|
【结 构 式】 
|
【分子编号】44449 【品名】allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane 【CA登记号】 |
【 分 子 式 】C23H39B 【 分 子 量 】326.37366 【元素组成】C 84.64% H 12.04% B 3.31% |
合成路线1
该中间体在本合成路线中的序号：(II)The synthesis of intermediate tridecenoic acid (VIII) has been performed as follows: The reaction of 2,2-dimethyl-3-oxopentanal (I) with (+)-diisopinocampheyl(allyl)borane (II) in ethyl ether gives the chiral beta-hydroxy ketone (III), which is protected with Tbdms-OTf, yielding the silyl ether (IV). The ozonolysis of the double bond of (IV) affords the aldehyde (V), which is oxidized with NaClO2 to the carboxylic acid (VI). Finally, this compound is condensed with 2(S)-methyl-6-heptenal (VII) by means of LDA in THF to provide the intermediate tridecenoic acid (VIII).
| 【1】 Nicolaou, K.C.; et al.; The olefin metathesis approach to epothilone A and its analogues. J Am Chem Soc 1997, 119, 34, 7960. |
| 【2】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 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) | 44448 | 2,2-dimethyl-3-oxopentanal | C7H12O2 | 详情 | 详情 | |
| (II) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (III) | 44450 | (5S)-5-hydroxy-4,4-dimethyl-7-octen-3-one | C10H18O2 | 详情 | 详情 | |
| (IV) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (V) | 44452 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanal | C15H30O3Si | 详情 | 详情 | |
| (VI) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 | |
| (VII) | 27185 | (2S)-2-methyl-6-heptenal | C8H14O | 详情 | 详情 | |
| (VIII) | 44453 | (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C23H44O5Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (IX) with DIBAL in dichloromethane gives the corresponding aldehyde (X), which is condensed with the phosphorane (XI) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2-propenal (XII). The alkylation of (XII) with (+)-diisopinocampheyl(allyl)borane (II) in ethyl ether affords the chiral secondary alcohol (XIII) (1), which is esterified with the intermediate tridecenoic acid (VIII) by means of EDC and DMAP in dichloromethane to provide the ester (XIV). Ring-closing metathesis of (XIV) catalyzed by a Ru catalyst gives the macrolactone (XV), which is desilylated by means of TFA in dichloromethane, yielding the dihydroxymacrolactone (XVI). Finally, the double bond of (XVI) is epoxidized by means of dimethyldioxirane (DMDO) or MCPBA in chloroform.
| 【1】 Nicolaou, K.C.; et al.; The olefin metathesis approach to epothilone A and its analogues. J Am Chem Soc 1997, 119, 34, 7960. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (VIII) | 44453 | (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C23H44O5Si | 详情 | 详情 | |
| (IX) | 44454 | ethyl 2-methyl-1,3-thiazole-4-carboxylate | 6436-59-5 | C7H9NO2S | 详情 | 详情 |
| (X) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (XI) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (XII) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (XIII) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (XIV) | 44457 | (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoate | C34H57NO5SSi | 详情 | 详情 | |
| (XV) | 43176 | (4S,7R,8S,9S,16S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C32H53NO5SSi | 详情 | 详情 | |
| (XVI) | 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3
该中间体在本合成路线中的序号：(II)The oxoacid intermediate (VI) has been obtained as follows: The condensation of 2,2-dimethyl-3-oxopentanal (I) with (+)-diisopinocampheyl(allyl)borane (II) gives the chiral 5(S)-hydroxy-4,4-dimethyl-7-octen-3-one (III), which is protected with Tbdms-OTf, yielding the silyl ether (IV). The ozonolysis of (IV) in dichloromethane affords the aldehyde (V), which is finally oxidized with NaClO2 in tert-butanol/water to provide the target oxoacid intermediate (VI).
| 【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 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) | 44448 | 2,2-dimethyl-3-oxopentanal | C7H12O2 | 详情 | 详情 | |
| (II) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (III) | 44450 | (5S)-5-hydroxy-4,4-dimethyl-7-octen-3-one | C10H18O2 | 详情 | 详情 | |
| (IV) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (V) | 44452 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanal | C15H30O3Si | 详情 | 详情 | |
| (VI) | 43162 | (4-methoxybutylidene)(triphenyl)phosphorane; methyl 4-(triphenylphosphoranylidene)butyl ether | C23H25OP | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The intermediate phosphonium salt (XVI) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (VII) with DIBAL in dichloromethane gives the corresponding aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (X). The allylation of (X) with (+)-diisopinocampheyl(allyl)borane (II) affords the chiral secondary alcohol (XI), which is protected with Tbdms-Cl and imidazole in DMF, providing the silyl ether (XII). The oxidation of the terminal double bond of (XII) with OsO4 and Pb(OAc)4 in THF/tert-butanol/water gives rise to the aldehyde (XIII), which is reduced with NaBH4 in methanol to give the corresponding primary alcohol (XIV). The reaction of (XIV) with I2, PPh3 and imidazole in ethyl ether/acetonitrile yields the expected iodo derivative (XV), which is finally condensed with PPh3 at 100 C to afford the desired intermediate phosphonium salt (XVI).
| 【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (VII) | 44454 | ethyl 2-methyl-1,3-thiazole-4-carboxylate | 6436-59-5 | C7H9NO2S | 详情 | 详情 |
| (VIII) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (IX) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (X) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (XI) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (XII) | 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 | |
| (XIII) | 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 | |
| (XIV) | 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 | |
| (XV) | 44458 | tert-butyl(dimethyl)silyl (1S,2E)-1-(2-iodoethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl ether; 4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-2-methyl-1-pentenyl)-2-methyl-1,3-thiazole | C16H28INOSSi | 详情 | 详情 | |
| (XVI) | 44459 | [(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl](triphenyl)phosphonium iodide | C34H43INOPSSi | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)The synthesis of the intermediate chiral aldehyde (XVIII) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid methyl ester (I) with DIBAL in dichloromethane gives the aldehyde (II), which by condensation with phosphorane (III) in refluxing benzene yields the unsaturated aldehyde (IV). The condensation of (IV) with the chiral borane (V) in ethyl ether affords the chiral unsaturated alcohol (VI), which is treated with Tbdms-Cl and imidazole to provide the sill ether (VII). The oxidation of the terminal double bond of (VIII) with OsO4 and Pb(OAc)4 in THF/tBuOH/water gives the aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield the carboxylic acid (X). The reduction of (X) with DIBAL in THF affords the carbinol (XI), which is reduced by reaction with CCl4 and PPh3, followed by a reductive dechlorination with LiBHEt3, to furnish the dimethylated olefin (XII). Hydroxylation of the terminal double bond of (XII) with 9-BBN in THF gives the primary alcohol (XIII), which is treated with I2 and PPh3 in ethyl ether/CH3CN to yield the iodo derivative (XIV). The condensation of (XIV) with the chiral 1-(propylideneamino)pyrrolidine (XV) by means of LDA in THF affords intermediate (XVI), which is converted into the nitrile (XVII) by reaction with monoperoxyphthalic acid magnesium salt (MMPP) in MeOH. Finally this compound is reduced with DIBAL in toluene to afford the target aldehyde intermediate (XVIII).
| 【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 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) | 44454 | ethyl 2-methyl-1,3-thiazole-4-carboxylate | 6436-59-5 | C7H9NO2S | 详情 | 详情 |
| (II) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (III) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (IV) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (V) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (VI) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (VII) | 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 | |
| (VIII) | 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 | |
| (IX) | 46110 | methyl 2-(triphenylphosphoranylidene)-4-pentenoate | C24H23O2P | 详情 | 详情 | |
| (X) | 46113 | 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-1,5,8-nonatrienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,6-heptadienyl ether | C21H35NOSSi | 详情 | 详情 | |
| (XI) | 46114 | (4Z,7S,8E)-7-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-9-(2-methyl-1,3-thiazol-4-yl)-4,8-nonadien-1-ol | C21H37NO2SSi | 详情 | 详情 | |
| (XII) | 46115 | 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-9-iodo-2,6-dimethyl-1,5-nonadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-7-iodo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-heptenyl ether | C21H36INOSSi | 详情 | 详情 | |
| (XIII) | 46116 | (2R)-N-[(Z,2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienylidene]-2-methoxy-1-pyrrolidinamine; N-[(Z,2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienylidene]-N-[(2R)-2-methoxypyrrolidinyl]amine | C29H51N3O2SSi | 详情 | 详情 | |
| (XIV) | 46117 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienenitrile | C24H40N2OSSi | 详情 | 详情 | |
| (XV) | 44460 | N-[(2R)-2-methoxypyrrolidinyl]-N-[(E)propylidene]amine; (2R)-2-methoxy-N-[(E)propylidene]-1-pyrrolidinamine | C8H16N2O | 详情 | 详情 | |
| (XVI) | 46118 | (3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C39H71NO6SSi2 | 详情 | 详情 | |
| (XVII) | 46119 | tert-butyl(dimethyl)silyl (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-heptadecadienoate | C51H99NO6SSi4 | 详情 | 详情 | |
| (XVIII) | 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 |
合成路线6
该中间体在本合成路线中的序号：(V)The condensation of 2,2-dimethyl-3-oxopentanal (XIX) with the chiral borane (V) in ethyl ether gives the chiral hydroxyketone (XX), which is treated with Tbdms-OTf and lutidine in dichloromethane to yield the silyl ether (XXI). Ozonolysis of the terminal double bond of (XXI) affords the aldehyde (XXII), which is oxidized to the carboxylic acid (XXIII) with NaClO2. The condensation of (XXIII) with the reported intermediate aldehyde (XVIII) by means of LDA in THF provides the hydroxyacid (XXIV), which is silylated with Tbdms-OTf and lutidine in dichloromethane to furnish the fully silylated compound (XXV). The hydrolysis of the silyl ester of (XXV) with K2CO3 in methanol gives the carboxylic acid (XXVI), which is selectively desilylated with TBAF in THF to yield the hydroxyacid (XXVII).The macrolactonization of (XXVII) by treatment with 2,4,6-trichlorobenzoyl chloride and TEA in THF, followed by a treatment with DMAP in toluene, affords the silylated macrolactone (XXVIII).
| 【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (XVIII) | 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 | |
| (XIX) | 44448 | 2,2-dimethyl-3-oxopentanal | C7H12O2 | 详情 | 详情 | |
| (XX) | 44450 | (5S)-5-hydroxy-4,4-dimethyl-7-octen-3-one | C10H18O2 | 详情 | 详情 | |
| (XXI) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (XXII) | 44452 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanal | C15H30O3Si | 详情 | 详情 | |
| (XXIII) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 | |
| (XXIV) | 46118 | (3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C39H71NO6SSi2 | 详情 | 详情 | |
| (XXV) | 46119 | tert-butyl(dimethyl)silyl (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-heptadecadienoate | C51H99NO6SSi4 | 详情 | 详情 | |
| (XXVI) | 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 | |
| (XXVII) | 40835 | (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C39H71NO6SSi2 | 详情 | 详情 | |
| (XXVIII) | 40836 | (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C39H69NO5SSi2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)The oxoacid intermediate (VI) has been obtained as follows: The condensation of 2,2-dimethyl-3-oxopentanal (I) with (+)-diisopinocampheyl(allyl)borane (II) gives the chiral 5(S)-hydroxy-4,4-dimethyl-7-octen-3-one (III), which is protected with Tbdms-OTf, yielding the silyl ether (IV). The ozonolysis of (IV) in dichloromethane affords the aldehyde (V), which is finally oxidized with NaClO2 in tert-butanol/water to provide the target oxoacid intermediate (VI).
| 【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 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) | 44448 | 2,2-dimethyl-3-oxopentanal | C7H12O2 | 详情 | 详情 | |
| (II) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (III) | 44450 | (5S)-5-hydroxy-4,4-dimethyl-7-octen-3-one | C10H18O2 | 详情 | 详情 | |
| (IV) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (V) | 44452 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanal | C15H30O3Si | 详情 | 详情 | |
| (VI) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)The intermediate phosphonium salt (XVI) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (VII) with DIBAL in dichloromethane gives the corresponding aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (X). The allylation of (X) with (+)-diisopinocampheyl(allyl)borane (II) affords the chiral secondary alcohol (XI), which is protected with Tbdms-Cl and imidazole in DMF, providing the silyl ether (XII). The oxidation of the terminal double bond of (XII) with OsO4 and Pb(OAc)4 in THF/tert-butanol/water gives rise to the aldehyde (XIII), which is reduced with NaBH4 in methanol to give the corresponding primary alcohol (XIV). The reaction of (XIV) with I2, PPh3 and imidazole in ethyl ether/acetonitrile yields the expected iodo derivative (XV), which is finally condensed with PPh3 at 100 C to afford the desired intermediate phosphonium salt (XVI).
| 【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (VII) | 44454 | ethyl 2-methyl-1,3-thiazole-4-carboxylate | 6436-59-5 | C7H9NO2S | 详情 | 详情 |
| (VIII) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (IX) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (X) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (XI) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (XII) | 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 | |
| (XIII) | 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 | |
| (XIV) | 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 | |
| (XV) | 44458 | tert-butyl(dimethyl)silyl (1S,2E)-1-(2-iodoethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl ether; 4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-2-methyl-1-pentenyl)-2-methyl-1,3-thiazole | C16H28INOSSi | 详情 | 详情 | |
| (XVI) | 44459 | [(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl](triphenyl)phosphonium iodide | C34H43INOPSSi | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(V)The synthesis of the intermediate chiral aldehyde (XVIII) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid methyl ester (I) with DIBAL in dichloromethane gives the aldehyde (II), which by condensation with phosphorane (III) in refluxing benzene yields the unsaturated aldehyde (IV). The condensation of (IV) with the chiral borane (V) in ethyl ether affords the chiral unsaturated alcohol (VI), which is treated with Tbdms-Cl and imidazole to provide the sill ether (VII). The oxidation of the terminal double bond of (VIII) with OsO4 and Pb(OAc)4 in THF/tBuOH/water gives the aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield the carboxylic acid (X). The reduction of (X) with DIBAL in THF affords the carbinol (XI), which is reduced by reaction with CCl4 and PPh3, followed by a reductive dechlorination with LiBHEt3, to furnish the dimethylated olefin (XII). Hydroxylation of the terminal double bond of (XII) with 9-BBN in THF gives the primary alcohol (XIII), which is treated with I2 and PPh3 in ethyl ether/acetonitrile to yield the iodo derivative (XIV). The condensation of (XIV) with the chiral 1-(propylideneamino)pyrrolidine (XV) by means of LDA in THF affords intermediate (XVI), which is converted into the nitrile (XVII) by reaction with monoperoxyphthalic acid magnesium salt (MMPP) in methanol. Finally, this compound is reduced with DIBAL in toluene to afford the target aldehyde intermediate (XVIII).
| 【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 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) | 44454 | ethyl 2-methyl-1,3-thiazole-4-carboxylate | 6436-59-5 | C7H9NO2S | 详情 | 详情 |
| (II) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (III) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (IV) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (V) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (VI) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (VII) | 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 | |
| (VIII) | 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 | |
| (IX) | 46110 | methyl 2-(triphenylphosphoranylidene)-4-pentenoate | C24H23O2P | 详情 | 详情 | |
| (X) | 46113 | 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-1,5,8-nonatrienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3,6-heptadienyl ether | C21H35NOSSi | 详情 | 详情 | |
| (XI) | 46114 | (4Z,7S,8E)-7-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-9-(2-methyl-1,3-thiazol-4-yl)-4,8-nonadien-1-ol | C21H37NO2SSi | 详情 | 详情 | |
| (XII) | 46115 | 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-9-iodo-2,6-dimethyl-1,5-nonadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-7-iodo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-heptenyl ether | C21H36INOSSi | 详情 | 详情 | |
| (XIII) | 46116 | (2R)-N-[(Z,2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienylidene]-2-methoxy-1-pyrrolidinamine; N-[(Z,2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienylidene]-N-[(2R)-2-methoxypyrrolidinyl]amine | C29H51N3O2SSi | 详情 | 详情 | |
| (XIV) | 46117 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienenitrile | C24H40N2OSSi | 详情 | 详情 | |
| (XV) | 44460 | N-[(2R)-2-methoxypyrrolidinyl]-N-[(E)propylidene]amine; (2R)-2-methoxy-N-[(E)propylidene]-1-pyrrolidinamine | C8H16N2O | 详情 | 详情 | |
| (XVI) | 46118 | (3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C39H71NO6SSi2 | 详情 | 详情 | |
| (XVII) | 46119 | tert-butyl(dimethyl)silyl (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-heptadecadienoate | C51H99NO6SSi4 | 详情 | 详情 | |
| (XVIII) | 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 |
合成路线10
该中间体在本合成路线中的序号：(V)The condensation of 2,2-dimethyl-3-oxopentanal (XIX) with the chiral borane (V) in ethyl ether gives the chiral hydroxyketone (XX), which is treated with Tbdms-OTf and lutidine in dichloromethane to yield the silyl ether (XXI). Ozonolysis of the terminal double bond of (XXI) affords the aldehyde (XXII), which is oxidized to the carboxylic acid (XXIII) with NaClO2. The condensation of (XXIII) with the reported intermediate aldehyde (XVIII) by means of LDA in THF provides the hydroxyacid (XXIV), which is silylated with Tbdms-OTf and lutidine in dichloromethane to furnish the fully silylated compound (XXV). The hydrolysis of the silyl ester of (XXV) with K2CO3 in methanol gives the carboxylic acid (XXVI), which is selectively desilylated with TBAF in THF to yield the hydroxyacid (XXVII).The macrolactonization of (XXVII) by treatment with 2,4,6-trichlorobenzoyl chloride and TEA in THF, followed by a treatment with DMAP in toluene, affords the silylated macrolactone (XXVIII), which is finally deprotected with TFA in dichloromethane to provide the target epothilone D.
| 【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (XVIII) | 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 | |
| (XIX) | 44448 | 2,2-dimethyl-3-oxopentanal | C7H12O2 | 详情 | 详情 | |
| (XX) | 44450 | (5S)-5-hydroxy-4,4-dimethyl-7-octen-3-one | C10H18O2 | 详情 | 详情 | |
| (XXI) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (XXII) | 44452 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanal | C15H30O3Si | 详情 | 详情 | |
| (XXIII) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 | |
| (XXIV) | 46118 | (3S,6R,7S,8S,12Z,15S,16E)-3,15-bis[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C39H71NO6SSi2 | 详情 | 详情 | |
| (XXV) | 46119 | tert-butyl(dimethyl)silyl (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-heptadecadienoate | C51H99NO6SSi4 | 详情 | 详情 | |
| (XXVI) | 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 | |
| (XXVII) | 40835 | (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid | C39H71NO6SSi2 | 详情 | 详情 | |
| (XXVIII) | 40836 | (4S,7R,8S,9S,16S)-4,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C39H69NO5SSi2 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(II)The oxoacid intermediate (VI) has been obtained as follows: The condensation of 2,2-dimethyl-3-oxopentanal (I) with (+)-diisopinocampheyl(allyl)borane (II) gives the chiral 5(S)-hydroxy-4,4-dimethyl-7-octen-3-one (III), which is protected with Tbdms-OTf, yielding the silyl ether (IV). The ozonolysis of (IV) in dichloromethane affords the aldehyde (V), which is finally oxidized with NaClO2 in tert-butanol/water to provide the target oxoacid intermediate (VI).
| 【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 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) | 44448 | 2,2-dimethyl-3-oxopentanal | C7H12O2 | 详情 | 详情 | |
| (II) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (III) | 44450 | (5S)-5-hydroxy-4,4-dimethyl-7-octen-3-one | C10H18O2 | 详情 | 详情 | |
| (IV) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (V) | 44452 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanal | C15H30O3Si | 详情 | 详情 | |
| (VI) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(II)The intermediate phosphonium salt (XVI) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (VII) with DIBAL in dichloromethane gives the corresponding aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (X). The allylation of (X) with (+)-diisopinocampheyl(allyl)borane (II) affords the chiral secondary alcohol (XI), which is protected with Tbdms-Cl and imidazole in DMF to provide the silyl ether (XII). The oxidation of the terminal double bond of (XII) with OsO4 and Pb(OAc)4 in THF/tert-butanol/water gives rise to the aldehyde (XIII), which is reduced with NaBH4 in methanol to give the corresponding primary alcohol (XIV). The reaction of (XIV) with I2, PPh3 and imidazole in ethyl ether/acetonitrile yields the expected iodo derivative (XV), which is finally condensed with PPh3 at 100 C to afford the desired intermediate phosphonium salt (XVI).
| 【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (VII) | 44454 | ethyl 2-methyl-1,3-thiazole-4-carboxylate | 6436-59-5 | C7H9NO2S | 详情 | 详情 |
| (VIII) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (IX) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (X) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (XI) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (XII) | 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 | |
| (XIII) | 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 | |
| (XIV) | 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 | |
| (XV) | 44458 | tert-butyl(dimethyl)silyl (1S,2E)-1-(2-iodoethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl ether; 4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-2-methyl-1-pentenyl)-2-methyl-1,3-thiazole | C16H28INOSSi | 详情 | 详情 | |
| (XVI) | 44459 | [(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl](triphenyl)phosphonium iodide | C34H43INOPSSi | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(XXXII)The reaction of 2,2-dimethyl-3-oxopentanal (XXXI) with (+)-diisopinocampheyl(allyl)borane (XXXII) in ethyl ether gives the chiral beta-hydroxy ketone (XXXIII), which is protected with Tbdms-OTf to yield the silyl ether (XXXIV). The ozonolysis of the double bond of (XXXIV) affords the aldehyde (XXXV), which is oxidized with NaClO2 to the carboxylic acid (XXXVI). Finally, this compound is condensed with 2(S)-methyl-6-heptenal (VII) by means of LDA in THF to provide the intermediate tridecenoic acid (XII).
| 【1】 Nicolaou, K.C.; et al.; The olefin metathesis approach to epothilone A and its analogues. J Am Chem Soc 1997, 119, 34, 7960. |
| 【2】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 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) | 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 | |
| (XXXI) | 44448 | 2,2-dimethyl-3-oxopentanal | C7H12O2 | 详情 | 详情 | |
| (XXXII) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (XXXIII) | 44450 | (5S)-5-hydroxy-4,4-dimethyl-7-octen-3-one | C10H18O2 | 详情 | 详情 | |
| (XXXIV) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (XXXV) | 44452 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanal | C15H30O3Si | 详情 | 详情 | |
| (XXXVI) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 | |
| (XXXVII) | 27185 | (2S)-2-methyl-6-heptenal | C8H14O | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(II)The synthesis of intermediate tridecenoic acid (VIII) has been performed as follows: The reaction of 2,2-dimethyl-3-oxopentanal (I) with (+)-diisopinocampheyl(allyl)borane (II) in ethyl ether gives the chiral beta-hydroxy ketone (III), which is protected with Tbdms-OTf, yielding the silyl ether (IV). The ozonolysis of the double bond of (IV) affords the aldehyde (V), which is oxidized with NaClO2 to the carboxylic acid (VI). Finally, this compound is condensed with 2(S)-methyl-6-heptenal (VII) by means of LDA in THF to provide the intermediate tridecenoic acid (VIII).
| 【1】 Nicolaou, K.C.; et al.; The olefin metathesis approach to epothilone A and its analogues. J Am Chem Soc 1997, 119, 34, 7960. |
| 【2】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 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) | 44448 | 2,2-dimethyl-3-oxopentanal | C7H12O2 | 详情 | 详情 | |
| (II) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (III) | 44450 | (5S)-5-hydroxy-4,4-dimethyl-7-octen-3-one | C10H18O2 | 详情 | 详情 | |
| (IV) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (V) | 44452 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanal | C15H30O3Si | 详情 | 详情 | |
| (VI) | 43166 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanoic acid | C15H30O4Si | 详情 | 详情 | |
| (VII) | 27185 | (2S)-2-methyl-6-heptenal | C8H14O | 详情 | 详情 | |
| (VIII) | 44453 | (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C23H44O5Si | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(II)The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (IX) with DIBAL in dichloromethane gives the corresponding aldehyde (X), which is condensed with the phosphorane (XI) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2-propenal (XII). The alkylation of (XII) with (+)-diisopinocampheyl(allyl)borane (II) in ethyl ether affords the chiral secondary alcohol (XIII) (1), which is esterified with the intermediate tridecenoic acid (VIII) by means of EDC and DMAP in dichloromethane to provide the ester (XIV). Ring-closing metathesis of (XIV) catalyzed by a Ru catalyst gives the macrolactone (XV), which is finally desilylated by means of TFA in dichloromethane, yielding the target epothilone C.
| 【1】 Nicolaou, K.C.; et al.; The olefin metathesis approach to epothilone A and its analogues. J Am Chem Soc 1997, 119, 34, 7960. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (VIII) | 44453 | (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid | C23H44O5Si | 详情 | 详情 | |
| (IX) | 44454 | ethyl 2-methyl-1,3-thiazole-4-carboxylate | 6436-59-5 | C7H9NO2S | 详情 | 详情 |
| (X) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (XI) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (XII) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (XIII) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (XIV) | 44457 | (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-4,4,6,8-tetramethyl-5-oxo-12-tridecenoate | C34H57NO5SSi | 详情 | 详情 | |
| (XV) | 43176 | (4S,7R,8S,9S,16S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione | C32H53NO5SSi | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(II)The oxoacid intermediate (VI) has been obtained as follows: The condensation of 2,2-dimethyl-3-oxopentanal (I) with (+)-diisopinocampheyl(allyl)borane (II) gives the chiral 5(S)-hydroxy-4,4-dimethyl-7-octen-3-one (III), which is protected with Tbdms-OTf, yielding the silyl ether (IV). The ozonolysis of (IV) in dichloromethane affords the aldehyde (V), which is finally oxidized with NaClO2 in tert-butanol/water to provide the target oxoacid intermediate (VI).
| 【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 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) | 44448 | 2,2-dimethyl-3-oxopentanal | C7H12O2 | 详情 | 详情 | |
| (II) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (III) | 44450 | (5S)-5-hydroxy-4,4-dimethyl-7-octen-3-one | C10H18O2 | 详情 | 详情 | |
| (IV) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (V) | 44452 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-5-oxoheptanal | C15H30O3Si | 详情 | 详情 | |
| (VI) | 43162 | (4-methoxybutylidene)(triphenyl)phosphorane; methyl 4-(triphenylphosphoranylidene)butyl ether | C23H25OP | 详情 | 详情 |
合成路线17
该中间体在本合成路线中的序号：(II)The intermediate phosphonium salt (XVI) has been obtained as follows: The reduction of 2-methylthiazole-4-carboxylic acid ethyl ester (VII) with DIBAL in dichloromethane gives the corresponding aldehyde (VIII), which is condensed with the phosphorane (IX) in refluxing benzene to yield 2-methyl-3-(2-methylthiazol-4-yl)-2(E)-propenal (X). The allylation of (X) with (+)-diisopinocampheyl(allyl)borane (II) affords the chiral secondary alcohol (XI), which is protected with Tbdms-Cl and imidazole in DMF, providing the silyl ether (XII). The oxidation of the terminal double bond of (XII) with OsO4 and Pb(OAc)4 in THF/tert-butanol/water gives rise to the aldehyde (XIII), which is reduced with NaBH4 in methanol to give the corresponding primary alcohol (XIV). The reaction of (XIV) with I2, PPh3 and imidazole in ethyl ether/acetonitrile yields the expected iodo derivative (XV), which is finally condensed with PPh3 at 100 C to afford the desired intermediate phosphonium salt (XVI).
| 【1】 Nicolaou, K.C.; et al.; Total syntheses of epothilones A and B via a macrolactonization-based strategy. J Am Chem Soc 1997, 119, 34, 7974. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 44449 | allyl[bis[(1R,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane | C23H39B | 详情 | 详情 | |
| (VII) | 44454 | ethyl 2-methyl-1,3-thiazole-4-carboxylate | 6436-59-5 | C7H9NO2S | 详情 | 详情 |
| (VIII) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (IX) | 39940 | 2-(triphenylphosphoranylidene)propanal | C21H19OP | 详情 | 详情 | |
| (X) | 44456 | (E)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenal | C8H9NOS | 详情 | 详情 | |
| (XI) | 43171 | (1E,3S)-2-methyl-1-(2-methyl-1,3-thiazol-4-yl)-1,5-hexadien-3-ol | C11H15NOS | 详情 | 详情 | |
| (XII) | 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 | |
| (XIII) | 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 | |
| (XIV) | 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 | |
| (XV) | 44458 | tert-butyl(dimethyl)silyl (1S,2E)-1-(2-iodoethyl)-2-methyl-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl ether; 4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-iodo-2-methyl-1-pentenyl)-2-methyl-1,3-thiazole | C16H28INOSSi | 详情 | 详情 | |
| (XVI) | 44459 | [(3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenyl](triphenyl)phosphonium iodide | C34H43INOPSSi | 详情 | 详情 |