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【结 构 式】 
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【分子编号】44443 【品名】tert-butyl(dimethyl)silyl (1S,2E)-1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl ether; 4-((E,3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1-pentenyl)-2-methyl-1,3-thiazole 【CA登记号】 |
【 分 子 式 】C22H43NO2SSi2 【 分 子 量 】441.82596 【元素组成】C 59.81% H 9.81% N 3.17% O 7.24% S 7.26% Si 12.71% |
合成路线1
该中间体在本合成路线中的序号：(XII)The silylation of 2-methyl-5-(tert-butyldimethylsilyloxy)-1-penten-3(s)-ol (VIII) with Tbdms-Cl and imidazole in DMF gives the disilylated compound (IX), which is treated with ozone and PPh3 in dichloromethane to yield the 2-pentanone (X). The condensation of (X) with phosphonate (XI) by means of BuLi in THF yields the fully silylated diol (XII), which is selectively monodesilylated with HF in acetonitrile to afford the primary alcohol (XIII). The oxidation of (XIII) with DMP in dichloromethane affords the aldehyde (XIV), which is methylenated with the phosphonium salt (XV) and NaNH2 in THF to provide the silylated hexadienol (XVI). The reaction of (XVI) with TBAF in THF gives the free secondary alcohol (XVII), which is esterified with the intermediate tridecenoic acid (VII) by means of DCC and DMAP in dichloromethane, yielding the ester (XVIII). Ring-closing metathesis of (XVIII), catalyzed by a Ru catalyst, affords the macrolactone (XIX), which is desilylated by means of HF in acetonitrile to furnish the dihydroxymacrolactone (XX). Finally, the double bond of (XX) is epoxidated with dimethyldioxirane (DMDO) in dichloromethane to provide the target epothilone A.
| 【1】 Schinzer, D.; et al.; Total synthesis of (-)-epothilone A. Angew Chem. Int Ed Engl 1997, 36, 5, 523. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 44438 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C29H58O5Si2 | 详情 | 详情 | |
| (VIII) | 44439 | (3S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1-penten-3-ol | C12H26O2Si | 详情 | 详情 | |
| (IX) | 44440 | (5S)-5-isopropenyl-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecane; tert-butyl(dimethyl)silyl (1S)-1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-methyl-2-propenyl ether | C18H40O2Si2 | 详情 | 详情 | |
| (X) | 44441 | (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-pentanone | C17H38O3Si2 | 详情 | 详情 | |
| (XI) | 44442 | diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate | C9H16NO3PS | 详情 | 详情 | |
| (XII) | 44443 | tert-butyl(dimethyl)silyl (1S,2E)-1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl ether; 4-((E,3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1-pentenyl)-2-methyl-1,3-thiazole | C22H43NO2SSi2 | 详情 | 详情 | |
| (XIII) | 40821 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-penten-1-ol | C16H29NO2SSi | 详情 | 详情 | |
| (XIV) | 40822 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal | C16H27NO2SSi | 详情 | 详情 | |
| (XV) | 30484 | Methyl(triphenyl)phosphonium bromide | 1779-49-3 | C19H18BrP | 详情 | 详情 |
| (XVI) | 44444 | 4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether | C17H29NOSSi | 详情 | 详情 | |
| (XVII) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (XVIII) | 44445 | (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoate | C40H71NO5SSi2 | 详情 | 详情 | |
| (XIX) | 44446 | (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C38H67NO5SSi2 | 详情 | 详情 | |
| (XX) | 44447 | (4S,7R,8S,9S,16S)-4,8-dihydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C26H39NO5S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)The silylation of 2-methyl-5-(tert-butyldimethylsilyloxy)-1-penten-3(s)-ol (VIII) with Tbdms-Cl and imidazole in DMF gives the disilylated compound (IX), which is treated with ozone and PPh3 in dichloromethane to yield the 2-pentanone (X). The condensation of (X) with phosphonate (XI) by means of BuLi in THF yields the fully silylated diol (XII), which is selectively monodesilylated with HF in acetonitrile to afford the primary alcohol (XIII). The oxidation of (XIII) with DMP in dichloromethane affords the aldehyde (XIV), which is methylenated with the phosphonium salt (XV) and Na-NH2 in THF to provide the silylated hexadienol (XVI). The reaction of (XVI) with TBAF in THF gives the free secondary alcohol (XVII), which is esterified with the intermediate tridecenoic acid (VII) by means of DCC and DMAP in dichloromethane yielding the ester (XVIII). Ring-closing metathesis of (XVIII), catalyzed by a Ru catalyst, affords the macrolactone (XIX), which is finally desilylated by means of HF in acetonitrile to furnish the target epothilone C.
| 【1】 Schinzer, D.; et al.; Total synthesis of (-)-epothilone A. Angew Chem. Int Ed Engl 1997, 36, 5, 523. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 44438 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C29H58O5Si2 | 详情 | 详情 | |
| (VIII) | 44439 | (3S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1-penten-3-ol | C12H26O2Si | 详情 | 详情 | |
| (IX) | 44440 | (5S)-5-isopropenyl-2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecane; tert-butyl(dimethyl)silyl (1S)-1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-methyl-2-propenyl ether | C18H40O2Si2 | 详情 | 详情 | |
| (X) | 44441 | (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-pentanone | C17H38O3Si2 | 详情 | 详情 | |
| (XI) | 44442 | diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate | C9H16NO3PS | 详情 | 详情 | |
| (XII) | 44443 | tert-butyl(dimethyl)silyl (1S,2E)-1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl ether; 4-((E,3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1-pentenyl)-2-methyl-1,3-thiazole | C22H43NO2SSi2 | 详情 | 详情 | |
| (XIII) | 40821 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-penten-1-ol | C16H29NO2SSi | 详情 | 详情 | |
| (XIV) | 40822 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal | C16H27NO2SSi | 详情 | 详情 | |
| (XV) | 30484 | Methyl(triphenyl)phosphonium bromide | 1779-49-3 | C19H18BrP | 详情 | 详情 |
| (XVI) | 44444 | 4-((1E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1,5-hexadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl ether | C17H29NOSSi | 详情 | 详情 | |
| (XVII) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (XVIII) | 44445 | (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoate | C40H71NO5SSi2 | 详情 | 详情 | |
| (XIX) | 44446 | (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C38H67NO5SSi2 | 详情 | 详情 |