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【结 构 式】 
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【分子编号】44451 【品名】(5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one 【CA登记号】 |
【 分 子 式 】C16H32O2Si 【 分 子 量 】284.51438 【元素组成】C 67.55% H 11.34% O 11.25% Si 9.87% |
合成路线1
该中间体在本合成路线中的序号：(IV)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：(IV)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3
该中间体在本合成路线中的序号：(XVII)The condensation of (XVI) with ketone (XVII) by means of LDA affords the open-chain precursor (XVIII), which is protected at the OH group with Troc-Cl and pyridine to afford compound (XIX). The oxidation of (XIX) at the terminal vinyl group by means of OsO4, NMO and Pb(OAc)4 provides the carboxylic acid (XVIII), which by selective cleavage of its Tes- protecting group with HF and pyridine furnishes the hydroxyacid (XIX). The macrolactonization of (XIX) by means of 2,4,6-trichlorobenzoyl chloride gives the protected macrolactone (XX). The reaction of (XX) with Zn and NH4Cl in methanol cleaves the Troc-protecting group, yielding the silylated precursor (XXI), which is finally treated with HF and pyridine to afford the target epothilone A
| 【1】 Bode, J.W.; Carreira, E.M.; Stereoselective syntheses of epothilones A and B via directed nitrile oxide cycloaddition. J Am Chem Soc 2001, 123, 18, 3611. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI) | 49316 | (2S)-2-methyl-5-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentanal | C23H39NO3SSi | 详情 | 详情 | |
| (XVII) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (XVIII) | 49317 | (4S,7R,8S,9S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-12-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-dodecen-6-one | C39H71NO5SSi2 | 详情 | 详情 | |
| (XIX) | 49318 | (1S,2R,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4,4-trimethyl-1-[(1S)-1-methyl-4-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)butyl]-3-oxo-7-octenyl 2,2,2-trichloroethyl carbonate | C42H72Cl3NO7SSi2 | 详情 | 详情 | |
| (XX) | 49319 | (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-11-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]undecanoic acid | C41H70Cl3NO9SSi2 | 详情 | 详情 | |
| (XXI) | 49320 | (3S,6R,7S,8S)-3-[[tert-butyl(dimethyl)silyl]oxy]-11-[(2R,3S)-3-[(2S,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]oxiranyl]-4,4,6,8-tetramethyl-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]undecanoic acid | C35H56Cl3NO9SSi | 详情 | 详情 | |
| (XXII) | 49321 | (1S,3S,7S,10R,11S,12S,16R)-7-[[tert-butyl(dimethyl)silyl]oxy]-8,8,10,12-tetramethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-11-yl 2,2,2-trichloroethyl carbonate | C35H54Cl3NO8SSi | 详情 | 详情 | |
| (XXIII) | 49322 | (1S,3S,7S,10R,11S,12S,16R)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-8,8,10,12-tetramethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione | C32H53NO6SSi | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXI)The oxidation of (XIX) by means of TPAP and NMO gives the aldehyde (XX), which is condensed with the chiral ketone (XXI) by means of LDA in THF to yield the aldol (XXII). The protection of the OH group of (XXII) with Troc-Cl and pyridine affords the Troc-ester (XXIII). The oxidation of the terminal vinyl group of (XXIII) with OsO4, NMO and Pb(OAc)4 provides the aldehyde (XXIV), which is selectively monodesilylated by treatment with HF and pyridine at 0 C to give the alcohol (XXV). The oxidation of the aldehyde group of (XXV) with NaClO2 yields the hydroxyacid (XXVI), which is submitted to macrolactonization by means of 2,4,6-trichlrobenzoyl chloride, TEA and DMAP to afford the protected macrolactone (XXVII). The cleavage of the Troc- protecting group of (XXVII) by means of Zn and NH4Cl in methanol provides the silylated precursor (XXVIII), which is finally treated with HF and pyridine at 40 C to furnish the target Epothilone A.
| 【1】 Bode, J.W.; Carreira, E.M.; Stereoselective syntheses of epothilones A and B via nitrile oxide cycloadditions and related studies. J Org Chem 2001, 66, 19, 6410. |
| 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) | 49315 | (2S)-2-methyl-5-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-pentanol | C23H41NO3SSi | 详情 | 详情 | |
| (XX) | 49316 | (2S)-2-methyl-5-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentanal | C23H39NO3SSi | 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) | 49317 | (4S,7R,8S,9S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-12-((2R,3S)-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-dodecen-6-one | C39H71NO5SSi2 | 详情 | 详情 | |
| (XXIII) | 60472 | trityl (3S,4R,7S)-7-{[tert-butyl(dimethyl)silyl]oxy}-4,6,6-trimethyl-3-[(1S)-1-methyl-4-((2R,3S)-3-{(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl}oxiranyl)butyl]-5-oxo-9-decenoate | C60H87NO6SSi2 | 详情 | 详情 | |
| (XXIV) | 60473 | trityl (3S,4R,7S)-7-{[tert-butyl(dimethyl)silyl]oxy}-4,6,6-trimethyl-3-[(1S)-1-methyl-4-((2R,3S)-3-{(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl}oxiranyl)butyl]-5,9-dioxononanoate | C59H85NO7SSi2 | 详情 | 详情 | |
| (XXV) | 60474 | trityl (3S,4R,7S)-7-{[tert-butyl(dimethyl)silyl]oxy}-3-((1S)-4-{(2R,3S)-3-[(2S,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]oxiranyl}-1-methylbutyl)-4,6,6-trimethyl-5,9-dioxononanoate | C53H71NO7SSi | 详情 | 详情 | |
| (XXVI) | 60475 | (3S,6R,7S,8S)-3-{[tert-butyl(dimethyl)silyl]oxy}-11-{(2R,3S)-3-[(2S,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]oxiranyl}-4,4,6,8-tetramethyl-5-oxo-7-[2-oxo-2-(trityloxy)ethyl]undecanoic acid | C53H71NO8SSi | 详情 | 详情 | |
| (XXVII) | 60476 | trityl 2-{(1S,3S,7S,10R,11S,12S,16R)-7-{[tert-butyl(dimethyl)silyl]oxy}-8,8,10,12-tetramethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-11-yl}acetate | C53H69NO7SSi | 详情 | 详情 | |
| (XXVIII) | 49322 | (1S,3S,7S,10R,11S,12S,16R)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-8,8,10,12-tetramethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione | C32H53NO6SSi | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XXI)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6
该中间体在本合成路线中的序号：(IV)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7
该中间体在本合成路线中的序号：(XVII)The condensation of the known ketone (XVII) with aldehyde (XVIII) by means of LDA in THF gives the hydroxyketone (XIX), which is silylated with Tbdms-OTf and TEA in dichloromethane, yielding the silyl ether (XX). The terminal vinyl group of (XX) is cleaved oxidatively by means of OsO4 and NaIO4 in THF/water, affording the aldehyde (XXI), which is oxidized to acid (XXII) by means of NaClO2 in t-butanol/water. Acid (XXII) is esterified to methyl ester (XXIII), which is selectively deprotected at the Pmb group by hydrogenation with H2 over Pd/C in ethanol to provide the primary alcohol (XXIV). The oxidation of (XXIV) with tetrapropylammonium perruthenate (TPAP) furnishes the aldehyde (XXV), which is submitted to a Wittig condensation with the intermediate phosphonium salt (XVI) by means of LiHMDS in THF to give the adduct (XXVI). The hydrolysis of the ester group of (XXVI) with NaOH in warm isopropanol yields the carboxylic acid (XXVII), which is selectively deprotected by means of TBAF in THF to afford the hydroxyacid (XXVIII).
| 【1】 White, J.D.; Carter, R.G.; Sundermann, K.F.; Wartmann, M.; Total synthesis of epothilone B, epothilone D, and cis- and trans-9,10-dehydroepothilone D. J Am Chem Soc 2001, 123, 23, 5407. |
| 【2】 White, J.D.; et al.; A highly stereoselective synthesis of epothilone B. J Org Chem 1999, 64, 3, 684. |
| 【3】 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 |
|---|---|---|---|---|---|---|
| (XVI) | 46148 | [(3Z,6S,7E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3,7-dimethyl-8-(2-methyl-1,3-thiazol-4-yl)-3,7-octadienyl](triphenyl)phosphonium bromide | C38H49BrNOPSSi | 详情 | 详情 | |
| (XVII) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (XVIII) | 42656 | (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanal | C12H16O3 | 详情 | 详情 | |
| (XIX) | 46149 | (2S,3S,4R,7S)-7-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-1-[(4-methoxybenzyl)oxy]-2,4,6,6-tetramethyl-9-decen-5-one | C28H48O5Si | 详情 | 详情 | |
| (XX) | 46150 | (5S,8R,9S)-5-allyl-9-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-4,10-dioxa-3,11-disilatridecan-7-one | C34H62O5Si2 | 详情 | 详情 | |
| (XXI) | 46151 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxononanal | C33H60O6Si2 | 详情 | 详情 | |
| (XXII) | 46152 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxononanoic acid | C33H60O7Si2 | 详情 | 详情 | |
| (XXIII) | 46153 | methyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxononanoate | C34H62O7Si2 | 详情 | 详情 | |
| (XXIV) | 46154 | methyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-9-hydroxy-4,4,6,8-tetramethyl-5-oxononanoate | C26H54O6Si2 | 详情 | 详情 | |
| (XXV) | 46155 | methyl (3S,6R,7S,8R)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5,9-dioxononanoate | C26H52O6Si2 | 详情 | 详情 | |
| (XXVI) | 46156 | methyl (3S,6R,7S,8S,9Z,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-9,12,16-heptadecatrienoate | C46H85NO6SSi3 | 详情 | 详情 | |
| (XXVII) | 46157 | (3S,6R,7S,8S,9Z,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-9,12,16-heptadecatrienoic acid | C45H83NO6SSi3 | 详情 | 详情 | |
| (XXVIII) | 46158 | (3S,6R,7S,8S,9Z,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-9,12,16-heptadecatrienoic acid | C39H69NO6SSi2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XVIII)Synthesis of intermediate ketone (XVIII): The reaction of 2,2-dimethyl-3-oxopentanal (XVI) with (+)-allyldi(isopinocampheyl)borane in ethyl ether gives the chiral beta-hydroxyketone (XVII), which is silylated with Tbdms-OTf and lutidine in dichloromethane to afford the desired intermediate ketone (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. |
合成路线9
该中间体在本合成路线中的序号：(XVIII)The selective deprotection of (XXX) with CSA in dichloromethane gives the primary alcohol (XXXI), which is oxidized with DMP in dichloromethane to yield the aldehyde (XXXII). The condensation of (XXXII) with methyltriphenylphosphonium iodide (XXXIII) by means of BuLi in hexane/THF, followed by treatment with HCl in ethanol, affords the diunsaturated vicinal diol (XXXIV), which is selectively silylated to provide the vicinal diol (XXXV). The monosulfonation of (XXXV) with Ms-Cl and TEA furnishes the mesylate (XXXVI), which is cyclized to the epoxide (XXXVII) by means of K2CO3 in methanol. The oxidation of the terminal double bond of (XXXVII) with OsO4 and NaIO4 gives the aldehyde (XXXVIII), which is condensed with the intermediate ketone (XVIII) by means of LDA in THF to provide the adduct (XXXIX).
| 【1】 Mulzer, J.; et al.; A novel highly stereoselective total synthesis of epothilone B and of its (12R,13R) acetonide. Tetrahedron Lett 2000, 41, 40, 7635. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXIIII) | 13484 | Methyl(triphenyl)phosphonium iodide; Methyltriphenylphosphonium iodide | 2065-66-9 | C19H18IP | 详情 | 详情 |
| (XVIII) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (XXX) | 46184 | tert-butyl(dimethyl)silyl (2S)-5-[(4R,5R)-5-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2,2,4-trimethyl-1,3-dioxolan-4-yl]-2-methylpentyl ether; 4-[(E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4R,5R)-5-((4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-methylpentyl)-2,2,5-trimethyl-1,3-dioxolan-4-yl]-2-methyl-1-butenyl]-2-methyl-1,3-thiazole | C33H63NO4SSi2 | 详情 | 详情 | |
| (XXXI) | 46186 | (2S)-5-[(4R,5R)-5-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2,2,4-trimethyl-1,3-dioxolan-4-yl]-2-methyl-1-pentanol | C27H49NO4SSi | 详情 | 详情 | |
| (XXXII) | 46187 | (2S)-5-[(4R,5R)-5-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2,2,4-trimethyl-1,3-dioxolan-4-yl]-2-methylpentanal | C27H47NO4SSi | 详情 | 详情 | |
| (XXXIV) | 46188 | (1E,3S,5R,6R,10S)-2,6,10-trimethyl-1-(2-methyl-1,3-thiazol-4-yl)-1,11-dodecadiene-3,5,6-triol | C19H31NO3S | 详情 | 详情 | |
| (XXXV) | 46189 | (1E,3S,5R,6R,10S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-1-(2-methyl-1,3-thiazol-4-yl)-1,11-dodecadiene-5,6-diol | C25H45NO3SSi | 详情 | 详情 | |
| (XXXVI) | 46190 | (1R,2R,6S)-1-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-hydroxy-2,6-dimethyl-7-octenyl methanesulfonate | C26H47NO5S2Si | 详情 | 详情 | |
| (XXXVII) | 46191 | tert-butyl(dimethyl)silyl (1S,2E)-2-methyl-1-([(2S,3R)-3-methyl-3-[(4S)-4-methyl-5-hexenyl]oxiranyl]methyl)-3-(2-methyl-1,3-thiazol-4-yl)-2-propenyl ether; 4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-4-[(2S,3R)-3-methyl-3-[(4S)-4-methyl-5-hexenyl]oxiranyl]-1-butenyl)-2-methyl-1,3-thiazole | C25H43NO2SSi | 详情 | 详情 | |
| (XXXVIII) | 46192 | (2S)-5-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-2-methylpentanal | C24H41NO3SSi | 详情 | 详情 | |
| (XXXIX) | 46193 | (4S,7R,8S,9S)-4-[[tert-butyl(dimethyl)silyl]oxy]-12-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-8-hydroxy-5,5,7,9-tetramethyl-1-dodecen-6-one | C40H73NO5SSi2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(XXIV)The reduction of the methyl ester of (XVI) with DIBAL in dichloromethane gives the aldehyde (XVIII), which is condensed with the chiral phosphonate (XIX) by means of BuLi in ethyl ether to yield the enoylsultam (XX). The methylation of (XX) with L-selectride and methyl iodide affords the methylated sultam (XXI), which is desilylated with TBAF and reprotected with Tes-Cl and TEA to provide triethylsilyl ether (XXII) with a more favorable silyl leaving group needed in the remaining synthetic steps. Elimination of the sultam group of (XXII) by means of DIBAL in dichloromethane gives the aldehyde (XXIII), which is condensed with the ketone (XXIV) by means of LDA to yield the aldol (XXV). The protection of the OH group of (XXV) with Troc-Cl ad pyridine affords compound (XXVI), which is oxidized at the terminal vinyl group by means of OsO4 and NaIO4 to provide the aldehyde (XXVII). The selective desilylation of (XXVII) by means of HF and pyridine furnishes the hydroxy aldehyde (XXVIII).
| 【1】 Martin, H.J.; et al.; How stable are epoxides? A novel synthesis of epothilone B. Angew Chem. Int Ed Engl 2000, 39, 3, 581. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI) | 49271 | methyl 3-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]propanoate | C22H37NO4SSi | 详情 | 详情 | |
| (XVIII) | 49273 | 3-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]propanal | C21H35NO3SSi | 详情 | 详情 | |
| (XIX) | 49274 | diethyl 2-(10,10-dimethyl-2,2-dioxo-2lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]dec-4-yl)-2-oxoethylphosphonate | C16H28NO6PS | 详情 | 详情 | |
| (XX) | 49275 | 4-((E)-5-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-2-pentenoyl)-10,10-dimethyl-2lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-2,2-dione | C33H52N2O5S2Si | 详情 | 详情 | |
| (XXI) | 49276 | 4-((2S)-5-[(2R,3S)-3-[(2S,3E)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-2-methylpentanoyl)-10,10-dimethyl-2lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-2,2-dione | C34H56N2O5S2Si | 详情 | 详情 | |
| (XXII) | 49277 | 10,10-dimethyl-4-[(2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentanoyl]-2lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-2,2-dione | C34H56N2O5S2Si | 详情 | 详情 | |
| (XXIII) | 49278 | (2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentanal | C24H41NO3SSi | 详情 | 详情 | |
| (XXIV) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (XXV) | 49279 | (4S,7R,8R,9S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-12-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-dodecen-6-one | C40H73NO5SSi2 | 详情 | 详情 | |
| (XXVI) | 49280 | (1R,2R,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4,4-trimethyl-1-[(1S)-1-methyl-4-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)butyl]-3-oxo-7-octenyl 2,2,2-trichloroethyl carbonate | C43H74Cl3NO7SSi2 | 详情 | 详情 | |
| (XXVII) | 49281 | (1R,2R,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4,4-trimethyl-1-[(1S)-1-methyl-4-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)butyl]-3,7-dioxoheptyl 2,2,2-trichloroethyl carbonate | C42H72Cl3NO8SSi2 | 详情 | 详情 | |
| (XXVIII) | 49282 | (1R,2R,5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-1-((1S)-4-[(2R,3S)-3-[(2S,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-1-methylbutyl)-2,4,4-trimethyl-3,7-dioxoheptyl 2,2,2-trichloroethyl carbonate | C36H58Cl3NO8SSi | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(XV)The cyclization of phosphonate (I) with the chiral alcohol (II) by means of tert-butyl hypochlorite and Et-MgBr gives the isoxazoline (III), which is condensed with 2-methylthiazole-4-carbaldehyde (IV) by means of DBU and LiCl in acetonitrile to yield the secondary alcohol (V). The oxidation of (V) with TPAP and NMO in dichloromethane affords the corresponding ketone (VI), which is treated with the Grignard reagent (VII) in THF to provide the expected secondary alcohol (VIII). The silylation of (VIII) with Tes-OTf in dichloromethane gives the silyl ether (IX), which is treated with SmI2, Et3B and NaBH4 to cleave the isoxazoline ring and yield the diol (X). The reaction of (X) with SOCl2, TEA and TBAF affords the chiral epoxide (XI), which is silylated with Tes-Cl and TEA to provide the silyl ether (XII). The selective hydrolysis of the primary silyl ether of (XII) with HOAc in THF/water gives the primary alcohol (XIII), which is oxidized with TPAP and NMO in dichloromethane to yield the corresponding aldehyde (XIV). The condensation of (XIV) with ketone (XV) by means of LDA affords the open-chain precursor (XVI).
| 【1】 Bode, J.W.; Carreira, E.M.; Stereoselective syntheses of epothilones A and B via directed nitrile oxide cycloaddition. J Am Chem Soc 2001, 123, 18, 3611. |
| 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) | 49286 | diethyl 2-(hydroxyimino)-1-methylethylphosphonate | C7H16NO4P | 详情 | 详情 | |
| (II) | 49287 | (2R)-3-buten-2-ol | 33447-72-2 | C4H8O | 详情 | 详情 |
| (III) | 49288 | diethyl 1-[(5R)-5-[(1R)-1-hydroxyethyl]-4,5-dihydro-3-isoxazolyl]ethylphosphonate | C11H22NO5P | 详情 | 详情 | |
| (IV) | 44455 | 2-methyl-1,3-thiazole-4-carbaldehyde | C5H5NOS | 详情 | 详情 | |
| (V) | 49289 | (1R)-1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-1-ethanol | C12H16N2O2S | 详情 | 详情 | |
| (VI) | 49290 | 1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-1-ethanone | C12H14N2O2S | 详情 | 详情 | |
| (VII) | 49291 | bromo[(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl]magnesium | C15H33BrMgOSi | 详情 | 详情 | |
| (VIII) | 49292 | (2R,6S)-6-methyl-2-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-7-[(triisopropylsilyl)oxy]-2-heptanol | C27H48N2O3SSi | 详情 | 详情 | |
| (IX) | 49293 | (5R)-5-[(1R,5S)-1,5-dimethyl-1-[(triethylsilyl)oxy]-6-[(triisopropylsilyl)oxy]hexyl]-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydroisoxazole; (1R,5S)-1,5-dimethyl-1-[(5R)-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,5-dihydro-5-isoxazolyl]-6-[(triisopropylsilyl)oxy]hexyl triethylsilyl ether | C33H62N2O3SSi2 | 详情 | 详情 | |
| (X) | 49294 | (E,3S,5R,6R,10S)-2,6,10-trimethyl-1-(2-methyl-1,3-thiazol-4-yl)-6-[(triethylsilyl)oxy]-11-[(triisopropylsilyl)oxy]-1-undecene-3,5-diol | C33H65NO4SSi2 | 详情 | 详情 | |
| (XI) | 49295 | (2S,3E)-3-methyl-1-((2S,3R)-3-methyl-3-[(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl]oxiranyl)-4-(2-methyl-1,3-thiazol-4-yl)-3-buten-2-ol | C27H49NO3SSi | 详情 | 详情 | |
| (XII) | 49296 | (2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentyl triisopropylsilyl ether; 2-methyl-4-[(E,3S)-2-methyl-4-((2S,3R)-3-methyl-3-[(4S)-4-methyl-5-[(triisopropylsilyl)oxy]pentyl]oxiranyl)-3-[(triethylsilyl)oxy]-1-butenyl]-1,3-thiazole | C33H63NO3SSi2 | 详情 | 详情 | |
| (XIII) | 49297 | (2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-pentanol | C24H43NO3SSi | 详情 | 详情 | |
| (XIV) | 49278 | (2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentanal | C24H41NO3SSi | 详情 | 详情 | |
| (XV) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (XVI) | 49298 | (4S,7R,8S,9S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-12-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-dodecen-6-one | C40H73NO5SSi2 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(XVI)The condensation of (XV) with the chiral ketone (XVI) by means of LDA in TH gives the aldol (XVII). The protection of the OH group of (XVII) with Troc-Cl and pyridine yields compound (XVIII), which is oxidized at the vinyl group by means of OsO4, NaIO4, selectively monodesilylated with HF and pyridine, and further oxidated with NaClO2 to afford the hydroxyacid (XIX). The Yamaguchi macrolactonization of (XIX) by means of 2,4,6-trichlorobenzoyl chloride provides the macrocyclic lactone (XX). Elimination of the Troc protecting group of (XX) by means of Zn and NH4Cl gives the silylated precursor (XXI), which is finally deprotected by means of HF and pyridine to yield the target epothilone B.
| 【1】 Bode, J.W.; Carreira, E.M.; Stereoselective syntheses of epothilones A and B via nitrile oxide cycloadditions and related studies. J Org Chem 2001, 66, 19, 6410. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 49278 | (2S)-2-methyl-5-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)pentanal | C24H41NO3SSi | 详情 | 详情 | |
| (XVI) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (XVII) | 49298 | (4S,7R,8S,9S)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-5,5,7,9-tetramethyl-12-((2R,3S)-2-methyl-3-[(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl]oxiranyl)-1-dodecen-6-one | C40H73NO5SSi2 | 详情 | 详情 | |
| (XVIII) | 60656 | trityl (3S,4R,7S)-7-{[tert-butyl(dimethyl)silyl]oxy}-4,6,6-trimethyl-3-[(1S)-1-methyl-4-((2R,3S)-2-methyl-3-{(2S,3E)-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-2-[(triethylsilyl)oxy]-3-butenyl}oxiranyl)butyl]-5-oxo-9-decenoate | C61H89NO6SSi2 | 详情 | 详情 | |
| (XIX) | 60657 | (3S,6R,7S,8S)-3-{[tert-butyl(dimethyl)silyl]oxy}-11-{(2R,3S)-3-[(2S,3E)-2-hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl}-4,4,6,8-tetramethyl-5-oxo-7-[2-oxo-2-(trityloxy)ethyl]undecanoic acid | C54H73NO8SSi | 详情 | 详情 | |
| (XX) | 60658 | trityl 2-{(1S,3S,7S,10R,11S,12S,16R)-7-{[tert-butyl(dimethyl)silyl]oxy}-8,8,10,12,16-pentamethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-11-yl}acetate | C54H71NO7SSi | 详情 | 详情 | |
| (XXI) | 49303 | (1S,3S,7S,10R,11S,12S,16R)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-8,8,10,12,16-pentamethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione | C33H55NO6SSi | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(XXI)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14
该中间体在本合成路线中的序号：(IV)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15
该中间体在本合成路线中的序号：(XVII)The condensation of the known ketone (XVII) (2) with aldehyde (XVIII) by means of LDA in THF gives the hydroxyketone (XIX), which is silylated with Tbdms-OTf and TEA in dichloromethane, yielding the silyl ether (XX). The terminal vinyl group of (XX) is cleaved oxidatively by means of OsO4 and NaIO4 in THF/water, affording the aldehyde (XXI), which is oxidized to acid (XXII) by means of NaClO2 in t-butanol/water. Acid (XXII) is esterified to methyl ester (XXIII), which is selectively deprotected at the Pmb group by hydrogenation with H2 over Pd/C in ethanol to provide the primary alcohol (XXIV). The oxidation of (XXIV) with tetrapropylammonium perruthenate (TPAP) furnishes the aldehyde (XXV), which is submitted to a Wittig condensation with the intermediate phosphonium salt (XVI) by means of LiHMDS in THF to give the adduct (XXVI). The hydrolysis of the ester group of (XXVI) with NaOH in warm isopropanol yields the carboxylic acid (XXVII), which is selectively deprotected by means of TBAF in THF to afford the hydroxyacid (XXVIII).
| 【1】 White, J.D.; Carter, R.G.; Sundermann, K.F.; Wartmann, M.; Total synthesis of epothilone B, epothilone D, and cis- and trans-9,10-dehydroepothilone D. J Am Chem Soc 2001, 123, 23, 5407. |
| 【2】 White, J.D.; et al.; A highly stereoselective synthesis of epothilone B. J Org Chem 1999, 64, 3, 684. |
| 【3】 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 |
|---|---|---|---|---|---|---|
| (XVI) | 46148 | [(3Z,6S,7E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3,7-dimethyl-8-(2-methyl-1,3-thiazol-4-yl)-3,7-octadienyl](triphenyl)phosphonium bromide | C38H49BrNOPSSi | 详情 | 详情 | |
| (XVII) | 44451 | (5S)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-7-octen-3-one | C16H32O2Si | 详情 | 详情 | |
| (XVIII) | 42656 | (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanal | C12H16O3 | 详情 | 详情 | |
| (XIX) | 46149 | (2S,3S,4R,7S)-7-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-1-[(4-methoxybenzyl)oxy]-2,4,6,6-tetramethyl-9-decen-5-one | C28H48O5Si | 详情 | 详情 | |
| (XX) | 46150 | (5S,8R,9S)-5-allyl-9-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-4,10-dioxa-3,11-disilatridecan-7-one | C34H62O5Si2 | 详情 | 详情 | |
| (XXI) | 46151 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxononanal | C33H60O6Si2 | 详情 | 详情 | |
| (XXII) | 46152 | (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxononanoic acid | C33H60O7Si2 | 详情 | 详情 | |
| (XXIII) | 46153 | methyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxononanoate | C34H62O7Si2 | 详情 | 详情 | |
| (XXIV) | 46154 | methyl (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-9-hydroxy-4,4,6,8-tetramethyl-5-oxononanoate | C26H54O6Si2 | 详情 | 详情 | |
| (XXV) | 46155 | methyl (3S,6R,7S,8R)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5,9-dioxononanoate | C26H52O6Si2 | 详情 | 详情 | |
| (XXVI) | 46156 | methyl (3S,6R,7S,8S,9Z,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-9,12,16-heptadecatrienoate | C46H85NO6SSi3 | 详情 | 详情 | |
| (XXVII) | 46157 | (3S,6R,7S,8S,9Z,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-9,12,16-heptadecatrienoic acid | C45H83NO6SSi3 | 详情 | 详情 | |
| (XXVIII) | 46158 | (3S,6R,7S,8S,9Z,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-9,12,16-heptadecatrienoic acid | C39H69NO6SSi2 | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(XXXIV)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17
该中间体在本合成路线中的序号：(IV)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18
该中间体在本合成路线中的序号：(IV)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 |