol (XXVI), which is oxidized with DMP as before to yield the ketone (XXVII). Alternatively, the silylated ester (XXIII) can be treated with Tms-CH2-Li in pentane/methanol to give the methyl ketone (XXVIII), which is methylated again with MeI and LDA in THF to afford the ketone (XXVII). The condensation of ketone (XXVII) with the intermediate carbaldehyde (XIX) by means of BuLi in THF gives the adduct (XXIX), which is silylated with Tbdms-OTf, yielding the fully silylated compound (XXX). The selective monodesilylation of (XXX) with CSA in MeOH/dichloromethane affords the primary alcohol (XXXI), which is oxidized with DMP and NaClO2 to provide the carboxylic acid (XXXII).
| 【1】 Mulzer, J.; et al.; Total synthesis of epothilones B and D. J Org Chem 2000, 65, 22, 7456. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIX) | 40829 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal | C24H41NO2SSi | 详情 | 详情 | |
| (XX) | 45546 | 3-[[tert-butyl(dimethyl)silyl]oxy]propanal | 570-24-1 | C9H20O2Si | 详情 | 详情 |
| (XXI) | 42016 | 1-Methoxy-2-methyl-1-(trimethylsiloxy)propene;1-Methoxy-2,2-dimethyl-1-(trimethylsiloxy)ethene;1-Methoxy-1-(trimethylsilyloxy)-2-methylpropene;[(1-methoxy-2-methyl-1-propenyl)oxy](trimethyl)silane; 1-methoxy-2-methyl-1-propenyl trimethylsilyl ether ;dimethylketene methyl trimethylsilyl acetal | 31469-15-5 | C8H18O2Si | 详情 | 详情 |
| (XXII) | 40843 | methyl (3S)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-2,2-dimethylpentanoate | C14H30O4Si | 详情 | 详情 | |
| (XXIII) | 40844 | methyl (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethylpentanoate | C20H44O4Si2 | 详情 | 详情 | |
| (XXIV) | 40845 | (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethyl-1-pentanol | C19H44O3Si2 | 详情 | 详情 | |
| (XXV) | 40846 | (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethylpentanal | C19H42O3Si2 | 详情 | 详情 | |
| (XXVI) | 40847 | (5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanol | C21H48O3Si2 | 详情 | 详情 | |
| (XXVII) | 40830 | (5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone | C21H46O3Si2 | 详情 | 详情 | |
| (XXVIII) | 46137 | (4S)-4,6-bis[[tert-butyl(dimethyl)silyl]oxy]-3,3-dimethyl-2-hexanone | C20H44O3Si2 | 详情 | 详情 | |
| (XXIX) | 40831 | (7S,10R,11S,12S,16Z,19S)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one | C45H87NO5SSi3 | 详情 | 详情 | |
| (XXX) | 40832 | (7S,10R,11S,12S,16Z,19S)-7,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one | C51H101NO5SSi4 | 详情 | 详情 | |
| (XXXI) | 40833 | (5S,8R,9S,10S,14Z,17S)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,10,14,19,19,20,20-tridecamethyl-17-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,18-dioxa-3,19-disila-14-henicosen-7-one | C45H87NO5SSi3 | 详情 | 详情 | |
| (XXXII) | 40834 | (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C45H85NO6SSi3 | 详情 | 详情 |